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C. León-Emérito Hospital Universitario de Valme Sevilla Candidas en UCI: 35 años de estudio Del estudio EPCAN a nuestros díasSOCMIC sesión BCN, ACM, 12 Novbre 2013 Recordant LÀngels

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Page 1: Recordant L Àngels - academia.cat

C Leoacuten-Emeacuterito

Hospital Universitario de Valme

Sevilla

Candidas en UCI 35 antildeos de estudio

ldquoDel estudio EPCAN a nuestros diacuteasrdquo

SOCMIC sesioacuten

BCN ACM 12 Novbre 2013

Recordant LrsquoAgravengels

1- Trayectoria profesional proyectos de investigacioacuten

2- Estudios cliacutenicos realizados

3- Estudios cliacutenicos derivados

bull CS Utilidad cliacutenica

bull Biomarcadores (BG CAGTA)

bull Biomarcadores (BG CAGTA Mananos Candida PCR)

4- Consecuencias cliacutenicas praacutecticas

5- Futuro

Guioacuten

1 What is already known on this topic

2 What question this studyproject addressed

3 What this studyproject adds to our knowledge

4 How this is relevant to clinical practice

Questions to ask before starting any study project

1 Introduccioacuten aumento frecuencia pacientes graves mort 60-80

2 El germen

3 Factores predisponentes

bull Enfermedad basal importante

bull Antibioacuteticos

bull Esteroides

bull Alt metaboacutelicas y hormonales DM hipocalcemia

4 Puertas entrada

5 Responsabilidad patoacutegena candidiasis y candidemia

1 What is already known on this topic

Etiopatogenia de las sepsis por Candida

J Figueras C Leon A Tomasa R Peracaula M Soler FJ de Latorre J Padroacute

Med Clin (Barc) 1974 62425-32

197378 1977 1978 1979 1980 1985 1986 2013

Angels trayectoria profesionalproyectos tema

197383 199192 199899 20067 200910 201112 210213

UAB ATS LMC MIRMF MIRMIN Staff Staff

HGVH HGC

ESTUDIO SGFIICU EPCAN CAVA CAVA CAVA CAVA

CLINICO I II FIS TREM

PROYECTOS

Funguemia 1973-83 Anaacutelisis de 67 pacientes Sanchez Rodriguez C Leoacuten Regidor MA Capell Font S Peacuterez Campos A Planes Reig A Leoacuten Gil C

Med Clin (Barc) 198584549-53

bull Estudio observacional uniceacutentrico retrospectivo

bull 67 pacientes68 episodios

bull EB Patologiacutea GI 626 (4267)

bull FR CVC antibioterapia NPT cirugiacutea abdominal (68)

bull Cliacutenica indistinguible de una bacteriemia (9 casos SS)

bull Infecciones bacterianas asociadas 4967

bull Estratificacioacuten Funguemia TransitoriaDiseminada (4522)

bull TAF 28 pacientes tratados (9 con AFBD)

bull Mortalidad global 585 (3967) Relacionada 328 (2267)

1 Alta proporcioacuten de CRC

2 Concepto Candidemia RC es autolimitada y no requiere trato

3 Retraso de inicio de tratamiento antifuacutengico

Funguemia 1973-83 Estudio epidemioloacutegico Capell Font S Peacuterez Campos A Sanchez Rodriguez C Leoacuten Regidor MA Planes Reig A

Leoacuten Gil C Med Clin (Barc) 198584600-5

bull Estudio uniceacutentrico retrospectivo

bull 67 pacientes68 episodios

bull Funguemia nosocomial 1000 ingresos

bull UCI 175

bull Resto Servicios 03

bull UCI media 8 casos x antildeo

bull Aparicioacuten entre la 2 y 3ordm semana

Candidiasis y candidemia Reexamen de una problemaacutetica actual Saacutenchez Rodriacuteguez C Leoacuten Gil C Leoacuten Regidor MA Capell Font S Peacuterez Campos A

Med Clin (Barc) 198585464-71

bull Revisioacuten 121 referencias

bull Epidemiologia

bull Definicioacuten de teacuterminos

bull Poblacioacuten susceptible Etiologiacutea

bull Recursos cliacutenicos (I) EF lesiones cutaacuteneas miositis cateacuteteres y TF supurada endoftalmitis

bull Recursos cliacutenicos (II) Valoracioacuten focos metastaacutesicos miocarditispericarditis artritis y osteomielitis

encefalitismeningitis afeccioacuten pulmonar

bull Recursos analiacuteticos y microbioloacutegicos

bull Diagnostico seroloacutegico

bull A quien tratar

1 Candidemia Aumento nuacutemero de casosnuacutemero de pacientes con candidemia

2 Difiacutecil establecer diferencias entre la CT y CD

3 Durante los episodios de CT ldquopudierardquo haber un cierto grado de diseminacioacuten

4 Apuesta desarrollo de mejores meacutetodos diagnoacutesticosdiagnostico tempranoTAF

adecuado

Candidemia in non-neutropenic critically ill patients analysis of prognostic

factors and assessment of systemic antifungal therapy Nolla-Salas J Sitges-Serra A Leoacuten-Gil C Martiacutenez-Gonzaacutelez J Leoacuten-Regidor MA Ibantildeez-Luciacutea P

Torres-Rodriacuteguez PM and Study Group of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

bull Multicenter prospective observacional

bull 28 ICUs 15 months (Oct 1991-Dcber 1992)

bull 418 bed 22937 admissions

bull Candidemia 46 mean age 59 y

bull 1 episodio500 ICU admissions

bull Surgicalmedical 3016

bull Candida specie C albicans (60) parapsilosis (17)

bull TAF 43 FCNZ 27 AFBD 10 sequential therapy 6

bull Overal mortality 56 attributable 217

bull Apache II (time of diagnosis) and survival 20

bull Time of diagnosis start of AFT ldquoearlyrdquo laterdquo

The utility of serology in diagnosing candidosis in non-neutropenic

critically ill patients (1) Ibantildeez-Nolla J Torres-Rodriacuteguez JM Nolla M Leoacuten MA Meacutendez R Soria G Diacuteaz RM Marrugat J

Mycoses 20014447-53

bull Prospective cohort one UCI (HGC)

bull Sept 1988-Oct 1995 (8 y)

bull Inclusion all patients with at least one sample + Candida

bull Screening and optional samples

bull Cutaneous testophthalmologic evaluationpost morten study

bull Serology Antibodies (IHA IFA) antigens (Cand-TecPastorex)

The utility of serology in diagnosing candidosis in non-neutropenic

critically ill patients (2) Ibantildeez-Nolla J Torres-Rodriacuteguez JM Nolla M Leoacuten MA Meacutendez R Soria G Diacuteaz RM Marrugat J

Mycoses 20014447-53

Test Sensitiv Specif

Antibodies 37 78

Antigens 0 90

bull 3389 pts ICU LOS 6 days (1-112) mortality 10

bull 145 cases included (overall mortality 46)

bull 120 cases with multifocal colonization Candidemia 24 (18 pts) Endopht 2 cases

bull ATF Therapy 109 (75)

Significant relation between mortality and low levels of antibodies

Fungal colonization andor infection in non-neutropenic critically ill patients

results of the EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J Jordaacute R Saavedra P Palomar M and

EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

bull Prospective cohort observational multicenter study

bull Adult non-neutropenic pts 73 ICUs MS (70 hospitals)

bull 9 months (May 1998-January 1999)

bull Underlying diseases comorbidities reasons for ICU admission RF (presence and duration)

bull 7 days of ICU admission Once a week APACHE II Clinical situation microbiological

screening (TA pharyngeal exudates gastric aspirates and urine)

bull Antifungal treatment and outcome

bull 1765 patients age 579 y APACHE II ICU admission 18 5

bull Overall mortality 435 Intra ICU 338

bull No CI (785) Colonized (883) infected (97)

bull 18385 samples 13849 (surveillance) and 4536 (optional)

bull C albicans 721 (screening) and 697 (optional)

Economic Impact of Candida Colonization and Candida Infection in the

Critically Ill Patient Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor MA

and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

bull Prospective cohort observational multicenter study

bull 1765 adult non-neutropenic pts 73 ICUs mixed (70 hospitals)

bull 9 months (May 1998-January 1999)

bull 7 days of ICU admission Once a week APACHE II SOFA Clinical situation

and microbiological screening

bull No CI Colonized Infected Comorbidities and RF ATF therapy Outcome

Cost (2000)

ICU 1153 E

Hospit 406 E

Direct Cost (1 day)

- Candida colonization 8000

- Candida infection 16000

1

1

1

2

Courtesy by J Mensa

Score gt 25 Sensitivity 81

Specificity 74

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in

nonneutropenic critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro Saavedra Benito Almirante Juan Nolla-Salas

Francisco Aacutelvarez-Lerma Joseacute Garnacho-Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group

Crit Care Med 2006 34730-37

Score gt 25

1

1

1

2

probability of Candida infection

x 775

Courtesy byJ Mensa

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in

nonneutropenic critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro Saavedra Benito Almirante Juan Nolla-Salas

Francisco Aacutelvarez-Lerma Joseacute Garnacho-Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group

Crit Care Med 2006 34730-37

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

bull Prospective cohort observational multicenter study

bull Adult non-neutropenic pts 36 ICUs MS (32 hospitals)

bull 14 months (April 2006-June 2007)

bull Underlying diseases comorbidities reasons for ICU admission RF (presence and duration)

bull Antifungal treatment and outcome

bull 7 days of ICU admission Once a week APACHE II SOFA Clinical situation and microbiological

screening (5) TA pharyngeal exudatesgastric aspirates urine perirectal swab skin and optional

samples

bull1107 patients age 60 y ICU admission APACHE II 184 SOFA 7 (median)

bull No CI (215) Colonized (834) infected (58)

bull Overall mortality 305 Intra ICU 217

bull ATFT 49 (844) patients Time between ICU admission and administration of ATFT 173 days

bull 240 patients with Candida species colonization or IC (18) (1ndash3)-beta-D-glucan serum levels

Candida Score lt 3 = 3 gt 3

IC rate medical surgical

patients (n = 1107) 23 59

115

(51 - 178)

IC rate Abdominal Surgery

(n = 182) 23 125

303

(192 - 414)

Abdominal Surgery IC rates according CS

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash1633

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash33

Candiduria in critically ill patients admitted to intensive care medical units

Francisco Aacutelvarez-Lerma Juan Nolla-Salas Cristobal Leon Mercedes Palomar Ricard

Jorda Nieves Carrasco Felipe Bobillo (EPCAN Study Group)

Intensive Care Med 2003291069ndash76

bull 1765 adult non-neutropenic pts (lt 7 days) Candiduria 389 patients (22)

bull Age 61 y Apache II 19

bull Incidence density 95 episodes1000 days

bull Length of ICU stay since presence of candiduria 16 days

bull Risk factor associated age over 65 y female gender LOS in hospital

before ICU admission diabetes TPN MV previous use of antibiotics

(C no albicans)

bull C albicans 266 (684) C glabrata 32 (82) C tropicalis 14 (36)

bull Candiduria is a risk factor for ICUhospital mortality (OR 158)

Jordaacute Marcos R Alvarez-Lerma F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C

and EPCAN Study Group Mycoses 200750302-10

Risk factors for candidaemia in critically ill patients a prospective

surveillance study

bull 1765 adult non-neutropenic pts (lt 7 days) Candidemia 63 pts

bull Age 63 y Apache II 18 ICUhospital stay 2848 Surgical 29 (46) Medical 26 (413 )

bull ATF treatment 4863 (76)

- FCNZ 32 (667) AFBD 8 (16) LAFB 5 (104) AFBLC 3 (63)

bull ICUhospital Mortality 34 (54)-39 (73)

Assessment of candidemia-attributable mortality in critically ill patients using

propensity score matching analysis Francisco J Gonzaacutelez de Molina Cristoacutebal Leoacuten Sergio Ruiz-Santana and Pedro Saavedra for the

CAVA I Study Group

Crit Care 201216 R105

Critical Care 2012 16R105

bull The use of propensity score matching analysis to control for all potential confounding

variables allowed the assessment of candidemia-attributable mortality in critically ill

patients

bull Candidemia was not associated with an increase in either ICU or hospital

mortality

bull Earlier treatment of bloodstream infection and better monitoring (surveillance sampling

weekly) resulting in appropriate antifungal agent may contribute to increased survival

bull APACHE II at the time of diagnosis of candidemia was the only predictor of death in

patients with candidemia

bull 1107 pts 38 (34) candidemias Propensity score matching analysis

(Candidemia 70 no 35 yes)

Multicenter observational prospective

C Score biomarkers amp IC

18 ICUs n = 176 (SAC) 4 wks Study 2009-10

ICU gt 7 days

C Score BG CAGTA others Weekly (x 2) screening

Optional Samples related clinical situation follow up

Variables demographics APACHE II SOFA (admission weekly x 2 starting antifungals) comorbid

diseases risk factors antifungal therapy and outcome

Adult patients admitted ICU ge 7 days SAC = Severe Abdominal Conditions

CAGTA = Candida albicans germ-tube antibody

1st 2nd 3rd 4th 3d

Intensive Care Med 2012 381315-25

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating between

Candida colonization and invasive candidiasis in patients with severe abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J Aacutelvarez L

Utande A Farintildeas O and the Study Group Cava II

- Patients with Candida colonization A model for IC prediction was obtained

using Classification And Regression Trees (CART)

- Variables used maximum values biomarkers before during development IC or highest value when IC did not

developed (Apache-II BG CAGTA)

- CART through a process of binary recursive spliting of the datasets based on rules of the form if-then-else identifies

a set of predictors of IC estimating the probabilities of IC according to the values of predictors

- The discriminate value of the probabilities of IC obtained by the CART was evaluated by the receiver characteristic

operating (ROC) curve

- Predictive rule identify patients have an IC risk when probability to develop

IC is ge 30(cut-off chosen by CART algorithm to minimize error measurement = deviance)

- Obtained rule estimated Sensitivity Specificity PPV NPV

- Data analysis carried out using R-package

CART prediction rule model

Breiman L et al (1984) Classfication and regression trees

Belmont CA Wadsworth International

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

n = 115 pts

IC = 31 (27 )

n = 27 pts

IC = 16 (599)

n = 88 pts

IC = 15 (170)

n = 49 pts

IC = 3 (61 )

n = 39 pts

IC = 12 (308 )

B-glucan ge 259 pgml

CAGTA positive B-glucan lt 329 pgml

B-glucan lt 259 pgml

CAGTA negative

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

Diagnostic accuracy of CART-derived prediction rule BG (cut-off

gt 259 pgmL) CAGTA (cutt-off positive) and CS for IC diagnosis

Area under

ROC curve

(95 CI)

Sensitivity

(95 CI)

Specificity

(95 CI)

Predictive value

Positive

(95 CI)

Negative

(95 CI)

CART analysis

078

(076-081)

903

(751-966)

547

(441-650)

424

(312-544)

939

(835-979)

BG

067

(059-074)

516

(348-680)

869

(780-925)

593

(407-755)

830

(738-894)

CAGTA

067

(063-070)

710

(534-839)

573

(465-675)

386

(271-516)

839

(722-913)

CS 062

(058-066)

935

(792-982)

181

(113-277)

299

(217-396)

882

(65-7-967)

CART classification and regression tree analysis BG beta-D-glucan CAGTA Candida albicans germ tube antibody Total number of patients with

Candida spp colonization = 115

Usefulness of the (13)--D-Glucan and Candida albicans germ tube antibody in the

Diagnosis of Invasive Candidiasis in Non-neutropenic Critically Ill Patients (non selected)

201112 One ICU (HUV) 105 NNCIP non selected gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida colonization

cultures (rectal swabs tracheal pharyngeal or gastric aspirates and urine) and serum

BG and CAGTA Were collected factors can interfere with the levels of BG (RRT AC

PT use of blood transfusions surgeryhellip)

NCNI

(n = 42)

Colonized

(n = 52)

Candidemia

(n = 6)

Peritonitis

(n =5)

P

value

Age years mean (range) 66 (50-73) 63 (54-76) 68 (62-78) 67 (62-70) 0820

Malefemale patients 3210 2527 42 50 0007

BG pgmL

Median (IQR)

Maximum (IQR)

44 (31-102)

77 (31-140)

40 (31-140)

150 (47-500)

72 ( 31-300)

194 (120-300)

31 (31-31)

50 (31-80)

0527

0037

CAGTA positives n () 13 (310) 26 (500) 3 (500) 1 (200) 0203

Instituto Salud Carlos III Madrid Spain (FIS PI 1002110) ICAAC 2013 (M-1380)

Conclusions

Patients with candidemia and Candida spp colonization showed significantly higher values

of serum BG than neither colonized or infected patients

NCNI neither colonized nor infected BG B-D- glucan IQR interquartile range (25th-75th percentile) CAGTA Candida albicans germ

tube antibodies Significant differences as compared with the NCNI group

CAVA FIS PROJECT

Prospective cohort observational multicenter study

201214 12 ICUs NNCIP selected (SAC) gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida

colonization cultures (rectal swabs tracheal pharyngeal urine) and serum (BG and

CAGTA)

Preliminary data (October 2013) 215 pts included 117 CC 26 IC AFT 94 (446)

Invasive Candidiasis in the critically ill patients Diagnostic utility of 1-3-Beta-D-

Glucan(BDG) anti-mycelium antibodies (CAGTA) mannanantimannan antibodies

(MAA) and detection of Candida DNA (PCR)rdquo CAVA TREM PROJECT

Candida DNA detection (PCR)

To evaluate CS performance ICU patients developing hospital-acquired severe sepsis or septic shock

Prospective multicenter (5 ICUs France) cohort study

n = 94 recruited (IC = 5 53 )

IC rates CS = 2 or 3 0 CS = 4 176 CS = 5 50 (p lt 00001)

CS gt 3 Benefit early SAT

Evaluation of ldquoCandida scorerdquo in critically ill patients a prospective multicenter

observational cohort study Leroy G Lamblotte F Thevenin D Lemaire C Parmentier E Devos P Leroy O

Ann Intens Care 2011150

bull To determine nordm patients w o documented IC received SAT

bull 1-day cross-sectional cohort study 169 ICUs France Belgium

bull n = 2047 recruited

bull n = 154 (75) with SAT (only 54 with IC)

bull Independent predictors SAT

ndash Center-related factors Hospital lt 800 beds (OR 29) organ transplant activity (OR26)

use fluoroquinolones (OR23) use SAT unresolved sepsis (OR19 22 20)

ndash Patient related factors Candida colonization (OR 124) severe sepsis and septic shock (OR47)

emergency surgery (OR 24) hematologic malignancies (OR71)

bull Trend greater impact SAT on survival when CS = 4 or 5

SAT Systemic Antifungal Treatment

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

Crit Care Med 201240813-22

Impact SAT on 28-d mortality according CS

Crit Care Med 201240813-22

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 2: Recordant L Àngels - academia.cat

1- Trayectoria profesional proyectos de investigacioacuten

2- Estudios cliacutenicos realizados

3- Estudios cliacutenicos derivados

bull CS Utilidad cliacutenica

bull Biomarcadores (BG CAGTA)

bull Biomarcadores (BG CAGTA Mananos Candida PCR)

4- Consecuencias cliacutenicas praacutecticas

5- Futuro

Guioacuten

1 What is already known on this topic

2 What question this studyproject addressed

3 What this studyproject adds to our knowledge

4 How this is relevant to clinical practice

Questions to ask before starting any study project

1 Introduccioacuten aumento frecuencia pacientes graves mort 60-80

2 El germen

3 Factores predisponentes

bull Enfermedad basal importante

bull Antibioacuteticos

bull Esteroides

bull Alt metaboacutelicas y hormonales DM hipocalcemia

4 Puertas entrada

5 Responsabilidad patoacutegena candidiasis y candidemia

1 What is already known on this topic

Etiopatogenia de las sepsis por Candida

J Figueras C Leon A Tomasa R Peracaula M Soler FJ de Latorre J Padroacute

Med Clin (Barc) 1974 62425-32

197378 1977 1978 1979 1980 1985 1986 2013

Angels trayectoria profesionalproyectos tema

197383 199192 199899 20067 200910 201112 210213

UAB ATS LMC MIRMF MIRMIN Staff Staff

HGVH HGC

ESTUDIO SGFIICU EPCAN CAVA CAVA CAVA CAVA

CLINICO I II FIS TREM

PROYECTOS

Funguemia 1973-83 Anaacutelisis de 67 pacientes Sanchez Rodriguez C Leoacuten Regidor MA Capell Font S Peacuterez Campos A Planes Reig A Leoacuten Gil C

Med Clin (Barc) 198584549-53

bull Estudio observacional uniceacutentrico retrospectivo

bull 67 pacientes68 episodios

bull EB Patologiacutea GI 626 (4267)

bull FR CVC antibioterapia NPT cirugiacutea abdominal (68)

bull Cliacutenica indistinguible de una bacteriemia (9 casos SS)

bull Infecciones bacterianas asociadas 4967

bull Estratificacioacuten Funguemia TransitoriaDiseminada (4522)

bull TAF 28 pacientes tratados (9 con AFBD)

bull Mortalidad global 585 (3967) Relacionada 328 (2267)

1 Alta proporcioacuten de CRC

2 Concepto Candidemia RC es autolimitada y no requiere trato

3 Retraso de inicio de tratamiento antifuacutengico

Funguemia 1973-83 Estudio epidemioloacutegico Capell Font S Peacuterez Campos A Sanchez Rodriguez C Leoacuten Regidor MA Planes Reig A

Leoacuten Gil C Med Clin (Barc) 198584600-5

bull Estudio uniceacutentrico retrospectivo

bull 67 pacientes68 episodios

bull Funguemia nosocomial 1000 ingresos

bull UCI 175

bull Resto Servicios 03

bull UCI media 8 casos x antildeo

bull Aparicioacuten entre la 2 y 3ordm semana

Candidiasis y candidemia Reexamen de una problemaacutetica actual Saacutenchez Rodriacuteguez C Leoacuten Gil C Leoacuten Regidor MA Capell Font S Peacuterez Campos A

Med Clin (Barc) 198585464-71

bull Revisioacuten 121 referencias

bull Epidemiologia

bull Definicioacuten de teacuterminos

bull Poblacioacuten susceptible Etiologiacutea

bull Recursos cliacutenicos (I) EF lesiones cutaacuteneas miositis cateacuteteres y TF supurada endoftalmitis

bull Recursos cliacutenicos (II) Valoracioacuten focos metastaacutesicos miocarditispericarditis artritis y osteomielitis

encefalitismeningitis afeccioacuten pulmonar

bull Recursos analiacuteticos y microbioloacutegicos

bull Diagnostico seroloacutegico

bull A quien tratar

1 Candidemia Aumento nuacutemero de casosnuacutemero de pacientes con candidemia

2 Difiacutecil establecer diferencias entre la CT y CD

3 Durante los episodios de CT ldquopudierardquo haber un cierto grado de diseminacioacuten

4 Apuesta desarrollo de mejores meacutetodos diagnoacutesticosdiagnostico tempranoTAF

adecuado

Candidemia in non-neutropenic critically ill patients analysis of prognostic

factors and assessment of systemic antifungal therapy Nolla-Salas J Sitges-Serra A Leoacuten-Gil C Martiacutenez-Gonzaacutelez J Leoacuten-Regidor MA Ibantildeez-Luciacutea P

Torres-Rodriacuteguez PM and Study Group of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

bull Multicenter prospective observacional

bull 28 ICUs 15 months (Oct 1991-Dcber 1992)

bull 418 bed 22937 admissions

bull Candidemia 46 mean age 59 y

bull 1 episodio500 ICU admissions

bull Surgicalmedical 3016

bull Candida specie C albicans (60) parapsilosis (17)

bull TAF 43 FCNZ 27 AFBD 10 sequential therapy 6

bull Overal mortality 56 attributable 217

bull Apache II (time of diagnosis) and survival 20

bull Time of diagnosis start of AFT ldquoearlyrdquo laterdquo

The utility of serology in diagnosing candidosis in non-neutropenic

critically ill patients (1) Ibantildeez-Nolla J Torres-Rodriacuteguez JM Nolla M Leoacuten MA Meacutendez R Soria G Diacuteaz RM Marrugat J

Mycoses 20014447-53

bull Prospective cohort one UCI (HGC)

bull Sept 1988-Oct 1995 (8 y)

bull Inclusion all patients with at least one sample + Candida

bull Screening and optional samples

bull Cutaneous testophthalmologic evaluationpost morten study

bull Serology Antibodies (IHA IFA) antigens (Cand-TecPastorex)

The utility of serology in diagnosing candidosis in non-neutropenic

critically ill patients (2) Ibantildeez-Nolla J Torres-Rodriacuteguez JM Nolla M Leoacuten MA Meacutendez R Soria G Diacuteaz RM Marrugat J

Mycoses 20014447-53

Test Sensitiv Specif

Antibodies 37 78

Antigens 0 90

bull 3389 pts ICU LOS 6 days (1-112) mortality 10

bull 145 cases included (overall mortality 46)

bull 120 cases with multifocal colonization Candidemia 24 (18 pts) Endopht 2 cases

bull ATF Therapy 109 (75)

Significant relation between mortality and low levels of antibodies

Fungal colonization andor infection in non-neutropenic critically ill patients

results of the EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J Jordaacute R Saavedra P Palomar M and

EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

bull Prospective cohort observational multicenter study

bull Adult non-neutropenic pts 73 ICUs MS (70 hospitals)

bull 9 months (May 1998-January 1999)

bull Underlying diseases comorbidities reasons for ICU admission RF (presence and duration)

bull 7 days of ICU admission Once a week APACHE II Clinical situation microbiological

screening (TA pharyngeal exudates gastric aspirates and urine)

bull Antifungal treatment and outcome

bull 1765 patients age 579 y APACHE II ICU admission 18 5

bull Overall mortality 435 Intra ICU 338

bull No CI (785) Colonized (883) infected (97)

bull 18385 samples 13849 (surveillance) and 4536 (optional)

bull C albicans 721 (screening) and 697 (optional)

Economic Impact of Candida Colonization and Candida Infection in the

Critically Ill Patient Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor MA

and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

bull Prospective cohort observational multicenter study

bull 1765 adult non-neutropenic pts 73 ICUs mixed (70 hospitals)

bull 9 months (May 1998-January 1999)

bull 7 days of ICU admission Once a week APACHE II SOFA Clinical situation

and microbiological screening

bull No CI Colonized Infected Comorbidities and RF ATF therapy Outcome

Cost (2000)

ICU 1153 E

Hospit 406 E

Direct Cost (1 day)

- Candida colonization 8000

- Candida infection 16000

1

1

1

2

Courtesy by J Mensa

Score gt 25 Sensitivity 81

Specificity 74

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in

nonneutropenic critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro Saavedra Benito Almirante Juan Nolla-Salas

Francisco Aacutelvarez-Lerma Joseacute Garnacho-Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group

Crit Care Med 2006 34730-37

Score gt 25

1

1

1

2

probability of Candida infection

x 775

Courtesy byJ Mensa

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in

nonneutropenic critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro Saavedra Benito Almirante Juan Nolla-Salas

Francisco Aacutelvarez-Lerma Joseacute Garnacho-Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group

Crit Care Med 2006 34730-37

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

bull Prospective cohort observational multicenter study

bull Adult non-neutropenic pts 36 ICUs MS (32 hospitals)

bull 14 months (April 2006-June 2007)

bull Underlying diseases comorbidities reasons for ICU admission RF (presence and duration)

bull Antifungal treatment and outcome

bull 7 days of ICU admission Once a week APACHE II SOFA Clinical situation and microbiological

screening (5) TA pharyngeal exudatesgastric aspirates urine perirectal swab skin and optional

samples

bull1107 patients age 60 y ICU admission APACHE II 184 SOFA 7 (median)

bull No CI (215) Colonized (834) infected (58)

bull Overall mortality 305 Intra ICU 217

bull ATFT 49 (844) patients Time between ICU admission and administration of ATFT 173 days

bull 240 patients with Candida species colonization or IC (18) (1ndash3)-beta-D-glucan serum levels

Candida Score lt 3 = 3 gt 3

IC rate medical surgical

patients (n = 1107) 23 59

115

(51 - 178)

IC rate Abdominal Surgery

(n = 182) 23 125

303

(192 - 414)

Abdominal Surgery IC rates according CS

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash1633

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash33

Candiduria in critically ill patients admitted to intensive care medical units

Francisco Aacutelvarez-Lerma Juan Nolla-Salas Cristobal Leon Mercedes Palomar Ricard

Jorda Nieves Carrasco Felipe Bobillo (EPCAN Study Group)

Intensive Care Med 2003291069ndash76

bull 1765 adult non-neutropenic pts (lt 7 days) Candiduria 389 patients (22)

bull Age 61 y Apache II 19

bull Incidence density 95 episodes1000 days

bull Length of ICU stay since presence of candiduria 16 days

bull Risk factor associated age over 65 y female gender LOS in hospital

before ICU admission diabetes TPN MV previous use of antibiotics

(C no albicans)

bull C albicans 266 (684) C glabrata 32 (82) C tropicalis 14 (36)

bull Candiduria is a risk factor for ICUhospital mortality (OR 158)

Jordaacute Marcos R Alvarez-Lerma F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C

and EPCAN Study Group Mycoses 200750302-10

Risk factors for candidaemia in critically ill patients a prospective

surveillance study

bull 1765 adult non-neutropenic pts (lt 7 days) Candidemia 63 pts

bull Age 63 y Apache II 18 ICUhospital stay 2848 Surgical 29 (46) Medical 26 (413 )

bull ATF treatment 4863 (76)

- FCNZ 32 (667) AFBD 8 (16) LAFB 5 (104) AFBLC 3 (63)

bull ICUhospital Mortality 34 (54)-39 (73)

Assessment of candidemia-attributable mortality in critically ill patients using

propensity score matching analysis Francisco J Gonzaacutelez de Molina Cristoacutebal Leoacuten Sergio Ruiz-Santana and Pedro Saavedra for the

CAVA I Study Group

Crit Care 201216 R105

Critical Care 2012 16R105

bull The use of propensity score matching analysis to control for all potential confounding

variables allowed the assessment of candidemia-attributable mortality in critically ill

patients

bull Candidemia was not associated with an increase in either ICU or hospital

mortality

bull Earlier treatment of bloodstream infection and better monitoring (surveillance sampling

weekly) resulting in appropriate antifungal agent may contribute to increased survival

bull APACHE II at the time of diagnosis of candidemia was the only predictor of death in

patients with candidemia

bull 1107 pts 38 (34) candidemias Propensity score matching analysis

(Candidemia 70 no 35 yes)

Multicenter observational prospective

C Score biomarkers amp IC

18 ICUs n = 176 (SAC) 4 wks Study 2009-10

ICU gt 7 days

C Score BG CAGTA others Weekly (x 2) screening

Optional Samples related clinical situation follow up

Variables demographics APACHE II SOFA (admission weekly x 2 starting antifungals) comorbid

diseases risk factors antifungal therapy and outcome

Adult patients admitted ICU ge 7 days SAC = Severe Abdominal Conditions

CAGTA = Candida albicans germ-tube antibody

1st 2nd 3rd 4th 3d

Intensive Care Med 2012 381315-25

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating between

Candida colonization and invasive candidiasis in patients with severe abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J Aacutelvarez L

Utande A Farintildeas O and the Study Group Cava II

- Patients with Candida colonization A model for IC prediction was obtained

using Classification And Regression Trees (CART)

- Variables used maximum values biomarkers before during development IC or highest value when IC did not

developed (Apache-II BG CAGTA)

- CART through a process of binary recursive spliting of the datasets based on rules of the form if-then-else identifies

a set of predictors of IC estimating the probabilities of IC according to the values of predictors

- The discriminate value of the probabilities of IC obtained by the CART was evaluated by the receiver characteristic

operating (ROC) curve

- Predictive rule identify patients have an IC risk when probability to develop

IC is ge 30(cut-off chosen by CART algorithm to minimize error measurement = deviance)

- Obtained rule estimated Sensitivity Specificity PPV NPV

- Data analysis carried out using R-package

CART prediction rule model

Breiman L et al (1984) Classfication and regression trees

Belmont CA Wadsworth International

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

n = 115 pts

IC = 31 (27 )

n = 27 pts

IC = 16 (599)

n = 88 pts

IC = 15 (170)

n = 49 pts

IC = 3 (61 )

n = 39 pts

IC = 12 (308 )

B-glucan ge 259 pgml

CAGTA positive B-glucan lt 329 pgml

B-glucan lt 259 pgml

CAGTA negative

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

Diagnostic accuracy of CART-derived prediction rule BG (cut-off

gt 259 pgmL) CAGTA (cutt-off positive) and CS for IC diagnosis

Area under

ROC curve

(95 CI)

Sensitivity

(95 CI)

Specificity

(95 CI)

Predictive value

Positive

(95 CI)

Negative

(95 CI)

CART analysis

078

(076-081)

903

(751-966)

547

(441-650)

424

(312-544)

939

(835-979)

BG

067

(059-074)

516

(348-680)

869

(780-925)

593

(407-755)

830

(738-894)

CAGTA

067

(063-070)

710

(534-839)

573

(465-675)

386

(271-516)

839

(722-913)

CS 062

(058-066)

935

(792-982)

181

(113-277)

299

(217-396)

882

(65-7-967)

CART classification and regression tree analysis BG beta-D-glucan CAGTA Candida albicans germ tube antibody Total number of patients with

Candida spp colonization = 115

Usefulness of the (13)--D-Glucan and Candida albicans germ tube antibody in the

Diagnosis of Invasive Candidiasis in Non-neutropenic Critically Ill Patients (non selected)

201112 One ICU (HUV) 105 NNCIP non selected gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida colonization

cultures (rectal swabs tracheal pharyngeal or gastric aspirates and urine) and serum

BG and CAGTA Were collected factors can interfere with the levels of BG (RRT AC

PT use of blood transfusions surgeryhellip)

NCNI

(n = 42)

Colonized

(n = 52)

Candidemia

(n = 6)

Peritonitis

(n =5)

P

value

Age years mean (range) 66 (50-73) 63 (54-76) 68 (62-78) 67 (62-70) 0820

Malefemale patients 3210 2527 42 50 0007

BG pgmL

Median (IQR)

Maximum (IQR)

44 (31-102)

77 (31-140)

40 (31-140)

150 (47-500)

72 ( 31-300)

194 (120-300)

31 (31-31)

50 (31-80)

0527

0037

CAGTA positives n () 13 (310) 26 (500) 3 (500) 1 (200) 0203

Instituto Salud Carlos III Madrid Spain (FIS PI 1002110) ICAAC 2013 (M-1380)

Conclusions

Patients with candidemia and Candida spp colonization showed significantly higher values

of serum BG than neither colonized or infected patients

NCNI neither colonized nor infected BG B-D- glucan IQR interquartile range (25th-75th percentile) CAGTA Candida albicans germ

tube antibodies Significant differences as compared with the NCNI group

CAVA FIS PROJECT

Prospective cohort observational multicenter study

201214 12 ICUs NNCIP selected (SAC) gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida

colonization cultures (rectal swabs tracheal pharyngeal urine) and serum (BG and

CAGTA)

Preliminary data (October 2013) 215 pts included 117 CC 26 IC AFT 94 (446)

Invasive Candidiasis in the critically ill patients Diagnostic utility of 1-3-Beta-D-

Glucan(BDG) anti-mycelium antibodies (CAGTA) mannanantimannan antibodies

(MAA) and detection of Candida DNA (PCR)rdquo CAVA TREM PROJECT

Candida DNA detection (PCR)

To evaluate CS performance ICU patients developing hospital-acquired severe sepsis or septic shock

Prospective multicenter (5 ICUs France) cohort study

n = 94 recruited (IC = 5 53 )

IC rates CS = 2 or 3 0 CS = 4 176 CS = 5 50 (p lt 00001)

CS gt 3 Benefit early SAT

Evaluation of ldquoCandida scorerdquo in critically ill patients a prospective multicenter

observational cohort study Leroy G Lamblotte F Thevenin D Lemaire C Parmentier E Devos P Leroy O

Ann Intens Care 2011150

bull To determine nordm patients w o documented IC received SAT

bull 1-day cross-sectional cohort study 169 ICUs France Belgium

bull n = 2047 recruited

bull n = 154 (75) with SAT (only 54 with IC)

bull Independent predictors SAT

ndash Center-related factors Hospital lt 800 beds (OR 29) organ transplant activity (OR26)

use fluoroquinolones (OR23) use SAT unresolved sepsis (OR19 22 20)

ndash Patient related factors Candida colonization (OR 124) severe sepsis and septic shock (OR47)

emergency surgery (OR 24) hematologic malignancies (OR71)

bull Trend greater impact SAT on survival when CS = 4 or 5

SAT Systemic Antifungal Treatment

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

Crit Care Med 201240813-22

Impact SAT on 28-d mortality according CS

Crit Care Med 201240813-22

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 3: Recordant L Àngels - academia.cat

1 What is already known on this topic

2 What question this studyproject addressed

3 What this studyproject adds to our knowledge

4 How this is relevant to clinical practice

Questions to ask before starting any study project

1 Introduccioacuten aumento frecuencia pacientes graves mort 60-80

2 El germen

3 Factores predisponentes

bull Enfermedad basal importante

bull Antibioacuteticos

bull Esteroides

bull Alt metaboacutelicas y hormonales DM hipocalcemia

4 Puertas entrada

5 Responsabilidad patoacutegena candidiasis y candidemia

1 What is already known on this topic

Etiopatogenia de las sepsis por Candida

J Figueras C Leon A Tomasa R Peracaula M Soler FJ de Latorre J Padroacute

Med Clin (Barc) 1974 62425-32

197378 1977 1978 1979 1980 1985 1986 2013

Angels trayectoria profesionalproyectos tema

197383 199192 199899 20067 200910 201112 210213

UAB ATS LMC MIRMF MIRMIN Staff Staff

HGVH HGC

ESTUDIO SGFIICU EPCAN CAVA CAVA CAVA CAVA

CLINICO I II FIS TREM

PROYECTOS

Funguemia 1973-83 Anaacutelisis de 67 pacientes Sanchez Rodriguez C Leoacuten Regidor MA Capell Font S Peacuterez Campos A Planes Reig A Leoacuten Gil C

Med Clin (Barc) 198584549-53

bull Estudio observacional uniceacutentrico retrospectivo

bull 67 pacientes68 episodios

bull EB Patologiacutea GI 626 (4267)

bull FR CVC antibioterapia NPT cirugiacutea abdominal (68)

bull Cliacutenica indistinguible de una bacteriemia (9 casos SS)

bull Infecciones bacterianas asociadas 4967

bull Estratificacioacuten Funguemia TransitoriaDiseminada (4522)

bull TAF 28 pacientes tratados (9 con AFBD)

bull Mortalidad global 585 (3967) Relacionada 328 (2267)

1 Alta proporcioacuten de CRC

2 Concepto Candidemia RC es autolimitada y no requiere trato

3 Retraso de inicio de tratamiento antifuacutengico

Funguemia 1973-83 Estudio epidemioloacutegico Capell Font S Peacuterez Campos A Sanchez Rodriguez C Leoacuten Regidor MA Planes Reig A

Leoacuten Gil C Med Clin (Barc) 198584600-5

bull Estudio uniceacutentrico retrospectivo

bull 67 pacientes68 episodios

bull Funguemia nosocomial 1000 ingresos

bull UCI 175

bull Resto Servicios 03

bull UCI media 8 casos x antildeo

bull Aparicioacuten entre la 2 y 3ordm semana

Candidiasis y candidemia Reexamen de una problemaacutetica actual Saacutenchez Rodriacuteguez C Leoacuten Gil C Leoacuten Regidor MA Capell Font S Peacuterez Campos A

Med Clin (Barc) 198585464-71

bull Revisioacuten 121 referencias

bull Epidemiologia

bull Definicioacuten de teacuterminos

bull Poblacioacuten susceptible Etiologiacutea

bull Recursos cliacutenicos (I) EF lesiones cutaacuteneas miositis cateacuteteres y TF supurada endoftalmitis

bull Recursos cliacutenicos (II) Valoracioacuten focos metastaacutesicos miocarditispericarditis artritis y osteomielitis

encefalitismeningitis afeccioacuten pulmonar

bull Recursos analiacuteticos y microbioloacutegicos

bull Diagnostico seroloacutegico

bull A quien tratar

1 Candidemia Aumento nuacutemero de casosnuacutemero de pacientes con candidemia

2 Difiacutecil establecer diferencias entre la CT y CD

3 Durante los episodios de CT ldquopudierardquo haber un cierto grado de diseminacioacuten

4 Apuesta desarrollo de mejores meacutetodos diagnoacutesticosdiagnostico tempranoTAF

adecuado

Candidemia in non-neutropenic critically ill patients analysis of prognostic

factors and assessment of systemic antifungal therapy Nolla-Salas J Sitges-Serra A Leoacuten-Gil C Martiacutenez-Gonzaacutelez J Leoacuten-Regidor MA Ibantildeez-Luciacutea P

Torres-Rodriacuteguez PM and Study Group of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

bull Multicenter prospective observacional

bull 28 ICUs 15 months (Oct 1991-Dcber 1992)

bull 418 bed 22937 admissions

bull Candidemia 46 mean age 59 y

bull 1 episodio500 ICU admissions

bull Surgicalmedical 3016

bull Candida specie C albicans (60) parapsilosis (17)

bull TAF 43 FCNZ 27 AFBD 10 sequential therapy 6

bull Overal mortality 56 attributable 217

bull Apache II (time of diagnosis) and survival 20

bull Time of diagnosis start of AFT ldquoearlyrdquo laterdquo

The utility of serology in diagnosing candidosis in non-neutropenic

critically ill patients (1) Ibantildeez-Nolla J Torres-Rodriacuteguez JM Nolla M Leoacuten MA Meacutendez R Soria G Diacuteaz RM Marrugat J

Mycoses 20014447-53

bull Prospective cohort one UCI (HGC)

bull Sept 1988-Oct 1995 (8 y)

bull Inclusion all patients with at least one sample + Candida

bull Screening and optional samples

bull Cutaneous testophthalmologic evaluationpost morten study

bull Serology Antibodies (IHA IFA) antigens (Cand-TecPastorex)

The utility of serology in diagnosing candidosis in non-neutropenic

critically ill patients (2) Ibantildeez-Nolla J Torres-Rodriacuteguez JM Nolla M Leoacuten MA Meacutendez R Soria G Diacuteaz RM Marrugat J

Mycoses 20014447-53

Test Sensitiv Specif

Antibodies 37 78

Antigens 0 90

bull 3389 pts ICU LOS 6 days (1-112) mortality 10

bull 145 cases included (overall mortality 46)

bull 120 cases with multifocal colonization Candidemia 24 (18 pts) Endopht 2 cases

bull ATF Therapy 109 (75)

Significant relation between mortality and low levels of antibodies

Fungal colonization andor infection in non-neutropenic critically ill patients

results of the EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J Jordaacute R Saavedra P Palomar M and

EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

bull Prospective cohort observational multicenter study

bull Adult non-neutropenic pts 73 ICUs MS (70 hospitals)

bull 9 months (May 1998-January 1999)

bull Underlying diseases comorbidities reasons for ICU admission RF (presence and duration)

bull 7 days of ICU admission Once a week APACHE II Clinical situation microbiological

screening (TA pharyngeal exudates gastric aspirates and urine)

bull Antifungal treatment and outcome

bull 1765 patients age 579 y APACHE II ICU admission 18 5

bull Overall mortality 435 Intra ICU 338

bull No CI (785) Colonized (883) infected (97)

bull 18385 samples 13849 (surveillance) and 4536 (optional)

bull C albicans 721 (screening) and 697 (optional)

Economic Impact of Candida Colonization and Candida Infection in the

Critically Ill Patient Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor MA

and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

bull Prospective cohort observational multicenter study

bull 1765 adult non-neutropenic pts 73 ICUs mixed (70 hospitals)

bull 9 months (May 1998-January 1999)

bull 7 days of ICU admission Once a week APACHE II SOFA Clinical situation

and microbiological screening

bull No CI Colonized Infected Comorbidities and RF ATF therapy Outcome

Cost (2000)

ICU 1153 E

Hospit 406 E

Direct Cost (1 day)

- Candida colonization 8000

- Candida infection 16000

1

1

1

2

Courtesy by J Mensa

Score gt 25 Sensitivity 81

Specificity 74

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in

nonneutropenic critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro Saavedra Benito Almirante Juan Nolla-Salas

Francisco Aacutelvarez-Lerma Joseacute Garnacho-Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group

Crit Care Med 2006 34730-37

Score gt 25

1

1

1

2

probability of Candida infection

x 775

Courtesy byJ Mensa

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in

nonneutropenic critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro Saavedra Benito Almirante Juan Nolla-Salas

Francisco Aacutelvarez-Lerma Joseacute Garnacho-Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group

Crit Care Med 2006 34730-37

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

bull Prospective cohort observational multicenter study

bull Adult non-neutropenic pts 36 ICUs MS (32 hospitals)

bull 14 months (April 2006-June 2007)

bull Underlying diseases comorbidities reasons for ICU admission RF (presence and duration)

bull Antifungal treatment and outcome

bull 7 days of ICU admission Once a week APACHE II SOFA Clinical situation and microbiological

screening (5) TA pharyngeal exudatesgastric aspirates urine perirectal swab skin and optional

samples

bull1107 patients age 60 y ICU admission APACHE II 184 SOFA 7 (median)

bull No CI (215) Colonized (834) infected (58)

bull Overall mortality 305 Intra ICU 217

bull ATFT 49 (844) patients Time between ICU admission and administration of ATFT 173 days

bull 240 patients with Candida species colonization or IC (18) (1ndash3)-beta-D-glucan serum levels

Candida Score lt 3 = 3 gt 3

IC rate medical surgical

patients (n = 1107) 23 59

115

(51 - 178)

IC rate Abdominal Surgery

(n = 182) 23 125

303

(192 - 414)

Abdominal Surgery IC rates according CS

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash1633

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash33

Candiduria in critically ill patients admitted to intensive care medical units

Francisco Aacutelvarez-Lerma Juan Nolla-Salas Cristobal Leon Mercedes Palomar Ricard

Jorda Nieves Carrasco Felipe Bobillo (EPCAN Study Group)

Intensive Care Med 2003291069ndash76

bull 1765 adult non-neutropenic pts (lt 7 days) Candiduria 389 patients (22)

bull Age 61 y Apache II 19

bull Incidence density 95 episodes1000 days

bull Length of ICU stay since presence of candiduria 16 days

bull Risk factor associated age over 65 y female gender LOS in hospital

before ICU admission diabetes TPN MV previous use of antibiotics

(C no albicans)

bull C albicans 266 (684) C glabrata 32 (82) C tropicalis 14 (36)

bull Candiduria is a risk factor for ICUhospital mortality (OR 158)

Jordaacute Marcos R Alvarez-Lerma F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C

and EPCAN Study Group Mycoses 200750302-10

Risk factors for candidaemia in critically ill patients a prospective

surveillance study

bull 1765 adult non-neutropenic pts (lt 7 days) Candidemia 63 pts

bull Age 63 y Apache II 18 ICUhospital stay 2848 Surgical 29 (46) Medical 26 (413 )

bull ATF treatment 4863 (76)

- FCNZ 32 (667) AFBD 8 (16) LAFB 5 (104) AFBLC 3 (63)

bull ICUhospital Mortality 34 (54)-39 (73)

Assessment of candidemia-attributable mortality in critically ill patients using

propensity score matching analysis Francisco J Gonzaacutelez de Molina Cristoacutebal Leoacuten Sergio Ruiz-Santana and Pedro Saavedra for the

CAVA I Study Group

Crit Care 201216 R105

Critical Care 2012 16R105

bull The use of propensity score matching analysis to control for all potential confounding

variables allowed the assessment of candidemia-attributable mortality in critically ill

patients

bull Candidemia was not associated with an increase in either ICU or hospital

mortality

bull Earlier treatment of bloodstream infection and better monitoring (surveillance sampling

weekly) resulting in appropriate antifungal agent may contribute to increased survival

bull APACHE II at the time of diagnosis of candidemia was the only predictor of death in

patients with candidemia

bull 1107 pts 38 (34) candidemias Propensity score matching analysis

(Candidemia 70 no 35 yes)

Multicenter observational prospective

C Score biomarkers amp IC

18 ICUs n = 176 (SAC) 4 wks Study 2009-10

ICU gt 7 days

C Score BG CAGTA others Weekly (x 2) screening

Optional Samples related clinical situation follow up

Variables demographics APACHE II SOFA (admission weekly x 2 starting antifungals) comorbid

diseases risk factors antifungal therapy and outcome

Adult patients admitted ICU ge 7 days SAC = Severe Abdominal Conditions

CAGTA = Candida albicans germ-tube antibody

1st 2nd 3rd 4th 3d

Intensive Care Med 2012 381315-25

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating between

Candida colonization and invasive candidiasis in patients with severe abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J Aacutelvarez L

Utande A Farintildeas O and the Study Group Cava II

- Patients with Candida colonization A model for IC prediction was obtained

using Classification And Regression Trees (CART)

- Variables used maximum values biomarkers before during development IC or highest value when IC did not

developed (Apache-II BG CAGTA)

- CART through a process of binary recursive spliting of the datasets based on rules of the form if-then-else identifies

a set of predictors of IC estimating the probabilities of IC according to the values of predictors

- The discriminate value of the probabilities of IC obtained by the CART was evaluated by the receiver characteristic

operating (ROC) curve

- Predictive rule identify patients have an IC risk when probability to develop

IC is ge 30(cut-off chosen by CART algorithm to minimize error measurement = deviance)

- Obtained rule estimated Sensitivity Specificity PPV NPV

- Data analysis carried out using R-package

CART prediction rule model

Breiman L et al (1984) Classfication and regression trees

Belmont CA Wadsworth International

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

n = 115 pts

IC = 31 (27 )

n = 27 pts

IC = 16 (599)

n = 88 pts

IC = 15 (170)

n = 49 pts

IC = 3 (61 )

n = 39 pts

IC = 12 (308 )

B-glucan ge 259 pgml

CAGTA positive B-glucan lt 329 pgml

B-glucan lt 259 pgml

CAGTA negative

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

Diagnostic accuracy of CART-derived prediction rule BG (cut-off

gt 259 pgmL) CAGTA (cutt-off positive) and CS for IC diagnosis

Area under

ROC curve

(95 CI)

Sensitivity

(95 CI)

Specificity

(95 CI)

Predictive value

Positive

(95 CI)

Negative

(95 CI)

CART analysis

078

(076-081)

903

(751-966)

547

(441-650)

424

(312-544)

939

(835-979)

BG

067

(059-074)

516

(348-680)

869

(780-925)

593

(407-755)

830

(738-894)

CAGTA

067

(063-070)

710

(534-839)

573

(465-675)

386

(271-516)

839

(722-913)

CS 062

(058-066)

935

(792-982)

181

(113-277)

299

(217-396)

882

(65-7-967)

CART classification and regression tree analysis BG beta-D-glucan CAGTA Candida albicans germ tube antibody Total number of patients with

Candida spp colonization = 115

Usefulness of the (13)--D-Glucan and Candida albicans germ tube antibody in the

Diagnosis of Invasive Candidiasis in Non-neutropenic Critically Ill Patients (non selected)

201112 One ICU (HUV) 105 NNCIP non selected gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida colonization

cultures (rectal swabs tracheal pharyngeal or gastric aspirates and urine) and serum

BG and CAGTA Were collected factors can interfere with the levels of BG (RRT AC

PT use of blood transfusions surgeryhellip)

NCNI

(n = 42)

Colonized

(n = 52)

Candidemia

(n = 6)

Peritonitis

(n =5)

P

value

Age years mean (range) 66 (50-73) 63 (54-76) 68 (62-78) 67 (62-70) 0820

Malefemale patients 3210 2527 42 50 0007

BG pgmL

Median (IQR)

Maximum (IQR)

44 (31-102)

77 (31-140)

40 (31-140)

150 (47-500)

72 ( 31-300)

194 (120-300)

31 (31-31)

50 (31-80)

0527

0037

CAGTA positives n () 13 (310) 26 (500) 3 (500) 1 (200) 0203

Instituto Salud Carlos III Madrid Spain (FIS PI 1002110) ICAAC 2013 (M-1380)

Conclusions

Patients with candidemia and Candida spp colonization showed significantly higher values

of serum BG than neither colonized or infected patients

NCNI neither colonized nor infected BG B-D- glucan IQR interquartile range (25th-75th percentile) CAGTA Candida albicans germ

tube antibodies Significant differences as compared with the NCNI group

CAVA FIS PROJECT

Prospective cohort observational multicenter study

201214 12 ICUs NNCIP selected (SAC) gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida

colonization cultures (rectal swabs tracheal pharyngeal urine) and serum (BG and

CAGTA)

Preliminary data (October 2013) 215 pts included 117 CC 26 IC AFT 94 (446)

Invasive Candidiasis in the critically ill patients Diagnostic utility of 1-3-Beta-D-

Glucan(BDG) anti-mycelium antibodies (CAGTA) mannanantimannan antibodies

(MAA) and detection of Candida DNA (PCR)rdquo CAVA TREM PROJECT

Candida DNA detection (PCR)

To evaluate CS performance ICU patients developing hospital-acquired severe sepsis or septic shock

Prospective multicenter (5 ICUs France) cohort study

n = 94 recruited (IC = 5 53 )

IC rates CS = 2 or 3 0 CS = 4 176 CS = 5 50 (p lt 00001)

CS gt 3 Benefit early SAT

Evaluation of ldquoCandida scorerdquo in critically ill patients a prospective multicenter

observational cohort study Leroy G Lamblotte F Thevenin D Lemaire C Parmentier E Devos P Leroy O

Ann Intens Care 2011150

bull To determine nordm patients w o documented IC received SAT

bull 1-day cross-sectional cohort study 169 ICUs France Belgium

bull n = 2047 recruited

bull n = 154 (75) with SAT (only 54 with IC)

bull Independent predictors SAT

ndash Center-related factors Hospital lt 800 beds (OR 29) organ transplant activity (OR26)

use fluoroquinolones (OR23) use SAT unresolved sepsis (OR19 22 20)

ndash Patient related factors Candida colonization (OR 124) severe sepsis and septic shock (OR47)

emergency surgery (OR 24) hematologic malignancies (OR71)

bull Trend greater impact SAT on survival when CS = 4 or 5

SAT Systemic Antifungal Treatment

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

Crit Care Med 201240813-22

Impact SAT on 28-d mortality according CS

Crit Care Med 201240813-22

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 4: Recordant L Àngels - academia.cat

1 Introduccioacuten aumento frecuencia pacientes graves mort 60-80

2 El germen

3 Factores predisponentes

bull Enfermedad basal importante

bull Antibioacuteticos

bull Esteroides

bull Alt metaboacutelicas y hormonales DM hipocalcemia

4 Puertas entrada

5 Responsabilidad patoacutegena candidiasis y candidemia

1 What is already known on this topic

Etiopatogenia de las sepsis por Candida

J Figueras C Leon A Tomasa R Peracaula M Soler FJ de Latorre J Padroacute

Med Clin (Barc) 1974 62425-32

197378 1977 1978 1979 1980 1985 1986 2013

Angels trayectoria profesionalproyectos tema

197383 199192 199899 20067 200910 201112 210213

UAB ATS LMC MIRMF MIRMIN Staff Staff

HGVH HGC

ESTUDIO SGFIICU EPCAN CAVA CAVA CAVA CAVA

CLINICO I II FIS TREM

PROYECTOS

Funguemia 1973-83 Anaacutelisis de 67 pacientes Sanchez Rodriguez C Leoacuten Regidor MA Capell Font S Peacuterez Campos A Planes Reig A Leoacuten Gil C

Med Clin (Barc) 198584549-53

bull Estudio observacional uniceacutentrico retrospectivo

bull 67 pacientes68 episodios

bull EB Patologiacutea GI 626 (4267)

bull FR CVC antibioterapia NPT cirugiacutea abdominal (68)

bull Cliacutenica indistinguible de una bacteriemia (9 casos SS)

bull Infecciones bacterianas asociadas 4967

bull Estratificacioacuten Funguemia TransitoriaDiseminada (4522)

bull TAF 28 pacientes tratados (9 con AFBD)

bull Mortalidad global 585 (3967) Relacionada 328 (2267)

1 Alta proporcioacuten de CRC

2 Concepto Candidemia RC es autolimitada y no requiere trato

3 Retraso de inicio de tratamiento antifuacutengico

Funguemia 1973-83 Estudio epidemioloacutegico Capell Font S Peacuterez Campos A Sanchez Rodriguez C Leoacuten Regidor MA Planes Reig A

Leoacuten Gil C Med Clin (Barc) 198584600-5

bull Estudio uniceacutentrico retrospectivo

bull 67 pacientes68 episodios

bull Funguemia nosocomial 1000 ingresos

bull UCI 175

bull Resto Servicios 03

bull UCI media 8 casos x antildeo

bull Aparicioacuten entre la 2 y 3ordm semana

Candidiasis y candidemia Reexamen de una problemaacutetica actual Saacutenchez Rodriacuteguez C Leoacuten Gil C Leoacuten Regidor MA Capell Font S Peacuterez Campos A

Med Clin (Barc) 198585464-71

bull Revisioacuten 121 referencias

bull Epidemiologia

bull Definicioacuten de teacuterminos

bull Poblacioacuten susceptible Etiologiacutea

bull Recursos cliacutenicos (I) EF lesiones cutaacuteneas miositis cateacuteteres y TF supurada endoftalmitis

bull Recursos cliacutenicos (II) Valoracioacuten focos metastaacutesicos miocarditispericarditis artritis y osteomielitis

encefalitismeningitis afeccioacuten pulmonar

bull Recursos analiacuteticos y microbioloacutegicos

bull Diagnostico seroloacutegico

bull A quien tratar

1 Candidemia Aumento nuacutemero de casosnuacutemero de pacientes con candidemia

2 Difiacutecil establecer diferencias entre la CT y CD

3 Durante los episodios de CT ldquopudierardquo haber un cierto grado de diseminacioacuten

4 Apuesta desarrollo de mejores meacutetodos diagnoacutesticosdiagnostico tempranoTAF

adecuado

Candidemia in non-neutropenic critically ill patients analysis of prognostic

factors and assessment of systemic antifungal therapy Nolla-Salas J Sitges-Serra A Leoacuten-Gil C Martiacutenez-Gonzaacutelez J Leoacuten-Regidor MA Ibantildeez-Luciacutea P

Torres-Rodriacuteguez PM and Study Group of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

bull Multicenter prospective observacional

bull 28 ICUs 15 months (Oct 1991-Dcber 1992)

bull 418 bed 22937 admissions

bull Candidemia 46 mean age 59 y

bull 1 episodio500 ICU admissions

bull Surgicalmedical 3016

bull Candida specie C albicans (60) parapsilosis (17)

bull TAF 43 FCNZ 27 AFBD 10 sequential therapy 6

bull Overal mortality 56 attributable 217

bull Apache II (time of diagnosis) and survival 20

bull Time of diagnosis start of AFT ldquoearlyrdquo laterdquo

The utility of serology in diagnosing candidosis in non-neutropenic

critically ill patients (1) Ibantildeez-Nolla J Torres-Rodriacuteguez JM Nolla M Leoacuten MA Meacutendez R Soria G Diacuteaz RM Marrugat J

Mycoses 20014447-53

bull Prospective cohort one UCI (HGC)

bull Sept 1988-Oct 1995 (8 y)

bull Inclusion all patients with at least one sample + Candida

bull Screening and optional samples

bull Cutaneous testophthalmologic evaluationpost morten study

bull Serology Antibodies (IHA IFA) antigens (Cand-TecPastorex)

The utility of serology in diagnosing candidosis in non-neutropenic

critically ill patients (2) Ibantildeez-Nolla J Torres-Rodriacuteguez JM Nolla M Leoacuten MA Meacutendez R Soria G Diacuteaz RM Marrugat J

Mycoses 20014447-53

Test Sensitiv Specif

Antibodies 37 78

Antigens 0 90

bull 3389 pts ICU LOS 6 days (1-112) mortality 10

bull 145 cases included (overall mortality 46)

bull 120 cases with multifocal colonization Candidemia 24 (18 pts) Endopht 2 cases

bull ATF Therapy 109 (75)

Significant relation between mortality and low levels of antibodies

Fungal colonization andor infection in non-neutropenic critically ill patients

results of the EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J Jordaacute R Saavedra P Palomar M and

EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

bull Prospective cohort observational multicenter study

bull Adult non-neutropenic pts 73 ICUs MS (70 hospitals)

bull 9 months (May 1998-January 1999)

bull Underlying diseases comorbidities reasons for ICU admission RF (presence and duration)

bull 7 days of ICU admission Once a week APACHE II Clinical situation microbiological

screening (TA pharyngeal exudates gastric aspirates and urine)

bull Antifungal treatment and outcome

bull 1765 patients age 579 y APACHE II ICU admission 18 5

bull Overall mortality 435 Intra ICU 338

bull No CI (785) Colonized (883) infected (97)

bull 18385 samples 13849 (surveillance) and 4536 (optional)

bull C albicans 721 (screening) and 697 (optional)

Economic Impact of Candida Colonization and Candida Infection in the

Critically Ill Patient Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor MA

and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

bull Prospective cohort observational multicenter study

bull 1765 adult non-neutropenic pts 73 ICUs mixed (70 hospitals)

bull 9 months (May 1998-January 1999)

bull 7 days of ICU admission Once a week APACHE II SOFA Clinical situation

and microbiological screening

bull No CI Colonized Infected Comorbidities and RF ATF therapy Outcome

Cost (2000)

ICU 1153 E

Hospit 406 E

Direct Cost (1 day)

- Candida colonization 8000

- Candida infection 16000

1

1

1

2

Courtesy by J Mensa

Score gt 25 Sensitivity 81

Specificity 74

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in

nonneutropenic critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro Saavedra Benito Almirante Juan Nolla-Salas

Francisco Aacutelvarez-Lerma Joseacute Garnacho-Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group

Crit Care Med 2006 34730-37

Score gt 25

1

1

1

2

probability of Candida infection

x 775

Courtesy byJ Mensa

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in

nonneutropenic critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro Saavedra Benito Almirante Juan Nolla-Salas

Francisco Aacutelvarez-Lerma Joseacute Garnacho-Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group

Crit Care Med 2006 34730-37

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

bull Prospective cohort observational multicenter study

bull Adult non-neutropenic pts 36 ICUs MS (32 hospitals)

bull 14 months (April 2006-June 2007)

bull Underlying diseases comorbidities reasons for ICU admission RF (presence and duration)

bull Antifungal treatment and outcome

bull 7 days of ICU admission Once a week APACHE II SOFA Clinical situation and microbiological

screening (5) TA pharyngeal exudatesgastric aspirates urine perirectal swab skin and optional

samples

bull1107 patients age 60 y ICU admission APACHE II 184 SOFA 7 (median)

bull No CI (215) Colonized (834) infected (58)

bull Overall mortality 305 Intra ICU 217

bull ATFT 49 (844) patients Time between ICU admission and administration of ATFT 173 days

bull 240 patients with Candida species colonization or IC (18) (1ndash3)-beta-D-glucan serum levels

Candida Score lt 3 = 3 gt 3

IC rate medical surgical

patients (n = 1107) 23 59

115

(51 - 178)

IC rate Abdominal Surgery

(n = 182) 23 125

303

(192 - 414)

Abdominal Surgery IC rates according CS

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash1633

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash33

Candiduria in critically ill patients admitted to intensive care medical units

Francisco Aacutelvarez-Lerma Juan Nolla-Salas Cristobal Leon Mercedes Palomar Ricard

Jorda Nieves Carrasco Felipe Bobillo (EPCAN Study Group)

Intensive Care Med 2003291069ndash76

bull 1765 adult non-neutropenic pts (lt 7 days) Candiduria 389 patients (22)

bull Age 61 y Apache II 19

bull Incidence density 95 episodes1000 days

bull Length of ICU stay since presence of candiduria 16 days

bull Risk factor associated age over 65 y female gender LOS in hospital

before ICU admission diabetes TPN MV previous use of antibiotics

(C no albicans)

bull C albicans 266 (684) C glabrata 32 (82) C tropicalis 14 (36)

bull Candiduria is a risk factor for ICUhospital mortality (OR 158)

Jordaacute Marcos R Alvarez-Lerma F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C

and EPCAN Study Group Mycoses 200750302-10

Risk factors for candidaemia in critically ill patients a prospective

surveillance study

bull 1765 adult non-neutropenic pts (lt 7 days) Candidemia 63 pts

bull Age 63 y Apache II 18 ICUhospital stay 2848 Surgical 29 (46) Medical 26 (413 )

bull ATF treatment 4863 (76)

- FCNZ 32 (667) AFBD 8 (16) LAFB 5 (104) AFBLC 3 (63)

bull ICUhospital Mortality 34 (54)-39 (73)

Assessment of candidemia-attributable mortality in critically ill patients using

propensity score matching analysis Francisco J Gonzaacutelez de Molina Cristoacutebal Leoacuten Sergio Ruiz-Santana and Pedro Saavedra for the

CAVA I Study Group

Crit Care 201216 R105

Critical Care 2012 16R105

bull The use of propensity score matching analysis to control for all potential confounding

variables allowed the assessment of candidemia-attributable mortality in critically ill

patients

bull Candidemia was not associated with an increase in either ICU or hospital

mortality

bull Earlier treatment of bloodstream infection and better monitoring (surveillance sampling

weekly) resulting in appropriate antifungal agent may contribute to increased survival

bull APACHE II at the time of diagnosis of candidemia was the only predictor of death in

patients with candidemia

bull 1107 pts 38 (34) candidemias Propensity score matching analysis

(Candidemia 70 no 35 yes)

Multicenter observational prospective

C Score biomarkers amp IC

18 ICUs n = 176 (SAC) 4 wks Study 2009-10

ICU gt 7 days

C Score BG CAGTA others Weekly (x 2) screening

Optional Samples related clinical situation follow up

Variables demographics APACHE II SOFA (admission weekly x 2 starting antifungals) comorbid

diseases risk factors antifungal therapy and outcome

Adult patients admitted ICU ge 7 days SAC = Severe Abdominal Conditions

CAGTA = Candida albicans germ-tube antibody

1st 2nd 3rd 4th 3d

Intensive Care Med 2012 381315-25

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating between

Candida colonization and invasive candidiasis in patients with severe abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J Aacutelvarez L

Utande A Farintildeas O and the Study Group Cava II

- Patients with Candida colonization A model for IC prediction was obtained

using Classification And Regression Trees (CART)

- Variables used maximum values biomarkers before during development IC or highest value when IC did not

developed (Apache-II BG CAGTA)

- CART through a process of binary recursive spliting of the datasets based on rules of the form if-then-else identifies

a set of predictors of IC estimating the probabilities of IC according to the values of predictors

- The discriminate value of the probabilities of IC obtained by the CART was evaluated by the receiver characteristic

operating (ROC) curve

- Predictive rule identify patients have an IC risk when probability to develop

IC is ge 30(cut-off chosen by CART algorithm to minimize error measurement = deviance)

- Obtained rule estimated Sensitivity Specificity PPV NPV

- Data analysis carried out using R-package

CART prediction rule model

Breiman L et al (1984) Classfication and regression trees

Belmont CA Wadsworth International

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

n = 115 pts

IC = 31 (27 )

n = 27 pts

IC = 16 (599)

n = 88 pts

IC = 15 (170)

n = 49 pts

IC = 3 (61 )

n = 39 pts

IC = 12 (308 )

B-glucan ge 259 pgml

CAGTA positive B-glucan lt 329 pgml

B-glucan lt 259 pgml

CAGTA negative

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

Diagnostic accuracy of CART-derived prediction rule BG (cut-off

gt 259 pgmL) CAGTA (cutt-off positive) and CS for IC diagnosis

Area under

ROC curve

(95 CI)

Sensitivity

(95 CI)

Specificity

(95 CI)

Predictive value

Positive

(95 CI)

Negative

(95 CI)

CART analysis

078

(076-081)

903

(751-966)

547

(441-650)

424

(312-544)

939

(835-979)

BG

067

(059-074)

516

(348-680)

869

(780-925)

593

(407-755)

830

(738-894)

CAGTA

067

(063-070)

710

(534-839)

573

(465-675)

386

(271-516)

839

(722-913)

CS 062

(058-066)

935

(792-982)

181

(113-277)

299

(217-396)

882

(65-7-967)

CART classification and regression tree analysis BG beta-D-glucan CAGTA Candida albicans germ tube antibody Total number of patients with

Candida spp colonization = 115

Usefulness of the (13)--D-Glucan and Candida albicans germ tube antibody in the

Diagnosis of Invasive Candidiasis in Non-neutropenic Critically Ill Patients (non selected)

201112 One ICU (HUV) 105 NNCIP non selected gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida colonization

cultures (rectal swabs tracheal pharyngeal or gastric aspirates and urine) and serum

BG and CAGTA Were collected factors can interfere with the levels of BG (RRT AC

PT use of blood transfusions surgeryhellip)

NCNI

(n = 42)

Colonized

(n = 52)

Candidemia

(n = 6)

Peritonitis

(n =5)

P

value

Age years mean (range) 66 (50-73) 63 (54-76) 68 (62-78) 67 (62-70) 0820

Malefemale patients 3210 2527 42 50 0007

BG pgmL

Median (IQR)

Maximum (IQR)

44 (31-102)

77 (31-140)

40 (31-140)

150 (47-500)

72 ( 31-300)

194 (120-300)

31 (31-31)

50 (31-80)

0527

0037

CAGTA positives n () 13 (310) 26 (500) 3 (500) 1 (200) 0203

Instituto Salud Carlos III Madrid Spain (FIS PI 1002110) ICAAC 2013 (M-1380)

Conclusions

Patients with candidemia and Candida spp colonization showed significantly higher values

of serum BG than neither colonized or infected patients

NCNI neither colonized nor infected BG B-D- glucan IQR interquartile range (25th-75th percentile) CAGTA Candida albicans germ

tube antibodies Significant differences as compared with the NCNI group

CAVA FIS PROJECT

Prospective cohort observational multicenter study

201214 12 ICUs NNCIP selected (SAC) gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida

colonization cultures (rectal swabs tracheal pharyngeal urine) and serum (BG and

CAGTA)

Preliminary data (October 2013) 215 pts included 117 CC 26 IC AFT 94 (446)

Invasive Candidiasis in the critically ill patients Diagnostic utility of 1-3-Beta-D-

Glucan(BDG) anti-mycelium antibodies (CAGTA) mannanantimannan antibodies

(MAA) and detection of Candida DNA (PCR)rdquo CAVA TREM PROJECT

Candida DNA detection (PCR)

To evaluate CS performance ICU patients developing hospital-acquired severe sepsis or septic shock

Prospective multicenter (5 ICUs France) cohort study

n = 94 recruited (IC = 5 53 )

IC rates CS = 2 or 3 0 CS = 4 176 CS = 5 50 (p lt 00001)

CS gt 3 Benefit early SAT

Evaluation of ldquoCandida scorerdquo in critically ill patients a prospective multicenter

observational cohort study Leroy G Lamblotte F Thevenin D Lemaire C Parmentier E Devos P Leroy O

Ann Intens Care 2011150

bull To determine nordm patients w o documented IC received SAT

bull 1-day cross-sectional cohort study 169 ICUs France Belgium

bull n = 2047 recruited

bull n = 154 (75) with SAT (only 54 with IC)

bull Independent predictors SAT

ndash Center-related factors Hospital lt 800 beds (OR 29) organ transplant activity (OR26)

use fluoroquinolones (OR23) use SAT unresolved sepsis (OR19 22 20)

ndash Patient related factors Candida colonization (OR 124) severe sepsis and septic shock (OR47)

emergency surgery (OR 24) hematologic malignancies (OR71)

bull Trend greater impact SAT on survival when CS = 4 or 5

SAT Systemic Antifungal Treatment

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

Crit Care Med 201240813-22

Impact SAT on 28-d mortality according CS

Crit Care Med 201240813-22

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 5: Recordant L Àngels - academia.cat

197378 1977 1978 1979 1980 1985 1986 2013

Angels trayectoria profesionalproyectos tema

197383 199192 199899 20067 200910 201112 210213

UAB ATS LMC MIRMF MIRMIN Staff Staff

HGVH HGC

ESTUDIO SGFIICU EPCAN CAVA CAVA CAVA CAVA

CLINICO I II FIS TREM

PROYECTOS

Funguemia 1973-83 Anaacutelisis de 67 pacientes Sanchez Rodriguez C Leoacuten Regidor MA Capell Font S Peacuterez Campos A Planes Reig A Leoacuten Gil C

Med Clin (Barc) 198584549-53

bull Estudio observacional uniceacutentrico retrospectivo

bull 67 pacientes68 episodios

bull EB Patologiacutea GI 626 (4267)

bull FR CVC antibioterapia NPT cirugiacutea abdominal (68)

bull Cliacutenica indistinguible de una bacteriemia (9 casos SS)

bull Infecciones bacterianas asociadas 4967

bull Estratificacioacuten Funguemia TransitoriaDiseminada (4522)

bull TAF 28 pacientes tratados (9 con AFBD)

bull Mortalidad global 585 (3967) Relacionada 328 (2267)

1 Alta proporcioacuten de CRC

2 Concepto Candidemia RC es autolimitada y no requiere trato

3 Retraso de inicio de tratamiento antifuacutengico

Funguemia 1973-83 Estudio epidemioloacutegico Capell Font S Peacuterez Campos A Sanchez Rodriguez C Leoacuten Regidor MA Planes Reig A

Leoacuten Gil C Med Clin (Barc) 198584600-5

bull Estudio uniceacutentrico retrospectivo

bull 67 pacientes68 episodios

bull Funguemia nosocomial 1000 ingresos

bull UCI 175

bull Resto Servicios 03

bull UCI media 8 casos x antildeo

bull Aparicioacuten entre la 2 y 3ordm semana

Candidiasis y candidemia Reexamen de una problemaacutetica actual Saacutenchez Rodriacuteguez C Leoacuten Gil C Leoacuten Regidor MA Capell Font S Peacuterez Campos A

Med Clin (Barc) 198585464-71

bull Revisioacuten 121 referencias

bull Epidemiologia

bull Definicioacuten de teacuterminos

bull Poblacioacuten susceptible Etiologiacutea

bull Recursos cliacutenicos (I) EF lesiones cutaacuteneas miositis cateacuteteres y TF supurada endoftalmitis

bull Recursos cliacutenicos (II) Valoracioacuten focos metastaacutesicos miocarditispericarditis artritis y osteomielitis

encefalitismeningitis afeccioacuten pulmonar

bull Recursos analiacuteticos y microbioloacutegicos

bull Diagnostico seroloacutegico

bull A quien tratar

1 Candidemia Aumento nuacutemero de casosnuacutemero de pacientes con candidemia

2 Difiacutecil establecer diferencias entre la CT y CD

3 Durante los episodios de CT ldquopudierardquo haber un cierto grado de diseminacioacuten

4 Apuesta desarrollo de mejores meacutetodos diagnoacutesticosdiagnostico tempranoTAF

adecuado

Candidemia in non-neutropenic critically ill patients analysis of prognostic

factors and assessment of systemic antifungal therapy Nolla-Salas J Sitges-Serra A Leoacuten-Gil C Martiacutenez-Gonzaacutelez J Leoacuten-Regidor MA Ibantildeez-Luciacutea P

Torres-Rodriacuteguez PM and Study Group of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

bull Multicenter prospective observacional

bull 28 ICUs 15 months (Oct 1991-Dcber 1992)

bull 418 bed 22937 admissions

bull Candidemia 46 mean age 59 y

bull 1 episodio500 ICU admissions

bull Surgicalmedical 3016

bull Candida specie C albicans (60) parapsilosis (17)

bull TAF 43 FCNZ 27 AFBD 10 sequential therapy 6

bull Overal mortality 56 attributable 217

bull Apache II (time of diagnosis) and survival 20

bull Time of diagnosis start of AFT ldquoearlyrdquo laterdquo

The utility of serology in diagnosing candidosis in non-neutropenic

critically ill patients (1) Ibantildeez-Nolla J Torres-Rodriacuteguez JM Nolla M Leoacuten MA Meacutendez R Soria G Diacuteaz RM Marrugat J

Mycoses 20014447-53

bull Prospective cohort one UCI (HGC)

bull Sept 1988-Oct 1995 (8 y)

bull Inclusion all patients with at least one sample + Candida

bull Screening and optional samples

bull Cutaneous testophthalmologic evaluationpost morten study

bull Serology Antibodies (IHA IFA) antigens (Cand-TecPastorex)

The utility of serology in diagnosing candidosis in non-neutropenic

critically ill patients (2) Ibantildeez-Nolla J Torres-Rodriacuteguez JM Nolla M Leoacuten MA Meacutendez R Soria G Diacuteaz RM Marrugat J

Mycoses 20014447-53

Test Sensitiv Specif

Antibodies 37 78

Antigens 0 90

bull 3389 pts ICU LOS 6 days (1-112) mortality 10

bull 145 cases included (overall mortality 46)

bull 120 cases with multifocal colonization Candidemia 24 (18 pts) Endopht 2 cases

bull ATF Therapy 109 (75)

Significant relation between mortality and low levels of antibodies

Fungal colonization andor infection in non-neutropenic critically ill patients

results of the EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J Jordaacute R Saavedra P Palomar M and

EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

bull Prospective cohort observational multicenter study

bull Adult non-neutropenic pts 73 ICUs MS (70 hospitals)

bull 9 months (May 1998-January 1999)

bull Underlying diseases comorbidities reasons for ICU admission RF (presence and duration)

bull 7 days of ICU admission Once a week APACHE II Clinical situation microbiological

screening (TA pharyngeal exudates gastric aspirates and urine)

bull Antifungal treatment and outcome

bull 1765 patients age 579 y APACHE II ICU admission 18 5

bull Overall mortality 435 Intra ICU 338

bull No CI (785) Colonized (883) infected (97)

bull 18385 samples 13849 (surveillance) and 4536 (optional)

bull C albicans 721 (screening) and 697 (optional)

Economic Impact of Candida Colonization and Candida Infection in the

Critically Ill Patient Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor MA

and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

bull Prospective cohort observational multicenter study

bull 1765 adult non-neutropenic pts 73 ICUs mixed (70 hospitals)

bull 9 months (May 1998-January 1999)

bull 7 days of ICU admission Once a week APACHE II SOFA Clinical situation

and microbiological screening

bull No CI Colonized Infected Comorbidities and RF ATF therapy Outcome

Cost (2000)

ICU 1153 E

Hospit 406 E

Direct Cost (1 day)

- Candida colonization 8000

- Candida infection 16000

1

1

1

2

Courtesy by J Mensa

Score gt 25 Sensitivity 81

Specificity 74

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in

nonneutropenic critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro Saavedra Benito Almirante Juan Nolla-Salas

Francisco Aacutelvarez-Lerma Joseacute Garnacho-Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group

Crit Care Med 2006 34730-37

Score gt 25

1

1

1

2

probability of Candida infection

x 775

Courtesy byJ Mensa

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in

nonneutropenic critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro Saavedra Benito Almirante Juan Nolla-Salas

Francisco Aacutelvarez-Lerma Joseacute Garnacho-Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group

Crit Care Med 2006 34730-37

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

bull Prospective cohort observational multicenter study

bull Adult non-neutropenic pts 36 ICUs MS (32 hospitals)

bull 14 months (April 2006-June 2007)

bull Underlying diseases comorbidities reasons for ICU admission RF (presence and duration)

bull Antifungal treatment and outcome

bull 7 days of ICU admission Once a week APACHE II SOFA Clinical situation and microbiological

screening (5) TA pharyngeal exudatesgastric aspirates urine perirectal swab skin and optional

samples

bull1107 patients age 60 y ICU admission APACHE II 184 SOFA 7 (median)

bull No CI (215) Colonized (834) infected (58)

bull Overall mortality 305 Intra ICU 217

bull ATFT 49 (844) patients Time between ICU admission and administration of ATFT 173 days

bull 240 patients with Candida species colonization or IC (18) (1ndash3)-beta-D-glucan serum levels

Candida Score lt 3 = 3 gt 3

IC rate medical surgical

patients (n = 1107) 23 59

115

(51 - 178)

IC rate Abdominal Surgery

(n = 182) 23 125

303

(192 - 414)

Abdominal Surgery IC rates according CS

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash1633

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash33

Candiduria in critically ill patients admitted to intensive care medical units

Francisco Aacutelvarez-Lerma Juan Nolla-Salas Cristobal Leon Mercedes Palomar Ricard

Jorda Nieves Carrasco Felipe Bobillo (EPCAN Study Group)

Intensive Care Med 2003291069ndash76

bull 1765 adult non-neutropenic pts (lt 7 days) Candiduria 389 patients (22)

bull Age 61 y Apache II 19

bull Incidence density 95 episodes1000 days

bull Length of ICU stay since presence of candiduria 16 days

bull Risk factor associated age over 65 y female gender LOS in hospital

before ICU admission diabetes TPN MV previous use of antibiotics

(C no albicans)

bull C albicans 266 (684) C glabrata 32 (82) C tropicalis 14 (36)

bull Candiduria is a risk factor for ICUhospital mortality (OR 158)

Jordaacute Marcos R Alvarez-Lerma F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C

and EPCAN Study Group Mycoses 200750302-10

Risk factors for candidaemia in critically ill patients a prospective

surveillance study

bull 1765 adult non-neutropenic pts (lt 7 days) Candidemia 63 pts

bull Age 63 y Apache II 18 ICUhospital stay 2848 Surgical 29 (46) Medical 26 (413 )

bull ATF treatment 4863 (76)

- FCNZ 32 (667) AFBD 8 (16) LAFB 5 (104) AFBLC 3 (63)

bull ICUhospital Mortality 34 (54)-39 (73)

Assessment of candidemia-attributable mortality in critically ill patients using

propensity score matching analysis Francisco J Gonzaacutelez de Molina Cristoacutebal Leoacuten Sergio Ruiz-Santana and Pedro Saavedra for the

CAVA I Study Group

Crit Care 201216 R105

Critical Care 2012 16R105

bull The use of propensity score matching analysis to control for all potential confounding

variables allowed the assessment of candidemia-attributable mortality in critically ill

patients

bull Candidemia was not associated with an increase in either ICU or hospital

mortality

bull Earlier treatment of bloodstream infection and better monitoring (surveillance sampling

weekly) resulting in appropriate antifungal agent may contribute to increased survival

bull APACHE II at the time of diagnosis of candidemia was the only predictor of death in

patients with candidemia

bull 1107 pts 38 (34) candidemias Propensity score matching analysis

(Candidemia 70 no 35 yes)

Multicenter observational prospective

C Score biomarkers amp IC

18 ICUs n = 176 (SAC) 4 wks Study 2009-10

ICU gt 7 days

C Score BG CAGTA others Weekly (x 2) screening

Optional Samples related clinical situation follow up

Variables demographics APACHE II SOFA (admission weekly x 2 starting antifungals) comorbid

diseases risk factors antifungal therapy and outcome

Adult patients admitted ICU ge 7 days SAC = Severe Abdominal Conditions

CAGTA = Candida albicans germ-tube antibody

1st 2nd 3rd 4th 3d

Intensive Care Med 2012 381315-25

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating between

Candida colonization and invasive candidiasis in patients with severe abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J Aacutelvarez L

Utande A Farintildeas O and the Study Group Cava II

- Patients with Candida colonization A model for IC prediction was obtained

using Classification And Regression Trees (CART)

- Variables used maximum values biomarkers before during development IC or highest value when IC did not

developed (Apache-II BG CAGTA)

- CART through a process of binary recursive spliting of the datasets based on rules of the form if-then-else identifies

a set of predictors of IC estimating the probabilities of IC according to the values of predictors

- The discriminate value of the probabilities of IC obtained by the CART was evaluated by the receiver characteristic

operating (ROC) curve

- Predictive rule identify patients have an IC risk when probability to develop

IC is ge 30(cut-off chosen by CART algorithm to minimize error measurement = deviance)

- Obtained rule estimated Sensitivity Specificity PPV NPV

- Data analysis carried out using R-package

CART prediction rule model

Breiman L et al (1984) Classfication and regression trees

Belmont CA Wadsworth International

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

n = 115 pts

IC = 31 (27 )

n = 27 pts

IC = 16 (599)

n = 88 pts

IC = 15 (170)

n = 49 pts

IC = 3 (61 )

n = 39 pts

IC = 12 (308 )

B-glucan ge 259 pgml

CAGTA positive B-glucan lt 329 pgml

B-glucan lt 259 pgml

CAGTA negative

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

Diagnostic accuracy of CART-derived prediction rule BG (cut-off

gt 259 pgmL) CAGTA (cutt-off positive) and CS for IC diagnosis

Area under

ROC curve

(95 CI)

Sensitivity

(95 CI)

Specificity

(95 CI)

Predictive value

Positive

(95 CI)

Negative

(95 CI)

CART analysis

078

(076-081)

903

(751-966)

547

(441-650)

424

(312-544)

939

(835-979)

BG

067

(059-074)

516

(348-680)

869

(780-925)

593

(407-755)

830

(738-894)

CAGTA

067

(063-070)

710

(534-839)

573

(465-675)

386

(271-516)

839

(722-913)

CS 062

(058-066)

935

(792-982)

181

(113-277)

299

(217-396)

882

(65-7-967)

CART classification and regression tree analysis BG beta-D-glucan CAGTA Candida albicans germ tube antibody Total number of patients with

Candida spp colonization = 115

Usefulness of the (13)--D-Glucan and Candida albicans germ tube antibody in the

Diagnosis of Invasive Candidiasis in Non-neutropenic Critically Ill Patients (non selected)

201112 One ICU (HUV) 105 NNCIP non selected gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida colonization

cultures (rectal swabs tracheal pharyngeal or gastric aspirates and urine) and serum

BG and CAGTA Were collected factors can interfere with the levels of BG (RRT AC

PT use of blood transfusions surgeryhellip)

NCNI

(n = 42)

Colonized

(n = 52)

Candidemia

(n = 6)

Peritonitis

(n =5)

P

value

Age years mean (range) 66 (50-73) 63 (54-76) 68 (62-78) 67 (62-70) 0820

Malefemale patients 3210 2527 42 50 0007

BG pgmL

Median (IQR)

Maximum (IQR)

44 (31-102)

77 (31-140)

40 (31-140)

150 (47-500)

72 ( 31-300)

194 (120-300)

31 (31-31)

50 (31-80)

0527

0037

CAGTA positives n () 13 (310) 26 (500) 3 (500) 1 (200) 0203

Instituto Salud Carlos III Madrid Spain (FIS PI 1002110) ICAAC 2013 (M-1380)

Conclusions

Patients with candidemia and Candida spp colonization showed significantly higher values

of serum BG than neither colonized or infected patients

NCNI neither colonized nor infected BG B-D- glucan IQR interquartile range (25th-75th percentile) CAGTA Candida albicans germ

tube antibodies Significant differences as compared with the NCNI group

CAVA FIS PROJECT

Prospective cohort observational multicenter study

201214 12 ICUs NNCIP selected (SAC) gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida

colonization cultures (rectal swabs tracheal pharyngeal urine) and serum (BG and

CAGTA)

Preliminary data (October 2013) 215 pts included 117 CC 26 IC AFT 94 (446)

Invasive Candidiasis in the critically ill patients Diagnostic utility of 1-3-Beta-D-

Glucan(BDG) anti-mycelium antibodies (CAGTA) mannanantimannan antibodies

(MAA) and detection of Candida DNA (PCR)rdquo CAVA TREM PROJECT

Candida DNA detection (PCR)

To evaluate CS performance ICU patients developing hospital-acquired severe sepsis or septic shock

Prospective multicenter (5 ICUs France) cohort study

n = 94 recruited (IC = 5 53 )

IC rates CS = 2 or 3 0 CS = 4 176 CS = 5 50 (p lt 00001)

CS gt 3 Benefit early SAT

Evaluation of ldquoCandida scorerdquo in critically ill patients a prospective multicenter

observational cohort study Leroy G Lamblotte F Thevenin D Lemaire C Parmentier E Devos P Leroy O

Ann Intens Care 2011150

bull To determine nordm patients w o documented IC received SAT

bull 1-day cross-sectional cohort study 169 ICUs France Belgium

bull n = 2047 recruited

bull n = 154 (75) with SAT (only 54 with IC)

bull Independent predictors SAT

ndash Center-related factors Hospital lt 800 beds (OR 29) organ transplant activity (OR26)

use fluoroquinolones (OR23) use SAT unresolved sepsis (OR19 22 20)

ndash Patient related factors Candida colonization (OR 124) severe sepsis and septic shock (OR47)

emergency surgery (OR 24) hematologic malignancies (OR71)

bull Trend greater impact SAT on survival when CS = 4 or 5

SAT Systemic Antifungal Treatment

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

Crit Care Med 201240813-22

Impact SAT on 28-d mortality according CS

Crit Care Med 201240813-22

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 6: Recordant L Àngels - academia.cat

Funguemia 1973-83 Anaacutelisis de 67 pacientes Sanchez Rodriguez C Leoacuten Regidor MA Capell Font S Peacuterez Campos A Planes Reig A Leoacuten Gil C

Med Clin (Barc) 198584549-53

bull Estudio observacional uniceacutentrico retrospectivo

bull 67 pacientes68 episodios

bull EB Patologiacutea GI 626 (4267)

bull FR CVC antibioterapia NPT cirugiacutea abdominal (68)

bull Cliacutenica indistinguible de una bacteriemia (9 casos SS)

bull Infecciones bacterianas asociadas 4967

bull Estratificacioacuten Funguemia TransitoriaDiseminada (4522)

bull TAF 28 pacientes tratados (9 con AFBD)

bull Mortalidad global 585 (3967) Relacionada 328 (2267)

1 Alta proporcioacuten de CRC

2 Concepto Candidemia RC es autolimitada y no requiere trato

3 Retraso de inicio de tratamiento antifuacutengico

Funguemia 1973-83 Estudio epidemioloacutegico Capell Font S Peacuterez Campos A Sanchez Rodriguez C Leoacuten Regidor MA Planes Reig A

Leoacuten Gil C Med Clin (Barc) 198584600-5

bull Estudio uniceacutentrico retrospectivo

bull 67 pacientes68 episodios

bull Funguemia nosocomial 1000 ingresos

bull UCI 175

bull Resto Servicios 03

bull UCI media 8 casos x antildeo

bull Aparicioacuten entre la 2 y 3ordm semana

Candidiasis y candidemia Reexamen de una problemaacutetica actual Saacutenchez Rodriacuteguez C Leoacuten Gil C Leoacuten Regidor MA Capell Font S Peacuterez Campos A

Med Clin (Barc) 198585464-71

bull Revisioacuten 121 referencias

bull Epidemiologia

bull Definicioacuten de teacuterminos

bull Poblacioacuten susceptible Etiologiacutea

bull Recursos cliacutenicos (I) EF lesiones cutaacuteneas miositis cateacuteteres y TF supurada endoftalmitis

bull Recursos cliacutenicos (II) Valoracioacuten focos metastaacutesicos miocarditispericarditis artritis y osteomielitis

encefalitismeningitis afeccioacuten pulmonar

bull Recursos analiacuteticos y microbioloacutegicos

bull Diagnostico seroloacutegico

bull A quien tratar

1 Candidemia Aumento nuacutemero de casosnuacutemero de pacientes con candidemia

2 Difiacutecil establecer diferencias entre la CT y CD

3 Durante los episodios de CT ldquopudierardquo haber un cierto grado de diseminacioacuten

4 Apuesta desarrollo de mejores meacutetodos diagnoacutesticosdiagnostico tempranoTAF

adecuado

Candidemia in non-neutropenic critically ill patients analysis of prognostic

factors and assessment of systemic antifungal therapy Nolla-Salas J Sitges-Serra A Leoacuten-Gil C Martiacutenez-Gonzaacutelez J Leoacuten-Regidor MA Ibantildeez-Luciacutea P

Torres-Rodriacuteguez PM and Study Group of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

bull Multicenter prospective observacional

bull 28 ICUs 15 months (Oct 1991-Dcber 1992)

bull 418 bed 22937 admissions

bull Candidemia 46 mean age 59 y

bull 1 episodio500 ICU admissions

bull Surgicalmedical 3016

bull Candida specie C albicans (60) parapsilosis (17)

bull TAF 43 FCNZ 27 AFBD 10 sequential therapy 6

bull Overal mortality 56 attributable 217

bull Apache II (time of diagnosis) and survival 20

bull Time of diagnosis start of AFT ldquoearlyrdquo laterdquo

The utility of serology in diagnosing candidosis in non-neutropenic

critically ill patients (1) Ibantildeez-Nolla J Torres-Rodriacuteguez JM Nolla M Leoacuten MA Meacutendez R Soria G Diacuteaz RM Marrugat J

Mycoses 20014447-53

bull Prospective cohort one UCI (HGC)

bull Sept 1988-Oct 1995 (8 y)

bull Inclusion all patients with at least one sample + Candida

bull Screening and optional samples

bull Cutaneous testophthalmologic evaluationpost morten study

bull Serology Antibodies (IHA IFA) antigens (Cand-TecPastorex)

The utility of serology in diagnosing candidosis in non-neutropenic

critically ill patients (2) Ibantildeez-Nolla J Torres-Rodriacuteguez JM Nolla M Leoacuten MA Meacutendez R Soria G Diacuteaz RM Marrugat J

Mycoses 20014447-53

Test Sensitiv Specif

Antibodies 37 78

Antigens 0 90

bull 3389 pts ICU LOS 6 days (1-112) mortality 10

bull 145 cases included (overall mortality 46)

bull 120 cases with multifocal colonization Candidemia 24 (18 pts) Endopht 2 cases

bull ATF Therapy 109 (75)

Significant relation between mortality and low levels of antibodies

Fungal colonization andor infection in non-neutropenic critically ill patients

results of the EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J Jordaacute R Saavedra P Palomar M and

EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

bull Prospective cohort observational multicenter study

bull Adult non-neutropenic pts 73 ICUs MS (70 hospitals)

bull 9 months (May 1998-January 1999)

bull Underlying diseases comorbidities reasons for ICU admission RF (presence and duration)

bull 7 days of ICU admission Once a week APACHE II Clinical situation microbiological

screening (TA pharyngeal exudates gastric aspirates and urine)

bull Antifungal treatment and outcome

bull 1765 patients age 579 y APACHE II ICU admission 18 5

bull Overall mortality 435 Intra ICU 338

bull No CI (785) Colonized (883) infected (97)

bull 18385 samples 13849 (surveillance) and 4536 (optional)

bull C albicans 721 (screening) and 697 (optional)

Economic Impact of Candida Colonization and Candida Infection in the

Critically Ill Patient Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor MA

and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

bull Prospective cohort observational multicenter study

bull 1765 adult non-neutropenic pts 73 ICUs mixed (70 hospitals)

bull 9 months (May 1998-January 1999)

bull 7 days of ICU admission Once a week APACHE II SOFA Clinical situation

and microbiological screening

bull No CI Colonized Infected Comorbidities and RF ATF therapy Outcome

Cost (2000)

ICU 1153 E

Hospit 406 E

Direct Cost (1 day)

- Candida colonization 8000

- Candida infection 16000

1

1

1

2

Courtesy by J Mensa

Score gt 25 Sensitivity 81

Specificity 74

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in

nonneutropenic critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro Saavedra Benito Almirante Juan Nolla-Salas

Francisco Aacutelvarez-Lerma Joseacute Garnacho-Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group

Crit Care Med 2006 34730-37

Score gt 25

1

1

1

2

probability of Candida infection

x 775

Courtesy byJ Mensa

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in

nonneutropenic critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro Saavedra Benito Almirante Juan Nolla-Salas

Francisco Aacutelvarez-Lerma Joseacute Garnacho-Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group

Crit Care Med 2006 34730-37

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

bull Prospective cohort observational multicenter study

bull Adult non-neutropenic pts 36 ICUs MS (32 hospitals)

bull 14 months (April 2006-June 2007)

bull Underlying diseases comorbidities reasons for ICU admission RF (presence and duration)

bull Antifungal treatment and outcome

bull 7 days of ICU admission Once a week APACHE II SOFA Clinical situation and microbiological

screening (5) TA pharyngeal exudatesgastric aspirates urine perirectal swab skin and optional

samples

bull1107 patients age 60 y ICU admission APACHE II 184 SOFA 7 (median)

bull No CI (215) Colonized (834) infected (58)

bull Overall mortality 305 Intra ICU 217

bull ATFT 49 (844) patients Time between ICU admission and administration of ATFT 173 days

bull 240 patients with Candida species colonization or IC (18) (1ndash3)-beta-D-glucan serum levels

Candida Score lt 3 = 3 gt 3

IC rate medical surgical

patients (n = 1107) 23 59

115

(51 - 178)

IC rate Abdominal Surgery

(n = 182) 23 125

303

(192 - 414)

Abdominal Surgery IC rates according CS

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash1633

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash33

Candiduria in critically ill patients admitted to intensive care medical units

Francisco Aacutelvarez-Lerma Juan Nolla-Salas Cristobal Leon Mercedes Palomar Ricard

Jorda Nieves Carrasco Felipe Bobillo (EPCAN Study Group)

Intensive Care Med 2003291069ndash76

bull 1765 adult non-neutropenic pts (lt 7 days) Candiduria 389 patients (22)

bull Age 61 y Apache II 19

bull Incidence density 95 episodes1000 days

bull Length of ICU stay since presence of candiduria 16 days

bull Risk factor associated age over 65 y female gender LOS in hospital

before ICU admission diabetes TPN MV previous use of antibiotics

(C no albicans)

bull C albicans 266 (684) C glabrata 32 (82) C tropicalis 14 (36)

bull Candiduria is a risk factor for ICUhospital mortality (OR 158)

Jordaacute Marcos R Alvarez-Lerma F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C

and EPCAN Study Group Mycoses 200750302-10

Risk factors for candidaemia in critically ill patients a prospective

surveillance study

bull 1765 adult non-neutropenic pts (lt 7 days) Candidemia 63 pts

bull Age 63 y Apache II 18 ICUhospital stay 2848 Surgical 29 (46) Medical 26 (413 )

bull ATF treatment 4863 (76)

- FCNZ 32 (667) AFBD 8 (16) LAFB 5 (104) AFBLC 3 (63)

bull ICUhospital Mortality 34 (54)-39 (73)

Assessment of candidemia-attributable mortality in critically ill patients using

propensity score matching analysis Francisco J Gonzaacutelez de Molina Cristoacutebal Leoacuten Sergio Ruiz-Santana and Pedro Saavedra for the

CAVA I Study Group

Crit Care 201216 R105

Critical Care 2012 16R105

bull The use of propensity score matching analysis to control for all potential confounding

variables allowed the assessment of candidemia-attributable mortality in critically ill

patients

bull Candidemia was not associated with an increase in either ICU or hospital

mortality

bull Earlier treatment of bloodstream infection and better monitoring (surveillance sampling

weekly) resulting in appropriate antifungal agent may contribute to increased survival

bull APACHE II at the time of diagnosis of candidemia was the only predictor of death in

patients with candidemia

bull 1107 pts 38 (34) candidemias Propensity score matching analysis

(Candidemia 70 no 35 yes)

Multicenter observational prospective

C Score biomarkers amp IC

18 ICUs n = 176 (SAC) 4 wks Study 2009-10

ICU gt 7 days

C Score BG CAGTA others Weekly (x 2) screening

Optional Samples related clinical situation follow up

Variables demographics APACHE II SOFA (admission weekly x 2 starting antifungals) comorbid

diseases risk factors antifungal therapy and outcome

Adult patients admitted ICU ge 7 days SAC = Severe Abdominal Conditions

CAGTA = Candida albicans germ-tube antibody

1st 2nd 3rd 4th 3d

Intensive Care Med 2012 381315-25

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating between

Candida colonization and invasive candidiasis in patients with severe abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J Aacutelvarez L

Utande A Farintildeas O and the Study Group Cava II

- Patients with Candida colonization A model for IC prediction was obtained

using Classification And Regression Trees (CART)

- Variables used maximum values biomarkers before during development IC or highest value when IC did not

developed (Apache-II BG CAGTA)

- CART through a process of binary recursive spliting of the datasets based on rules of the form if-then-else identifies

a set of predictors of IC estimating the probabilities of IC according to the values of predictors

- The discriminate value of the probabilities of IC obtained by the CART was evaluated by the receiver characteristic

operating (ROC) curve

- Predictive rule identify patients have an IC risk when probability to develop

IC is ge 30(cut-off chosen by CART algorithm to minimize error measurement = deviance)

- Obtained rule estimated Sensitivity Specificity PPV NPV

- Data analysis carried out using R-package

CART prediction rule model

Breiman L et al (1984) Classfication and regression trees

Belmont CA Wadsworth International

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

n = 115 pts

IC = 31 (27 )

n = 27 pts

IC = 16 (599)

n = 88 pts

IC = 15 (170)

n = 49 pts

IC = 3 (61 )

n = 39 pts

IC = 12 (308 )

B-glucan ge 259 pgml

CAGTA positive B-glucan lt 329 pgml

B-glucan lt 259 pgml

CAGTA negative

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

Diagnostic accuracy of CART-derived prediction rule BG (cut-off

gt 259 pgmL) CAGTA (cutt-off positive) and CS for IC diagnosis

Area under

ROC curve

(95 CI)

Sensitivity

(95 CI)

Specificity

(95 CI)

Predictive value

Positive

(95 CI)

Negative

(95 CI)

CART analysis

078

(076-081)

903

(751-966)

547

(441-650)

424

(312-544)

939

(835-979)

BG

067

(059-074)

516

(348-680)

869

(780-925)

593

(407-755)

830

(738-894)

CAGTA

067

(063-070)

710

(534-839)

573

(465-675)

386

(271-516)

839

(722-913)

CS 062

(058-066)

935

(792-982)

181

(113-277)

299

(217-396)

882

(65-7-967)

CART classification and regression tree analysis BG beta-D-glucan CAGTA Candida albicans germ tube antibody Total number of patients with

Candida spp colonization = 115

Usefulness of the (13)--D-Glucan and Candida albicans germ tube antibody in the

Diagnosis of Invasive Candidiasis in Non-neutropenic Critically Ill Patients (non selected)

201112 One ICU (HUV) 105 NNCIP non selected gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida colonization

cultures (rectal swabs tracheal pharyngeal or gastric aspirates and urine) and serum

BG and CAGTA Were collected factors can interfere with the levels of BG (RRT AC

PT use of blood transfusions surgeryhellip)

NCNI

(n = 42)

Colonized

(n = 52)

Candidemia

(n = 6)

Peritonitis

(n =5)

P

value

Age years mean (range) 66 (50-73) 63 (54-76) 68 (62-78) 67 (62-70) 0820

Malefemale patients 3210 2527 42 50 0007

BG pgmL

Median (IQR)

Maximum (IQR)

44 (31-102)

77 (31-140)

40 (31-140)

150 (47-500)

72 ( 31-300)

194 (120-300)

31 (31-31)

50 (31-80)

0527

0037

CAGTA positives n () 13 (310) 26 (500) 3 (500) 1 (200) 0203

Instituto Salud Carlos III Madrid Spain (FIS PI 1002110) ICAAC 2013 (M-1380)

Conclusions

Patients with candidemia and Candida spp colonization showed significantly higher values

of serum BG than neither colonized or infected patients

NCNI neither colonized nor infected BG B-D- glucan IQR interquartile range (25th-75th percentile) CAGTA Candida albicans germ

tube antibodies Significant differences as compared with the NCNI group

CAVA FIS PROJECT

Prospective cohort observational multicenter study

201214 12 ICUs NNCIP selected (SAC) gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida

colonization cultures (rectal swabs tracheal pharyngeal urine) and serum (BG and

CAGTA)

Preliminary data (October 2013) 215 pts included 117 CC 26 IC AFT 94 (446)

Invasive Candidiasis in the critically ill patients Diagnostic utility of 1-3-Beta-D-

Glucan(BDG) anti-mycelium antibodies (CAGTA) mannanantimannan antibodies

(MAA) and detection of Candida DNA (PCR)rdquo CAVA TREM PROJECT

Candida DNA detection (PCR)

To evaluate CS performance ICU patients developing hospital-acquired severe sepsis or septic shock

Prospective multicenter (5 ICUs France) cohort study

n = 94 recruited (IC = 5 53 )

IC rates CS = 2 or 3 0 CS = 4 176 CS = 5 50 (p lt 00001)

CS gt 3 Benefit early SAT

Evaluation of ldquoCandida scorerdquo in critically ill patients a prospective multicenter

observational cohort study Leroy G Lamblotte F Thevenin D Lemaire C Parmentier E Devos P Leroy O

Ann Intens Care 2011150

bull To determine nordm patients w o documented IC received SAT

bull 1-day cross-sectional cohort study 169 ICUs France Belgium

bull n = 2047 recruited

bull n = 154 (75) with SAT (only 54 with IC)

bull Independent predictors SAT

ndash Center-related factors Hospital lt 800 beds (OR 29) organ transplant activity (OR26)

use fluoroquinolones (OR23) use SAT unresolved sepsis (OR19 22 20)

ndash Patient related factors Candida colonization (OR 124) severe sepsis and septic shock (OR47)

emergency surgery (OR 24) hematologic malignancies (OR71)

bull Trend greater impact SAT on survival when CS = 4 or 5

SAT Systemic Antifungal Treatment

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

Crit Care Med 201240813-22

Impact SAT on 28-d mortality according CS

Crit Care Med 201240813-22

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 7: Recordant L Àngels - academia.cat

Funguemia 1973-83 Estudio epidemioloacutegico Capell Font S Peacuterez Campos A Sanchez Rodriguez C Leoacuten Regidor MA Planes Reig A

Leoacuten Gil C Med Clin (Barc) 198584600-5

bull Estudio uniceacutentrico retrospectivo

bull 67 pacientes68 episodios

bull Funguemia nosocomial 1000 ingresos

bull UCI 175

bull Resto Servicios 03

bull UCI media 8 casos x antildeo

bull Aparicioacuten entre la 2 y 3ordm semana

Candidiasis y candidemia Reexamen de una problemaacutetica actual Saacutenchez Rodriacuteguez C Leoacuten Gil C Leoacuten Regidor MA Capell Font S Peacuterez Campos A

Med Clin (Barc) 198585464-71

bull Revisioacuten 121 referencias

bull Epidemiologia

bull Definicioacuten de teacuterminos

bull Poblacioacuten susceptible Etiologiacutea

bull Recursos cliacutenicos (I) EF lesiones cutaacuteneas miositis cateacuteteres y TF supurada endoftalmitis

bull Recursos cliacutenicos (II) Valoracioacuten focos metastaacutesicos miocarditispericarditis artritis y osteomielitis

encefalitismeningitis afeccioacuten pulmonar

bull Recursos analiacuteticos y microbioloacutegicos

bull Diagnostico seroloacutegico

bull A quien tratar

1 Candidemia Aumento nuacutemero de casosnuacutemero de pacientes con candidemia

2 Difiacutecil establecer diferencias entre la CT y CD

3 Durante los episodios de CT ldquopudierardquo haber un cierto grado de diseminacioacuten

4 Apuesta desarrollo de mejores meacutetodos diagnoacutesticosdiagnostico tempranoTAF

adecuado

Candidemia in non-neutropenic critically ill patients analysis of prognostic

factors and assessment of systemic antifungal therapy Nolla-Salas J Sitges-Serra A Leoacuten-Gil C Martiacutenez-Gonzaacutelez J Leoacuten-Regidor MA Ibantildeez-Luciacutea P

Torres-Rodriacuteguez PM and Study Group of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

bull Multicenter prospective observacional

bull 28 ICUs 15 months (Oct 1991-Dcber 1992)

bull 418 bed 22937 admissions

bull Candidemia 46 mean age 59 y

bull 1 episodio500 ICU admissions

bull Surgicalmedical 3016

bull Candida specie C albicans (60) parapsilosis (17)

bull TAF 43 FCNZ 27 AFBD 10 sequential therapy 6

bull Overal mortality 56 attributable 217

bull Apache II (time of diagnosis) and survival 20

bull Time of diagnosis start of AFT ldquoearlyrdquo laterdquo

The utility of serology in diagnosing candidosis in non-neutropenic

critically ill patients (1) Ibantildeez-Nolla J Torres-Rodriacuteguez JM Nolla M Leoacuten MA Meacutendez R Soria G Diacuteaz RM Marrugat J

Mycoses 20014447-53

bull Prospective cohort one UCI (HGC)

bull Sept 1988-Oct 1995 (8 y)

bull Inclusion all patients with at least one sample + Candida

bull Screening and optional samples

bull Cutaneous testophthalmologic evaluationpost morten study

bull Serology Antibodies (IHA IFA) antigens (Cand-TecPastorex)

The utility of serology in diagnosing candidosis in non-neutropenic

critically ill patients (2) Ibantildeez-Nolla J Torres-Rodriacuteguez JM Nolla M Leoacuten MA Meacutendez R Soria G Diacuteaz RM Marrugat J

Mycoses 20014447-53

Test Sensitiv Specif

Antibodies 37 78

Antigens 0 90

bull 3389 pts ICU LOS 6 days (1-112) mortality 10

bull 145 cases included (overall mortality 46)

bull 120 cases with multifocal colonization Candidemia 24 (18 pts) Endopht 2 cases

bull ATF Therapy 109 (75)

Significant relation between mortality and low levels of antibodies

Fungal colonization andor infection in non-neutropenic critically ill patients

results of the EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J Jordaacute R Saavedra P Palomar M and

EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

bull Prospective cohort observational multicenter study

bull Adult non-neutropenic pts 73 ICUs MS (70 hospitals)

bull 9 months (May 1998-January 1999)

bull Underlying diseases comorbidities reasons for ICU admission RF (presence and duration)

bull 7 days of ICU admission Once a week APACHE II Clinical situation microbiological

screening (TA pharyngeal exudates gastric aspirates and urine)

bull Antifungal treatment and outcome

bull 1765 patients age 579 y APACHE II ICU admission 18 5

bull Overall mortality 435 Intra ICU 338

bull No CI (785) Colonized (883) infected (97)

bull 18385 samples 13849 (surveillance) and 4536 (optional)

bull C albicans 721 (screening) and 697 (optional)

Economic Impact of Candida Colonization and Candida Infection in the

Critically Ill Patient Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor MA

and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

bull Prospective cohort observational multicenter study

bull 1765 adult non-neutropenic pts 73 ICUs mixed (70 hospitals)

bull 9 months (May 1998-January 1999)

bull 7 days of ICU admission Once a week APACHE II SOFA Clinical situation

and microbiological screening

bull No CI Colonized Infected Comorbidities and RF ATF therapy Outcome

Cost (2000)

ICU 1153 E

Hospit 406 E

Direct Cost (1 day)

- Candida colonization 8000

- Candida infection 16000

1

1

1

2

Courtesy by J Mensa

Score gt 25 Sensitivity 81

Specificity 74

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in

nonneutropenic critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro Saavedra Benito Almirante Juan Nolla-Salas

Francisco Aacutelvarez-Lerma Joseacute Garnacho-Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group

Crit Care Med 2006 34730-37

Score gt 25

1

1

1

2

probability of Candida infection

x 775

Courtesy byJ Mensa

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in

nonneutropenic critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro Saavedra Benito Almirante Juan Nolla-Salas

Francisco Aacutelvarez-Lerma Joseacute Garnacho-Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group

Crit Care Med 2006 34730-37

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

bull Prospective cohort observational multicenter study

bull Adult non-neutropenic pts 36 ICUs MS (32 hospitals)

bull 14 months (April 2006-June 2007)

bull Underlying diseases comorbidities reasons for ICU admission RF (presence and duration)

bull Antifungal treatment and outcome

bull 7 days of ICU admission Once a week APACHE II SOFA Clinical situation and microbiological

screening (5) TA pharyngeal exudatesgastric aspirates urine perirectal swab skin and optional

samples

bull1107 patients age 60 y ICU admission APACHE II 184 SOFA 7 (median)

bull No CI (215) Colonized (834) infected (58)

bull Overall mortality 305 Intra ICU 217

bull ATFT 49 (844) patients Time between ICU admission and administration of ATFT 173 days

bull 240 patients with Candida species colonization or IC (18) (1ndash3)-beta-D-glucan serum levels

Candida Score lt 3 = 3 gt 3

IC rate medical surgical

patients (n = 1107) 23 59

115

(51 - 178)

IC rate Abdominal Surgery

(n = 182) 23 125

303

(192 - 414)

Abdominal Surgery IC rates according CS

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash1633

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash33

Candiduria in critically ill patients admitted to intensive care medical units

Francisco Aacutelvarez-Lerma Juan Nolla-Salas Cristobal Leon Mercedes Palomar Ricard

Jorda Nieves Carrasco Felipe Bobillo (EPCAN Study Group)

Intensive Care Med 2003291069ndash76

bull 1765 adult non-neutropenic pts (lt 7 days) Candiduria 389 patients (22)

bull Age 61 y Apache II 19

bull Incidence density 95 episodes1000 days

bull Length of ICU stay since presence of candiduria 16 days

bull Risk factor associated age over 65 y female gender LOS in hospital

before ICU admission diabetes TPN MV previous use of antibiotics

(C no albicans)

bull C albicans 266 (684) C glabrata 32 (82) C tropicalis 14 (36)

bull Candiduria is a risk factor for ICUhospital mortality (OR 158)

Jordaacute Marcos R Alvarez-Lerma F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C

and EPCAN Study Group Mycoses 200750302-10

Risk factors for candidaemia in critically ill patients a prospective

surveillance study

bull 1765 adult non-neutropenic pts (lt 7 days) Candidemia 63 pts

bull Age 63 y Apache II 18 ICUhospital stay 2848 Surgical 29 (46) Medical 26 (413 )

bull ATF treatment 4863 (76)

- FCNZ 32 (667) AFBD 8 (16) LAFB 5 (104) AFBLC 3 (63)

bull ICUhospital Mortality 34 (54)-39 (73)

Assessment of candidemia-attributable mortality in critically ill patients using

propensity score matching analysis Francisco J Gonzaacutelez de Molina Cristoacutebal Leoacuten Sergio Ruiz-Santana and Pedro Saavedra for the

CAVA I Study Group

Crit Care 201216 R105

Critical Care 2012 16R105

bull The use of propensity score matching analysis to control for all potential confounding

variables allowed the assessment of candidemia-attributable mortality in critically ill

patients

bull Candidemia was not associated with an increase in either ICU or hospital

mortality

bull Earlier treatment of bloodstream infection and better monitoring (surveillance sampling

weekly) resulting in appropriate antifungal agent may contribute to increased survival

bull APACHE II at the time of diagnosis of candidemia was the only predictor of death in

patients with candidemia

bull 1107 pts 38 (34) candidemias Propensity score matching analysis

(Candidemia 70 no 35 yes)

Multicenter observational prospective

C Score biomarkers amp IC

18 ICUs n = 176 (SAC) 4 wks Study 2009-10

ICU gt 7 days

C Score BG CAGTA others Weekly (x 2) screening

Optional Samples related clinical situation follow up

Variables demographics APACHE II SOFA (admission weekly x 2 starting antifungals) comorbid

diseases risk factors antifungal therapy and outcome

Adult patients admitted ICU ge 7 days SAC = Severe Abdominal Conditions

CAGTA = Candida albicans germ-tube antibody

1st 2nd 3rd 4th 3d

Intensive Care Med 2012 381315-25

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating between

Candida colonization and invasive candidiasis in patients with severe abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J Aacutelvarez L

Utande A Farintildeas O and the Study Group Cava II

- Patients with Candida colonization A model for IC prediction was obtained

using Classification And Regression Trees (CART)

- Variables used maximum values biomarkers before during development IC or highest value when IC did not

developed (Apache-II BG CAGTA)

- CART through a process of binary recursive spliting of the datasets based on rules of the form if-then-else identifies

a set of predictors of IC estimating the probabilities of IC according to the values of predictors

- The discriminate value of the probabilities of IC obtained by the CART was evaluated by the receiver characteristic

operating (ROC) curve

- Predictive rule identify patients have an IC risk when probability to develop

IC is ge 30(cut-off chosen by CART algorithm to minimize error measurement = deviance)

- Obtained rule estimated Sensitivity Specificity PPV NPV

- Data analysis carried out using R-package

CART prediction rule model

Breiman L et al (1984) Classfication and regression trees

Belmont CA Wadsworth International

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

n = 115 pts

IC = 31 (27 )

n = 27 pts

IC = 16 (599)

n = 88 pts

IC = 15 (170)

n = 49 pts

IC = 3 (61 )

n = 39 pts

IC = 12 (308 )

B-glucan ge 259 pgml

CAGTA positive B-glucan lt 329 pgml

B-glucan lt 259 pgml

CAGTA negative

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

Diagnostic accuracy of CART-derived prediction rule BG (cut-off

gt 259 pgmL) CAGTA (cutt-off positive) and CS for IC diagnosis

Area under

ROC curve

(95 CI)

Sensitivity

(95 CI)

Specificity

(95 CI)

Predictive value

Positive

(95 CI)

Negative

(95 CI)

CART analysis

078

(076-081)

903

(751-966)

547

(441-650)

424

(312-544)

939

(835-979)

BG

067

(059-074)

516

(348-680)

869

(780-925)

593

(407-755)

830

(738-894)

CAGTA

067

(063-070)

710

(534-839)

573

(465-675)

386

(271-516)

839

(722-913)

CS 062

(058-066)

935

(792-982)

181

(113-277)

299

(217-396)

882

(65-7-967)

CART classification and regression tree analysis BG beta-D-glucan CAGTA Candida albicans germ tube antibody Total number of patients with

Candida spp colonization = 115

Usefulness of the (13)--D-Glucan and Candida albicans germ tube antibody in the

Diagnosis of Invasive Candidiasis in Non-neutropenic Critically Ill Patients (non selected)

201112 One ICU (HUV) 105 NNCIP non selected gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida colonization

cultures (rectal swabs tracheal pharyngeal or gastric aspirates and urine) and serum

BG and CAGTA Were collected factors can interfere with the levels of BG (RRT AC

PT use of blood transfusions surgeryhellip)

NCNI

(n = 42)

Colonized

(n = 52)

Candidemia

(n = 6)

Peritonitis

(n =5)

P

value

Age years mean (range) 66 (50-73) 63 (54-76) 68 (62-78) 67 (62-70) 0820

Malefemale patients 3210 2527 42 50 0007

BG pgmL

Median (IQR)

Maximum (IQR)

44 (31-102)

77 (31-140)

40 (31-140)

150 (47-500)

72 ( 31-300)

194 (120-300)

31 (31-31)

50 (31-80)

0527

0037

CAGTA positives n () 13 (310) 26 (500) 3 (500) 1 (200) 0203

Instituto Salud Carlos III Madrid Spain (FIS PI 1002110) ICAAC 2013 (M-1380)

Conclusions

Patients with candidemia and Candida spp colonization showed significantly higher values

of serum BG than neither colonized or infected patients

NCNI neither colonized nor infected BG B-D- glucan IQR interquartile range (25th-75th percentile) CAGTA Candida albicans germ

tube antibodies Significant differences as compared with the NCNI group

CAVA FIS PROJECT

Prospective cohort observational multicenter study

201214 12 ICUs NNCIP selected (SAC) gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida

colonization cultures (rectal swabs tracheal pharyngeal urine) and serum (BG and

CAGTA)

Preliminary data (October 2013) 215 pts included 117 CC 26 IC AFT 94 (446)

Invasive Candidiasis in the critically ill patients Diagnostic utility of 1-3-Beta-D-

Glucan(BDG) anti-mycelium antibodies (CAGTA) mannanantimannan antibodies

(MAA) and detection of Candida DNA (PCR)rdquo CAVA TREM PROJECT

Candida DNA detection (PCR)

To evaluate CS performance ICU patients developing hospital-acquired severe sepsis or septic shock

Prospective multicenter (5 ICUs France) cohort study

n = 94 recruited (IC = 5 53 )

IC rates CS = 2 or 3 0 CS = 4 176 CS = 5 50 (p lt 00001)

CS gt 3 Benefit early SAT

Evaluation of ldquoCandida scorerdquo in critically ill patients a prospective multicenter

observational cohort study Leroy G Lamblotte F Thevenin D Lemaire C Parmentier E Devos P Leroy O

Ann Intens Care 2011150

bull To determine nordm patients w o documented IC received SAT

bull 1-day cross-sectional cohort study 169 ICUs France Belgium

bull n = 2047 recruited

bull n = 154 (75) with SAT (only 54 with IC)

bull Independent predictors SAT

ndash Center-related factors Hospital lt 800 beds (OR 29) organ transplant activity (OR26)

use fluoroquinolones (OR23) use SAT unresolved sepsis (OR19 22 20)

ndash Patient related factors Candida colonization (OR 124) severe sepsis and septic shock (OR47)

emergency surgery (OR 24) hematologic malignancies (OR71)

bull Trend greater impact SAT on survival when CS = 4 or 5

SAT Systemic Antifungal Treatment

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

Crit Care Med 201240813-22

Impact SAT on 28-d mortality according CS

Crit Care Med 201240813-22

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 8: Recordant L Àngels - academia.cat

Candidiasis y candidemia Reexamen de una problemaacutetica actual Saacutenchez Rodriacuteguez C Leoacuten Gil C Leoacuten Regidor MA Capell Font S Peacuterez Campos A

Med Clin (Barc) 198585464-71

bull Revisioacuten 121 referencias

bull Epidemiologia

bull Definicioacuten de teacuterminos

bull Poblacioacuten susceptible Etiologiacutea

bull Recursos cliacutenicos (I) EF lesiones cutaacuteneas miositis cateacuteteres y TF supurada endoftalmitis

bull Recursos cliacutenicos (II) Valoracioacuten focos metastaacutesicos miocarditispericarditis artritis y osteomielitis

encefalitismeningitis afeccioacuten pulmonar

bull Recursos analiacuteticos y microbioloacutegicos

bull Diagnostico seroloacutegico

bull A quien tratar

1 Candidemia Aumento nuacutemero de casosnuacutemero de pacientes con candidemia

2 Difiacutecil establecer diferencias entre la CT y CD

3 Durante los episodios de CT ldquopudierardquo haber un cierto grado de diseminacioacuten

4 Apuesta desarrollo de mejores meacutetodos diagnoacutesticosdiagnostico tempranoTAF

adecuado

Candidemia in non-neutropenic critically ill patients analysis of prognostic

factors and assessment of systemic antifungal therapy Nolla-Salas J Sitges-Serra A Leoacuten-Gil C Martiacutenez-Gonzaacutelez J Leoacuten-Regidor MA Ibantildeez-Luciacutea P

Torres-Rodriacuteguez PM and Study Group of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

bull Multicenter prospective observacional

bull 28 ICUs 15 months (Oct 1991-Dcber 1992)

bull 418 bed 22937 admissions

bull Candidemia 46 mean age 59 y

bull 1 episodio500 ICU admissions

bull Surgicalmedical 3016

bull Candida specie C albicans (60) parapsilosis (17)

bull TAF 43 FCNZ 27 AFBD 10 sequential therapy 6

bull Overal mortality 56 attributable 217

bull Apache II (time of diagnosis) and survival 20

bull Time of diagnosis start of AFT ldquoearlyrdquo laterdquo

The utility of serology in diagnosing candidosis in non-neutropenic

critically ill patients (1) Ibantildeez-Nolla J Torres-Rodriacuteguez JM Nolla M Leoacuten MA Meacutendez R Soria G Diacuteaz RM Marrugat J

Mycoses 20014447-53

bull Prospective cohort one UCI (HGC)

bull Sept 1988-Oct 1995 (8 y)

bull Inclusion all patients with at least one sample + Candida

bull Screening and optional samples

bull Cutaneous testophthalmologic evaluationpost morten study

bull Serology Antibodies (IHA IFA) antigens (Cand-TecPastorex)

The utility of serology in diagnosing candidosis in non-neutropenic

critically ill patients (2) Ibantildeez-Nolla J Torres-Rodriacuteguez JM Nolla M Leoacuten MA Meacutendez R Soria G Diacuteaz RM Marrugat J

Mycoses 20014447-53

Test Sensitiv Specif

Antibodies 37 78

Antigens 0 90

bull 3389 pts ICU LOS 6 days (1-112) mortality 10

bull 145 cases included (overall mortality 46)

bull 120 cases with multifocal colonization Candidemia 24 (18 pts) Endopht 2 cases

bull ATF Therapy 109 (75)

Significant relation between mortality and low levels of antibodies

Fungal colonization andor infection in non-neutropenic critically ill patients

results of the EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J Jordaacute R Saavedra P Palomar M and

EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

bull Prospective cohort observational multicenter study

bull Adult non-neutropenic pts 73 ICUs MS (70 hospitals)

bull 9 months (May 1998-January 1999)

bull Underlying diseases comorbidities reasons for ICU admission RF (presence and duration)

bull 7 days of ICU admission Once a week APACHE II Clinical situation microbiological

screening (TA pharyngeal exudates gastric aspirates and urine)

bull Antifungal treatment and outcome

bull 1765 patients age 579 y APACHE II ICU admission 18 5

bull Overall mortality 435 Intra ICU 338

bull No CI (785) Colonized (883) infected (97)

bull 18385 samples 13849 (surveillance) and 4536 (optional)

bull C albicans 721 (screening) and 697 (optional)

Economic Impact of Candida Colonization and Candida Infection in the

Critically Ill Patient Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor MA

and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

bull Prospective cohort observational multicenter study

bull 1765 adult non-neutropenic pts 73 ICUs mixed (70 hospitals)

bull 9 months (May 1998-January 1999)

bull 7 days of ICU admission Once a week APACHE II SOFA Clinical situation

and microbiological screening

bull No CI Colonized Infected Comorbidities and RF ATF therapy Outcome

Cost (2000)

ICU 1153 E

Hospit 406 E

Direct Cost (1 day)

- Candida colonization 8000

- Candida infection 16000

1

1

1

2

Courtesy by J Mensa

Score gt 25 Sensitivity 81

Specificity 74

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in

nonneutropenic critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro Saavedra Benito Almirante Juan Nolla-Salas

Francisco Aacutelvarez-Lerma Joseacute Garnacho-Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group

Crit Care Med 2006 34730-37

Score gt 25

1

1

1

2

probability of Candida infection

x 775

Courtesy byJ Mensa

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in

nonneutropenic critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro Saavedra Benito Almirante Juan Nolla-Salas

Francisco Aacutelvarez-Lerma Joseacute Garnacho-Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group

Crit Care Med 2006 34730-37

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

bull Prospective cohort observational multicenter study

bull Adult non-neutropenic pts 36 ICUs MS (32 hospitals)

bull 14 months (April 2006-June 2007)

bull Underlying diseases comorbidities reasons for ICU admission RF (presence and duration)

bull Antifungal treatment and outcome

bull 7 days of ICU admission Once a week APACHE II SOFA Clinical situation and microbiological

screening (5) TA pharyngeal exudatesgastric aspirates urine perirectal swab skin and optional

samples

bull1107 patients age 60 y ICU admission APACHE II 184 SOFA 7 (median)

bull No CI (215) Colonized (834) infected (58)

bull Overall mortality 305 Intra ICU 217

bull ATFT 49 (844) patients Time between ICU admission and administration of ATFT 173 days

bull 240 patients with Candida species colonization or IC (18) (1ndash3)-beta-D-glucan serum levels

Candida Score lt 3 = 3 gt 3

IC rate medical surgical

patients (n = 1107) 23 59

115

(51 - 178)

IC rate Abdominal Surgery

(n = 182) 23 125

303

(192 - 414)

Abdominal Surgery IC rates according CS

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash1633

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash33

Candiduria in critically ill patients admitted to intensive care medical units

Francisco Aacutelvarez-Lerma Juan Nolla-Salas Cristobal Leon Mercedes Palomar Ricard

Jorda Nieves Carrasco Felipe Bobillo (EPCAN Study Group)

Intensive Care Med 2003291069ndash76

bull 1765 adult non-neutropenic pts (lt 7 days) Candiduria 389 patients (22)

bull Age 61 y Apache II 19

bull Incidence density 95 episodes1000 days

bull Length of ICU stay since presence of candiduria 16 days

bull Risk factor associated age over 65 y female gender LOS in hospital

before ICU admission diabetes TPN MV previous use of antibiotics

(C no albicans)

bull C albicans 266 (684) C glabrata 32 (82) C tropicalis 14 (36)

bull Candiduria is a risk factor for ICUhospital mortality (OR 158)

Jordaacute Marcos R Alvarez-Lerma F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C

and EPCAN Study Group Mycoses 200750302-10

Risk factors for candidaemia in critically ill patients a prospective

surveillance study

bull 1765 adult non-neutropenic pts (lt 7 days) Candidemia 63 pts

bull Age 63 y Apache II 18 ICUhospital stay 2848 Surgical 29 (46) Medical 26 (413 )

bull ATF treatment 4863 (76)

- FCNZ 32 (667) AFBD 8 (16) LAFB 5 (104) AFBLC 3 (63)

bull ICUhospital Mortality 34 (54)-39 (73)

Assessment of candidemia-attributable mortality in critically ill patients using

propensity score matching analysis Francisco J Gonzaacutelez de Molina Cristoacutebal Leoacuten Sergio Ruiz-Santana and Pedro Saavedra for the

CAVA I Study Group

Crit Care 201216 R105

Critical Care 2012 16R105

bull The use of propensity score matching analysis to control for all potential confounding

variables allowed the assessment of candidemia-attributable mortality in critically ill

patients

bull Candidemia was not associated with an increase in either ICU or hospital

mortality

bull Earlier treatment of bloodstream infection and better monitoring (surveillance sampling

weekly) resulting in appropriate antifungal agent may contribute to increased survival

bull APACHE II at the time of diagnosis of candidemia was the only predictor of death in

patients with candidemia

bull 1107 pts 38 (34) candidemias Propensity score matching analysis

(Candidemia 70 no 35 yes)

Multicenter observational prospective

C Score biomarkers amp IC

18 ICUs n = 176 (SAC) 4 wks Study 2009-10

ICU gt 7 days

C Score BG CAGTA others Weekly (x 2) screening

Optional Samples related clinical situation follow up

Variables demographics APACHE II SOFA (admission weekly x 2 starting antifungals) comorbid

diseases risk factors antifungal therapy and outcome

Adult patients admitted ICU ge 7 days SAC = Severe Abdominal Conditions

CAGTA = Candida albicans germ-tube antibody

1st 2nd 3rd 4th 3d

Intensive Care Med 2012 381315-25

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating between

Candida colonization and invasive candidiasis in patients with severe abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J Aacutelvarez L

Utande A Farintildeas O and the Study Group Cava II

- Patients with Candida colonization A model for IC prediction was obtained

using Classification And Regression Trees (CART)

- Variables used maximum values biomarkers before during development IC or highest value when IC did not

developed (Apache-II BG CAGTA)

- CART through a process of binary recursive spliting of the datasets based on rules of the form if-then-else identifies

a set of predictors of IC estimating the probabilities of IC according to the values of predictors

- The discriminate value of the probabilities of IC obtained by the CART was evaluated by the receiver characteristic

operating (ROC) curve

- Predictive rule identify patients have an IC risk when probability to develop

IC is ge 30(cut-off chosen by CART algorithm to minimize error measurement = deviance)

- Obtained rule estimated Sensitivity Specificity PPV NPV

- Data analysis carried out using R-package

CART prediction rule model

Breiman L et al (1984) Classfication and regression trees

Belmont CA Wadsworth International

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

n = 115 pts

IC = 31 (27 )

n = 27 pts

IC = 16 (599)

n = 88 pts

IC = 15 (170)

n = 49 pts

IC = 3 (61 )

n = 39 pts

IC = 12 (308 )

B-glucan ge 259 pgml

CAGTA positive B-glucan lt 329 pgml

B-glucan lt 259 pgml

CAGTA negative

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

Diagnostic accuracy of CART-derived prediction rule BG (cut-off

gt 259 pgmL) CAGTA (cutt-off positive) and CS for IC diagnosis

Area under

ROC curve

(95 CI)

Sensitivity

(95 CI)

Specificity

(95 CI)

Predictive value

Positive

(95 CI)

Negative

(95 CI)

CART analysis

078

(076-081)

903

(751-966)

547

(441-650)

424

(312-544)

939

(835-979)

BG

067

(059-074)

516

(348-680)

869

(780-925)

593

(407-755)

830

(738-894)

CAGTA

067

(063-070)

710

(534-839)

573

(465-675)

386

(271-516)

839

(722-913)

CS 062

(058-066)

935

(792-982)

181

(113-277)

299

(217-396)

882

(65-7-967)

CART classification and regression tree analysis BG beta-D-glucan CAGTA Candida albicans germ tube antibody Total number of patients with

Candida spp colonization = 115

Usefulness of the (13)--D-Glucan and Candida albicans germ tube antibody in the

Diagnosis of Invasive Candidiasis in Non-neutropenic Critically Ill Patients (non selected)

201112 One ICU (HUV) 105 NNCIP non selected gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida colonization

cultures (rectal swabs tracheal pharyngeal or gastric aspirates and urine) and serum

BG and CAGTA Were collected factors can interfere with the levels of BG (RRT AC

PT use of blood transfusions surgeryhellip)

NCNI

(n = 42)

Colonized

(n = 52)

Candidemia

(n = 6)

Peritonitis

(n =5)

P

value

Age years mean (range) 66 (50-73) 63 (54-76) 68 (62-78) 67 (62-70) 0820

Malefemale patients 3210 2527 42 50 0007

BG pgmL

Median (IQR)

Maximum (IQR)

44 (31-102)

77 (31-140)

40 (31-140)

150 (47-500)

72 ( 31-300)

194 (120-300)

31 (31-31)

50 (31-80)

0527

0037

CAGTA positives n () 13 (310) 26 (500) 3 (500) 1 (200) 0203

Instituto Salud Carlos III Madrid Spain (FIS PI 1002110) ICAAC 2013 (M-1380)

Conclusions

Patients with candidemia and Candida spp colonization showed significantly higher values

of serum BG than neither colonized or infected patients

NCNI neither colonized nor infected BG B-D- glucan IQR interquartile range (25th-75th percentile) CAGTA Candida albicans germ

tube antibodies Significant differences as compared with the NCNI group

CAVA FIS PROJECT

Prospective cohort observational multicenter study

201214 12 ICUs NNCIP selected (SAC) gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida

colonization cultures (rectal swabs tracheal pharyngeal urine) and serum (BG and

CAGTA)

Preliminary data (October 2013) 215 pts included 117 CC 26 IC AFT 94 (446)

Invasive Candidiasis in the critically ill patients Diagnostic utility of 1-3-Beta-D-

Glucan(BDG) anti-mycelium antibodies (CAGTA) mannanantimannan antibodies

(MAA) and detection of Candida DNA (PCR)rdquo CAVA TREM PROJECT

Candida DNA detection (PCR)

To evaluate CS performance ICU patients developing hospital-acquired severe sepsis or septic shock

Prospective multicenter (5 ICUs France) cohort study

n = 94 recruited (IC = 5 53 )

IC rates CS = 2 or 3 0 CS = 4 176 CS = 5 50 (p lt 00001)

CS gt 3 Benefit early SAT

Evaluation of ldquoCandida scorerdquo in critically ill patients a prospective multicenter

observational cohort study Leroy G Lamblotte F Thevenin D Lemaire C Parmentier E Devos P Leroy O

Ann Intens Care 2011150

bull To determine nordm patients w o documented IC received SAT

bull 1-day cross-sectional cohort study 169 ICUs France Belgium

bull n = 2047 recruited

bull n = 154 (75) with SAT (only 54 with IC)

bull Independent predictors SAT

ndash Center-related factors Hospital lt 800 beds (OR 29) organ transplant activity (OR26)

use fluoroquinolones (OR23) use SAT unresolved sepsis (OR19 22 20)

ndash Patient related factors Candida colonization (OR 124) severe sepsis and septic shock (OR47)

emergency surgery (OR 24) hematologic malignancies (OR71)

bull Trend greater impact SAT on survival when CS = 4 or 5

SAT Systemic Antifungal Treatment

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

Crit Care Med 201240813-22

Impact SAT on 28-d mortality according CS

Crit Care Med 201240813-22

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 9: Recordant L Àngels - academia.cat

Candidemia in non-neutropenic critically ill patients analysis of prognostic

factors and assessment of systemic antifungal therapy Nolla-Salas J Sitges-Serra A Leoacuten-Gil C Martiacutenez-Gonzaacutelez J Leoacuten-Regidor MA Ibantildeez-Luciacutea P

Torres-Rodriacuteguez PM and Study Group of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

bull Multicenter prospective observacional

bull 28 ICUs 15 months (Oct 1991-Dcber 1992)

bull 418 bed 22937 admissions

bull Candidemia 46 mean age 59 y

bull 1 episodio500 ICU admissions

bull Surgicalmedical 3016

bull Candida specie C albicans (60) parapsilosis (17)

bull TAF 43 FCNZ 27 AFBD 10 sequential therapy 6

bull Overal mortality 56 attributable 217

bull Apache II (time of diagnosis) and survival 20

bull Time of diagnosis start of AFT ldquoearlyrdquo laterdquo

The utility of serology in diagnosing candidosis in non-neutropenic

critically ill patients (1) Ibantildeez-Nolla J Torres-Rodriacuteguez JM Nolla M Leoacuten MA Meacutendez R Soria G Diacuteaz RM Marrugat J

Mycoses 20014447-53

bull Prospective cohort one UCI (HGC)

bull Sept 1988-Oct 1995 (8 y)

bull Inclusion all patients with at least one sample + Candida

bull Screening and optional samples

bull Cutaneous testophthalmologic evaluationpost morten study

bull Serology Antibodies (IHA IFA) antigens (Cand-TecPastorex)

The utility of serology in diagnosing candidosis in non-neutropenic

critically ill patients (2) Ibantildeez-Nolla J Torres-Rodriacuteguez JM Nolla M Leoacuten MA Meacutendez R Soria G Diacuteaz RM Marrugat J

Mycoses 20014447-53

Test Sensitiv Specif

Antibodies 37 78

Antigens 0 90

bull 3389 pts ICU LOS 6 days (1-112) mortality 10

bull 145 cases included (overall mortality 46)

bull 120 cases with multifocal colonization Candidemia 24 (18 pts) Endopht 2 cases

bull ATF Therapy 109 (75)

Significant relation between mortality and low levels of antibodies

Fungal colonization andor infection in non-neutropenic critically ill patients

results of the EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J Jordaacute R Saavedra P Palomar M and

EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

bull Prospective cohort observational multicenter study

bull Adult non-neutropenic pts 73 ICUs MS (70 hospitals)

bull 9 months (May 1998-January 1999)

bull Underlying diseases comorbidities reasons for ICU admission RF (presence and duration)

bull 7 days of ICU admission Once a week APACHE II Clinical situation microbiological

screening (TA pharyngeal exudates gastric aspirates and urine)

bull Antifungal treatment and outcome

bull 1765 patients age 579 y APACHE II ICU admission 18 5

bull Overall mortality 435 Intra ICU 338

bull No CI (785) Colonized (883) infected (97)

bull 18385 samples 13849 (surveillance) and 4536 (optional)

bull C albicans 721 (screening) and 697 (optional)

Economic Impact of Candida Colonization and Candida Infection in the

Critically Ill Patient Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor MA

and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

bull Prospective cohort observational multicenter study

bull 1765 adult non-neutropenic pts 73 ICUs mixed (70 hospitals)

bull 9 months (May 1998-January 1999)

bull 7 days of ICU admission Once a week APACHE II SOFA Clinical situation

and microbiological screening

bull No CI Colonized Infected Comorbidities and RF ATF therapy Outcome

Cost (2000)

ICU 1153 E

Hospit 406 E

Direct Cost (1 day)

- Candida colonization 8000

- Candida infection 16000

1

1

1

2

Courtesy by J Mensa

Score gt 25 Sensitivity 81

Specificity 74

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in

nonneutropenic critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro Saavedra Benito Almirante Juan Nolla-Salas

Francisco Aacutelvarez-Lerma Joseacute Garnacho-Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group

Crit Care Med 2006 34730-37

Score gt 25

1

1

1

2

probability of Candida infection

x 775

Courtesy byJ Mensa

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in

nonneutropenic critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro Saavedra Benito Almirante Juan Nolla-Salas

Francisco Aacutelvarez-Lerma Joseacute Garnacho-Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group

Crit Care Med 2006 34730-37

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

bull Prospective cohort observational multicenter study

bull Adult non-neutropenic pts 36 ICUs MS (32 hospitals)

bull 14 months (April 2006-June 2007)

bull Underlying diseases comorbidities reasons for ICU admission RF (presence and duration)

bull Antifungal treatment and outcome

bull 7 days of ICU admission Once a week APACHE II SOFA Clinical situation and microbiological

screening (5) TA pharyngeal exudatesgastric aspirates urine perirectal swab skin and optional

samples

bull1107 patients age 60 y ICU admission APACHE II 184 SOFA 7 (median)

bull No CI (215) Colonized (834) infected (58)

bull Overall mortality 305 Intra ICU 217

bull ATFT 49 (844) patients Time between ICU admission and administration of ATFT 173 days

bull 240 patients with Candida species colonization or IC (18) (1ndash3)-beta-D-glucan serum levels

Candida Score lt 3 = 3 gt 3

IC rate medical surgical

patients (n = 1107) 23 59

115

(51 - 178)

IC rate Abdominal Surgery

(n = 182) 23 125

303

(192 - 414)

Abdominal Surgery IC rates according CS

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash1633

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash33

Candiduria in critically ill patients admitted to intensive care medical units

Francisco Aacutelvarez-Lerma Juan Nolla-Salas Cristobal Leon Mercedes Palomar Ricard

Jorda Nieves Carrasco Felipe Bobillo (EPCAN Study Group)

Intensive Care Med 2003291069ndash76

bull 1765 adult non-neutropenic pts (lt 7 days) Candiduria 389 patients (22)

bull Age 61 y Apache II 19

bull Incidence density 95 episodes1000 days

bull Length of ICU stay since presence of candiduria 16 days

bull Risk factor associated age over 65 y female gender LOS in hospital

before ICU admission diabetes TPN MV previous use of antibiotics

(C no albicans)

bull C albicans 266 (684) C glabrata 32 (82) C tropicalis 14 (36)

bull Candiduria is a risk factor for ICUhospital mortality (OR 158)

Jordaacute Marcos R Alvarez-Lerma F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C

and EPCAN Study Group Mycoses 200750302-10

Risk factors for candidaemia in critically ill patients a prospective

surveillance study

bull 1765 adult non-neutropenic pts (lt 7 days) Candidemia 63 pts

bull Age 63 y Apache II 18 ICUhospital stay 2848 Surgical 29 (46) Medical 26 (413 )

bull ATF treatment 4863 (76)

- FCNZ 32 (667) AFBD 8 (16) LAFB 5 (104) AFBLC 3 (63)

bull ICUhospital Mortality 34 (54)-39 (73)

Assessment of candidemia-attributable mortality in critically ill patients using

propensity score matching analysis Francisco J Gonzaacutelez de Molina Cristoacutebal Leoacuten Sergio Ruiz-Santana and Pedro Saavedra for the

CAVA I Study Group

Crit Care 201216 R105

Critical Care 2012 16R105

bull The use of propensity score matching analysis to control for all potential confounding

variables allowed the assessment of candidemia-attributable mortality in critically ill

patients

bull Candidemia was not associated with an increase in either ICU or hospital

mortality

bull Earlier treatment of bloodstream infection and better monitoring (surveillance sampling

weekly) resulting in appropriate antifungal agent may contribute to increased survival

bull APACHE II at the time of diagnosis of candidemia was the only predictor of death in

patients with candidemia

bull 1107 pts 38 (34) candidemias Propensity score matching analysis

(Candidemia 70 no 35 yes)

Multicenter observational prospective

C Score biomarkers amp IC

18 ICUs n = 176 (SAC) 4 wks Study 2009-10

ICU gt 7 days

C Score BG CAGTA others Weekly (x 2) screening

Optional Samples related clinical situation follow up

Variables demographics APACHE II SOFA (admission weekly x 2 starting antifungals) comorbid

diseases risk factors antifungal therapy and outcome

Adult patients admitted ICU ge 7 days SAC = Severe Abdominal Conditions

CAGTA = Candida albicans germ-tube antibody

1st 2nd 3rd 4th 3d

Intensive Care Med 2012 381315-25

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating between

Candida colonization and invasive candidiasis in patients with severe abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J Aacutelvarez L

Utande A Farintildeas O and the Study Group Cava II

- Patients with Candida colonization A model for IC prediction was obtained

using Classification And Regression Trees (CART)

- Variables used maximum values biomarkers before during development IC or highest value when IC did not

developed (Apache-II BG CAGTA)

- CART through a process of binary recursive spliting of the datasets based on rules of the form if-then-else identifies

a set of predictors of IC estimating the probabilities of IC according to the values of predictors

- The discriminate value of the probabilities of IC obtained by the CART was evaluated by the receiver characteristic

operating (ROC) curve

- Predictive rule identify patients have an IC risk when probability to develop

IC is ge 30(cut-off chosen by CART algorithm to minimize error measurement = deviance)

- Obtained rule estimated Sensitivity Specificity PPV NPV

- Data analysis carried out using R-package

CART prediction rule model

Breiman L et al (1984) Classfication and regression trees

Belmont CA Wadsworth International

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

n = 115 pts

IC = 31 (27 )

n = 27 pts

IC = 16 (599)

n = 88 pts

IC = 15 (170)

n = 49 pts

IC = 3 (61 )

n = 39 pts

IC = 12 (308 )

B-glucan ge 259 pgml

CAGTA positive B-glucan lt 329 pgml

B-glucan lt 259 pgml

CAGTA negative

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

Diagnostic accuracy of CART-derived prediction rule BG (cut-off

gt 259 pgmL) CAGTA (cutt-off positive) and CS for IC diagnosis

Area under

ROC curve

(95 CI)

Sensitivity

(95 CI)

Specificity

(95 CI)

Predictive value

Positive

(95 CI)

Negative

(95 CI)

CART analysis

078

(076-081)

903

(751-966)

547

(441-650)

424

(312-544)

939

(835-979)

BG

067

(059-074)

516

(348-680)

869

(780-925)

593

(407-755)

830

(738-894)

CAGTA

067

(063-070)

710

(534-839)

573

(465-675)

386

(271-516)

839

(722-913)

CS 062

(058-066)

935

(792-982)

181

(113-277)

299

(217-396)

882

(65-7-967)

CART classification and regression tree analysis BG beta-D-glucan CAGTA Candida albicans germ tube antibody Total number of patients with

Candida spp colonization = 115

Usefulness of the (13)--D-Glucan and Candida albicans germ tube antibody in the

Diagnosis of Invasive Candidiasis in Non-neutropenic Critically Ill Patients (non selected)

201112 One ICU (HUV) 105 NNCIP non selected gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida colonization

cultures (rectal swabs tracheal pharyngeal or gastric aspirates and urine) and serum

BG and CAGTA Were collected factors can interfere with the levels of BG (RRT AC

PT use of blood transfusions surgeryhellip)

NCNI

(n = 42)

Colonized

(n = 52)

Candidemia

(n = 6)

Peritonitis

(n =5)

P

value

Age years mean (range) 66 (50-73) 63 (54-76) 68 (62-78) 67 (62-70) 0820

Malefemale patients 3210 2527 42 50 0007

BG pgmL

Median (IQR)

Maximum (IQR)

44 (31-102)

77 (31-140)

40 (31-140)

150 (47-500)

72 ( 31-300)

194 (120-300)

31 (31-31)

50 (31-80)

0527

0037

CAGTA positives n () 13 (310) 26 (500) 3 (500) 1 (200) 0203

Instituto Salud Carlos III Madrid Spain (FIS PI 1002110) ICAAC 2013 (M-1380)

Conclusions

Patients with candidemia and Candida spp colonization showed significantly higher values

of serum BG than neither colonized or infected patients

NCNI neither colonized nor infected BG B-D- glucan IQR interquartile range (25th-75th percentile) CAGTA Candida albicans germ

tube antibodies Significant differences as compared with the NCNI group

CAVA FIS PROJECT

Prospective cohort observational multicenter study

201214 12 ICUs NNCIP selected (SAC) gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida

colonization cultures (rectal swabs tracheal pharyngeal urine) and serum (BG and

CAGTA)

Preliminary data (October 2013) 215 pts included 117 CC 26 IC AFT 94 (446)

Invasive Candidiasis in the critically ill patients Diagnostic utility of 1-3-Beta-D-

Glucan(BDG) anti-mycelium antibodies (CAGTA) mannanantimannan antibodies

(MAA) and detection of Candida DNA (PCR)rdquo CAVA TREM PROJECT

Candida DNA detection (PCR)

To evaluate CS performance ICU patients developing hospital-acquired severe sepsis or septic shock

Prospective multicenter (5 ICUs France) cohort study

n = 94 recruited (IC = 5 53 )

IC rates CS = 2 or 3 0 CS = 4 176 CS = 5 50 (p lt 00001)

CS gt 3 Benefit early SAT

Evaluation of ldquoCandida scorerdquo in critically ill patients a prospective multicenter

observational cohort study Leroy G Lamblotte F Thevenin D Lemaire C Parmentier E Devos P Leroy O

Ann Intens Care 2011150

bull To determine nordm patients w o documented IC received SAT

bull 1-day cross-sectional cohort study 169 ICUs France Belgium

bull n = 2047 recruited

bull n = 154 (75) with SAT (only 54 with IC)

bull Independent predictors SAT

ndash Center-related factors Hospital lt 800 beds (OR 29) organ transplant activity (OR26)

use fluoroquinolones (OR23) use SAT unresolved sepsis (OR19 22 20)

ndash Patient related factors Candida colonization (OR 124) severe sepsis and septic shock (OR47)

emergency surgery (OR 24) hematologic malignancies (OR71)

bull Trend greater impact SAT on survival when CS = 4 or 5

SAT Systemic Antifungal Treatment

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

Crit Care Med 201240813-22

Impact SAT on 28-d mortality according CS

Crit Care Med 201240813-22

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 10: Recordant L Àngels - academia.cat

The utility of serology in diagnosing candidosis in non-neutropenic

critically ill patients (1) Ibantildeez-Nolla J Torres-Rodriacuteguez JM Nolla M Leoacuten MA Meacutendez R Soria G Diacuteaz RM Marrugat J

Mycoses 20014447-53

bull Prospective cohort one UCI (HGC)

bull Sept 1988-Oct 1995 (8 y)

bull Inclusion all patients with at least one sample + Candida

bull Screening and optional samples

bull Cutaneous testophthalmologic evaluationpost morten study

bull Serology Antibodies (IHA IFA) antigens (Cand-TecPastorex)

The utility of serology in diagnosing candidosis in non-neutropenic

critically ill patients (2) Ibantildeez-Nolla J Torres-Rodriacuteguez JM Nolla M Leoacuten MA Meacutendez R Soria G Diacuteaz RM Marrugat J

Mycoses 20014447-53

Test Sensitiv Specif

Antibodies 37 78

Antigens 0 90

bull 3389 pts ICU LOS 6 days (1-112) mortality 10

bull 145 cases included (overall mortality 46)

bull 120 cases with multifocal colonization Candidemia 24 (18 pts) Endopht 2 cases

bull ATF Therapy 109 (75)

Significant relation between mortality and low levels of antibodies

Fungal colonization andor infection in non-neutropenic critically ill patients

results of the EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J Jordaacute R Saavedra P Palomar M and

EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

bull Prospective cohort observational multicenter study

bull Adult non-neutropenic pts 73 ICUs MS (70 hospitals)

bull 9 months (May 1998-January 1999)

bull Underlying diseases comorbidities reasons for ICU admission RF (presence and duration)

bull 7 days of ICU admission Once a week APACHE II Clinical situation microbiological

screening (TA pharyngeal exudates gastric aspirates and urine)

bull Antifungal treatment and outcome

bull 1765 patients age 579 y APACHE II ICU admission 18 5

bull Overall mortality 435 Intra ICU 338

bull No CI (785) Colonized (883) infected (97)

bull 18385 samples 13849 (surveillance) and 4536 (optional)

bull C albicans 721 (screening) and 697 (optional)

Economic Impact of Candida Colonization and Candida Infection in the

Critically Ill Patient Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor MA

and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

bull Prospective cohort observational multicenter study

bull 1765 adult non-neutropenic pts 73 ICUs mixed (70 hospitals)

bull 9 months (May 1998-January 1999)

bull 7 days of ICU admission Once a week APACHE II SOFA Clinical situation

and microbiological screening

bull No CI Colonized Infected Comorbidities and RF ATF therapy Outcome

Cost (2000)

ICU 1153 E

Hospit 406 E

Direct Cost (1 day)

- Candida colonization 8000

- Candida infection 16000

1

1

1

2

Courtesy by J Mensa

Score gt 25 Sensitivity 81

Specificity 74

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in

nonneutropenic critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro Saavedra Benito Almirante Juan Nolla-Salas

Francisco Aacutelvarez-Lerma Joseacute Garnacho-Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group

Crit Care Med 2006 34730-37

Score gt 25

1

1

1

2

probability of Candida infection

x 775

Courtesy byJ Mensa

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in

nonneutropenic critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro Saavedra Benito Almirante Juan Nolla-Salas

Francisco Aacutelvarez-Lerma Joseacute Garnacho-Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group

Crit Care Med 2006 34730-37

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

bull Prospective cohort observational multicenter study

bull Adult non-neutropenic pts 36 ICUs MS (32 hospitals)

bull 14 months (April 2006-June 2007)

bull Underlying diseases comorbidities reasons for ICU admission RF (presence and duration)

bull Antifungal treatment and outcome

bull 7 days of ICU admission Once a week APACHE II SOFA Clinical situation and microbiological

screening (5) TA pharyngeal exudatesgastric aspirates urine perirectal swab skin and optional

samples

bull1107 patients age 60 y ICU admission APACHE II 184 SOFA 7 (median)

bull No CI (215) Colonized (834) infected (58)

bull Overall mortality 305 Intra ICU 217

bull ATFT 49 (844) patients Time between ICU admission and administration of ATFT 173 days

bull 240 patients with Candida species colonization or IC (18) (1ndash3)-beta-D-glucan serum levels

Candida Score lt 3 = 3 gt 3

IC rate medical surgical

patients (n = 1107) 23 59

115

(51 - 178)

IC rate Abdominal Surgery

(n = 182) 23 125

303

(192 - 414)

Abdominal Surgery IC rates according CS

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash1633

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash33

Candiduria in critically ill patients admitted to intensive care medical units

Francisco Aacutelvarez-Lerma Juan Nolla-Salas Cristobal Leon Mercedes Palomar Ricard

Jorda Nieves Carrasco Felipe Bobillo (EPCAN Study Group)

Intensive Care Med 2003291069ndash76

bull 1765 adult non-neutropenic pts (lt 7 days) Candiduria 389 patients (22)

bull Age 61 y Apache II 19

bull Incidence density 95 episodes1000 days

bull Length of ICU stay since presence of candiduria 16 days

bull Risk factor associated age over 65 y female gender LOS in hospital

before ICU admission diabetes TPN MV previous use of antibiotics

(C no albicans)

bull C albicans 266 (684) C glabrata 32 (82) C tropicalis 14 (36)

bull Candiduria is a risk factor for ICUhospital mortality (OR 158)

Jordaacute Marcos R Alvarez-Lerma F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C

and EPCAN Study Group Mycoses 200750302-10

Risk factors for candidaemia in critically ill patients a prospective

surveillance study

bull 1765 adult non-neutropenic pts (lt 7 days) Candidemia 63 pts

bull Age 63 y Apache II 18 ICUhospital stay 2848 Surgical 29 (46) Medical 26 (413 )

bull ATF treatment 4863 (76)

- FCNZ 32 (667) AFBD 8 (16) LAFB 5 (104) AFBLC 3 (63)

bull ICUhospital Mortality 34 (54)-39 (73)

Assessment of candidemia-attributable mortality in critically ill patients using

propensity score matching analysis Francisco J Gonzaacutelez de Molina Cristoacutebal Leoacuten Sergio Ruiz-Santana and Pedro Saavedra for the

CAVA I Study Group

Crit Care 201216 R105

Critical Care 2012 16R105

bull The use of propensity score matching analysis to control for all potential confounding

variables allowed the assessment of candidemia-attributable mortality in critically ill

patients

bull Candidemia was not associated with an increase in either ICU or hospital

mortality

bull Earlier treatment of bloodstream infection and better monitoring (surveillance sampling

weekly) resulting in appropriate antifungal agent may contribute to increased survival

bull APACHE II at the time of diagnosis of candidemia was the only predictor of death in

patients with candidemia

bull 1107 pts 38 (34) candidemias Propensity score matching analysis

(Candidemia 70 no 35 yes)

Multicenter observational prospective

C Score biomarkers amp IC

18 ICUs n = 176 (SAC) 4 wks Study 2009-10

ICU gt 7 days

C Score BG CAGTA others Weekly (x 2) screening

Optional Samples related clinical situation follow up

Variables demographics APACHE II SOFA (admission weekly x 2 starting antifungals) comorbid

diseases risk factors antifungal therapy and outcome

Adult patients admitted ICU ge 7 days SAC = Severe Abdominal Conditions

CAGTA = Candida albicans germ-tube antibody

1st 2nd 3rd 4th 3d

Intensive Care Med 2012 381315-25

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating between

Candida colonization and invasive candidiasis in patients with severe abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J Aacutelvarez L

Utande A Farintildeas O and the Study Group Cava II

- Patients with Candida colonization A model for IC prediction was obtained

using Classification And Regression Trees (CART)

- Variables used maximum values biomarkers before during development IC or highest value when IC did not

developed (Apache-II BG CAGTA)

- CART through a process of binary recursive spliting of the datasets based on rules of the form if-then-else identifies

a set of predictors of IC estimating the probabilities of IC according to the values of predictors

- The discriminate value of the probabilities of IC obtained by the CART was evaluated by the receiver characteristic

operating (ROC) curve

- Predictive rule identify patients have an IC risk when probability to develop

IC is ge 30(cut-off chosen by CART algorithm to minimize error measurement = deviance)

- Obtained rule estimated Sensitivity Specificity PPV NPV

- Data analysis carried out using R-package

CART prediction rule model

Breiman L et al (1984) Classfication and regression trees

Belmont CA Wadsworth International

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

n = 115 pts

IC = 31 (27 )

n = 27 pts

IC = 16 (599)

n = 88 pts

IC = 15 (170)

n = 49 pts

IC = 3 (61 )

n = 39 pts

IC = 12 (308 )

B-glucan ge 259 pgml

CAGTA positive B-glucan lt 329 pgml

B-glucan lt 259 pgml

CAGTA negative

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

Diagnostic accuracy of CART-derived prediction rule BG (cut-off

gt 259 pgmL) CAGTA (cutt-off positive) and CS for IC diagnosis

Area under

ROC curve

(95 CI)

Sensitivity

(95 CI)

Specificity

(95 CI)

Predictive value

Positive

(95 CI)

Negative

(95 CI)

CART analysis

078

(076-081)

903

(751-966)

547

(441-650)

424

(312-544)

939

(835-979)

BG

067

(059-074)

516

(348-680)

869

(780-925)

593

(407-755)

830

(738-894)

CAGTA

067

(063-070)

710

(534-839)

573

(465-675)

386

(271-516)

839

(722-913)

CS 062

(058-066)

935

(792-982)

181

(113-277)

299

(217-396)

882

(65-7-967)

CART classification and regression tree analysis BG beta-D-glucan CAGTA Candida albicans germ tube antibody Total number of patients with

Candida spp colonization = 115

Usefulness of the (13)--D-Glucan and Candida albicans germ tube antibody in the

Diagnosis of Invasive Candidiasis in Non-neutropenic Critically Ill Patients (non selected)

201112 One ICU (HUV) 105 NNCIP non selected gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida colonization

cultures (rectal swabs tracheal pharyngeal or gastric aspirates and urine) and serum

BG and CAGTA Were collected factors can interfere with the levels of BG (RRT AC

PT use of blood transfusions surgeryhellip)

NCNI

(n = 42)

Colonized

(n = 52)

Candidemia

(n = 6)

Peritonitis

(n =5)

P

value

Age years mean (range) 66 (50-73) 63 (54-76) 68 (62-78) 67 (62-70) 0820

Malefemale patients 3210 2527 42 50 0007

BG pgmL

Median (IQR)

Maximum (IQR)

44 (31-102)

77 (31-140)

40 (31-140)

150 (47-500)

72 ( 31-300)

194 (120-300)

31 (31-31)

50 (31-80)

0527

0037

CAGTA positives n () 13 (310) 26 (500) 3 (500) 1 (200) 0203

Instituto Salud Carlos III Madrid Spain (FIS PI 1002110) ICAAC 2013 (M-1380)

Conclusions

Patients with candidemia and Candida spp colonization showed significantly higher values

of serum BG than neither colonized or infected patients

NCNI neither colonized nor infected BG B-D- glucan IQR interquartile range (25th-75th percentile) CAGTA Candida albicans germ

tube antibodies Significant differences as compared with the NCNI group

CAVA FIS PROJECT

Prospective cohort observational multicenter study

201214 12 ICUs NNCIP selected (SAC) gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida

colonization cultures (rectal swabs tracheal pharyngeal urine) and serum (BG and

CAGTA)

Preliminary data (October 2013) 215 pts included 117 CC 26 IC AFT 94 (446)

Invasive Candidiasis in the critically ill patients Diagnostic utility of 1-3-Beta-D-

Glucan(BDG) anti-mycelium antibodies (CAGTA) mannanantimannan antibodies

(MAA) and detection of Candida DNA (PCR)rdquo CAVA TREM PROJECT

Candida DNA detection (PCR)

To evaluate CS performance ICU patients developing hospital-acquired severe sepsis or septic shock

Prospective multicenter (5 ICUs France) cohort study

n = 94 recruited (IC = 5 53 )

IC rates CS = 2 or 3 0 CS = 4 176 CS = 5 50 (p lt 00001)

CS gt 3 Benefit early SAT

Evaluation of ldquoCandida scorerdquo in critically ill patients a prospective multicenter

observational cohort study Leroy G Lamblotte F Thevenin D Lemaire C Parmentier E Devos P Leroy O

Ann Intens Care 2011150

bull To determine nordm patients w o documented IC received SAT

bull 1-day cross-sectional cohort study 169 ICUs France Belgium

bull n = 2047 recruited

bull n = 154 (75) with SAT (only 54 with IC)

bull Independent predictors SAT

ndash Center-related factors Hospital lt 800 beds (OR 29) organ transplant activity (OR26)

use fluoroquinolones (OR23) use SAT unresolved sepsis (OR19 22 20)

ndash Patient related factors Candida colonization (OR 124) severe sepsis and septic shock (OR47)

emergency surgery (OR 24) hematologic malignancies (OR71)

bull Trend greater impact SAT on survival when CS = 4 or 5

SAT Systemic Antifungal Treatment

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

Crit Care Med 201240813-22

Impact SAT on 28-d mortality according CS

Crit Care Med 201240813-22

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 11: Recordant L Àngels - academia.cat

The utility of serology in diagnosing candidosis in non-neutropenic

critically ill patients (2) Ibantildeez-Nolla J Torres-Rodriacuteguez JM Nolla M Leoacuten MA Meacutendez R Soria G Diacuteaz RM Marrugat J

Mycoses 20014447-53

Test Sensitiv Specif

Antibodies 37 78

Antigens 0 90

bull 3389 pts ICU LOS 6 days (1-112) mortality 10

bull 145 cases included (overall mortality 46)

bull 120 cases with multifocal colonization Candidemia 24 (18 pts) Endopht 2 cases

bull ATF Therapy 109 (75)

Significant relation between mortality and low levels of antibodies

Fungal colonization andor infection in non-neutropenic critically ill patients

results of the EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J Jordaacute R Saavedra P Palomar M and

EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

bull Prospective cohort observational multicenter study

bull Adult non-neutropenic pts 73 ICUs MS (70 hospitals)

bull 9 months (May 1998-January 1999)

bull Underlying diseases comorbidities reasons for ICU admission RF (presence and duration)

bull 7 days of ICU admission Once a week APACHE II Clinical situation microbiological

screening (TA pharyngeal exudates gastric aspirates and urine)

bull Antifungal treatment and outcome

bull 1765 patients age 579 y APACHE II ICU admission 18 5

bull Overall mortality 435 Intra ICU 338

bull No CI (785) Colonized (883) infected (97)

bull 18385 samples 13849 (surveillance) and 4536 (optional)

bull C albicans 721 (screening) and 697 (optional)

Economic Impact of Candida Colonization and Candida Infection in the

Critically Ill Patient Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor MA

and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

bull Prospective cohort observational multicenter study

bull 1765 adult non-neutropenic pts 73 ICUs mixed (70 hospitals)

bull 9 months (May 1998-January 1999)

bull 7 days of ICU admission Once a week APACHE II SOFA Clinical situation

and microbiological screening

bull No CI Colonized Infected Comorbidities and RF ATF therapy Outcome

Cost (2000)

ICU 1153 E

Hospit 406 E

Direct Cost (1 day)

- Candida colonization 8000

- Candida infection 16000

1

1

1

2

Courtesy by J Mensa

Score gt 25 Sensitivity 81

Specificity 74

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in

nonneutropenic critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro Saavedra Benito Almirante Juan Nolla-Salas

Francisco Aacutelvarez-Lerma Joseacute Garnacho-Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group

Crit Care Med 2006 34730-37

Score gt 25

1

1

1

2

probability of Candida infection

x 775

Courtesy byJ Mensa

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in

nonneutropenic critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro Saavedra Benito Almirante Juan Nolla-Salas

Francisco Aacutelvarez-Lerma Joseacute Garnacho-Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group

Crit Care Med 2006 34730-37

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

bull Prospective cohort observational multicenter study

bull Adult non-neutropenic pts 36 ICUs MS (32 hospitals)

bull 14 months (April 2006-June 2007)

bull Underlying diseases comorbidities reasons for ICU admission RF (presence and duration)

bull Antifungal treatment and outcome

bull 7 days of ICU admission Once a week APACHE II SOFA Clinical situation and microbiological

screening (5) TA pharyngeal exudatesgastric aspirates urine perirectal swab skin and optional

samples

bull1107 patients age 60 y ICU admission APACHE II 184 SOFA 7 (median)

bull No CI (215) Colonized (834) infected (58)

bull Overall mortality 305 Intra ICU 217

bull ATFT 49 (844) patients Time between ICU admission and administration of ATFT 173 days

bull 240 patients with Candida species colonization or IC (18) (1ndash3)-beta-D-glucan serum levels

Candida Score lt 3 = 3 gt 3

IC rate medical surgical

patients (n = 1107) 23 59

115

(51 - 178)

IC rate Abdominal Surgery

(n = 182) 23 125

303

(192 - 414)

Abdominal Surgery IC rates according CS

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash1633

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash33

Candiduria in critically ill patients admitted to intensive care medical units

Francisco Aacutelvarez-Lerma Juan Nolla-Salas Cristobal Leon Mercedes Palomar Ricard

Jorda Nieves Carrasco Felipe Bobillo (EPCAN Study Group)

Intensive Care Med 2003291069ndash76

bull 1765 adult non-neutropenic pts (lt 7 days) Candiduria 389 patients (22)

bull Age 61 y Apache II 19

bull Incidence density 95 episodes1000 days

bull Length of ICU stay since presence of candiduria 16 days

bull Risk factor associated age over 65 y female gender LOS in hospital

before ICU admission diabetes TPN MV previous use of antibiotics

(C no albicans)

bull C albicans 266 (684) C glabrata 32 (82) C tropicalis 14 (36)

bull Candiduria is a risk factor for ICUhospital mortality (OR 158)

Jordaacute Marcos R Alvarez-Lerma F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C

and EPCAN Study Group Mycoses 200750302-10

Risk factors for candidaemia in critically ill patients a prospective

surveillance study

bull 1765 adult non-neutropenic pts (lt 7 days) Candidemia 63 pts

bull Age 63 y Apache II 18 ICUhospital stay 2848 Surgical 29 (46) Medical 26 (413 )

bull ATF treatment 4863 (76)

- FCNZ 32 (667) AFBD 8 (16) LAFB 5 (104) AFBLC 3 (63)

bull ICUhospital Mortality 34 (54)-39 (73)

Assessment of candidemia-attributable mortality in critically ill patients using

propensity score matching analysis Francisco J Gonzaacutelez de Molina Cristoacutebal Leoacuten Sergio Ruiz-Santana and Pedro Saavedra for the

CAVA I Study Group

Crit Care 201216 R105

Critical Care 2012 16R105

bull The use of propensity score matching analysis to control for all potential confounding

variables allowed the assessment of candidemia-attributable mortality in critically ill

patients

bull Candidemia was not associated with an increase in either ICU or hospital

mortality

bull Earlier treatment of bloodstream infection and better monitoring (surveillance sampling

weekly) resulting in appropriate antifungal agent may contribute to increased survival

bull APACHE II at the time of diagnosis of candidemia was the only predictor of death in

patients with candidemia

bull 1107 pts 38 (34) candidemias Propensity score matching analysis

(Candidemia 70 no 35 yes)

Multicenter observational prospective

C Score biomarkers amp IC

18 ICUs n = 176 (SAC) 4 wks Study 2009-10

ICU gt 7 days

C Score BG CAGTA others Weekly (x 2) screening

Optional Samples related clinical situation follow up

Variables demographics APACHE II SOFA (admission weekly x 2 starting antifungals) comorbid

diseases risk factors antifungal therapy and outcome

Adult patients admitted ICU ge 7 days SAC = Severe Abdominal Conditions

CAGTA = Candida albicans germ-tube antibody

1st 2nd 3rd 4th 3d

Intensive Care Med 2012 381315-25

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating between

Candida colonization and invasive candidiasis in patients with severe abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J Aacutelvarez L

Utande A Farintildeas O and the Study Group Cava II

- Patients with Candida colonization A model for IC prediction was obtained

using Classification And Regression Trees (CART)

- Variables used maximum values biomarkers before during development IC or highest value when IC did not

developed (Apache-II BG CAGTA)

- CART through a process of binary recursive spliting of the datasets based on rules of the form if-then-else identifies

a set of predictors of IC estimating the probabilities of IC according to the values of predictors

- The discriminate value of the probabilities of IC obtained by the CART was evaluated by the receiver characteristic

operating (ROC) curve

- Predictive rule identify patients have an IC risk when probability to develop

IC is ge 30(cut-off chosen by CART algorithm to minimize error measurement = deviance)

- Obtained rule estimated Sensitivity Specificity PPV NPV

- Data analysis carried out using R-package

CART prediction rule model

Breiman L et al (1984) Classfication and regression trees

Belmont CA Wadsworth International

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

n = 115 pts

IC = 31 (27 )

n = 27 pts

IC = 16 (599)

n = 88 pts

IC = 15 (170)

n = 49 pts

IC = 3 (61 )

n = 39 pts

IC = 12 (308 )

B-glucan ge 259 pgml

CAGTA positive B-glucan lt 329 pgml

B-glucan lt 259 pgml

CAGTA negative

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

Diagnostic accuracy of CART-derived prediction rule BG (cut-off

gt 259 pgmL) CAGTA (cutt-off positive) and CS for IC diagnosis

Area under

ROC curve

(95 CI)

Sensitivity

(95 CI)

Specificity

(95 CI)

Predictive value

Positive

(95 CI)

Negative

(95 CI)

CART analysis

078

(076-081)

903

(751-966)

547

(441-650)

424

(312-544)

939

(835-979)

BG

067

(059-074)

516

(348-680)

869

(780-925)

593

(407-755)

830

(738-894)

CAGTA

067

(063-070)

710

(534-839)

573

(465-675)

386

(271-516)

839

(722-913)

CS 062

(058-066)

935

(792-982)

181

(113-277)

299

(217-396)

882

(65-7-967)

CART classification and regression tree analysis BG beta-D-glucan CAGTA Candida albicans germ tube antibody Total number of patients with

Candida spp colonization = 115

Usefulness of the (13)--D-Glucan and Candida albicans germ tube antibody in the

Diagnosis of Invasive Candidiasis in Non-neutropenic Critically Ill Patients (non selected)

201112 One ICU (HUV) 105 NNCIP non selected gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida colonization

cultures (rectal swabs tracheal pharyngeal or gastric aspirates and urine) and serum

BG and CAGTA Were collected factors can interfere with the levels of BG (RRT AC

PT use of blood transfusions surgeryhellip)

NCNI

(n = 42)

Colonized

(n = 52)

Candidemia

(n = 6)

Peritonitis

(n =5)

P

value

Age years mean (range) 66 (50-73) 63 (54-76) 68 (62-78) 67 (62-70) 0820

Malefemale patients 3210 2527 42 50 0007

BG pgmL

Median (IQR)

Maximum (IQR)

44 (31-102)

77 (31-140)

40 (31-140)

150 (47-500)

72 ( 31-300)

194 (120-300)

31 (31-31)

50 (31-80)

0527

0037

CAGTA positives n () 13 (310) 26 (500) 3 (500) 1 (200) 0203

Instituto Salud Carlos III Madrid Spain (FIS PI 1002110) ICAAC 2013 (M-1380)

Conclusions

Patients with candidemia and Candida spp colonization showed significantly higher values

of serum BG than neither colonized or infected patients

NCNI neither colonized nor infected BG B-D- glucan IQR interquartile range (25th-75th percentile) CAGTA Candida albicans germ

tube antibodies Significant differences as compared with the NCNI group

CAVA FIS PROJECT

Prospective cohort observational multicenter study

201214 12 ICUs NNCIP selected (SAC) gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida

colonization cultures (rectal swabs tracheal pharyngeal urine) and serum (BG and

CAGTA)

Preliminary data (October 2013) 215 pts included 117 CC 26 IC AFT 94 (446)

Invasive Candidiasis in the critically ill patients Diagnostic utility of 1-3-Beta-D-

Glucan(BDG) anti-mycelium antibodies (CAGTA) mannanantimannan antibodies

(MAA) and detection of Candida DNA (PCR)rdquo CAVA TREM PROJECT

Candida DNA detection (PCR)

To evaluate CS performance ICU patients developing hospital-acquired severe sepsis or septic shock

Prospective multicenter (5 ICUs France) cohort study

n = 94 recruited (IC = 5 53 )

IC rates CS = 2 or 3 0 CS = 4 176 CS = 5 50 (p lt 00001)

CS gt 3 Benefit early SAT

Evaluation of ldquoCandida scorerdquo in critically ill patients a prospective multicenter

observational cohort study Leroy G Lamblotte F Thevenin D Lemaire C Parmentier E Devos P Leroy O

Ann Intens Care 2011150

bull To determine nordm patients w o documented IC received SAT

bull 1-day cross-sectional cohort study 169 ICUs France Belgium

bull n = 2047 recruited

bull n = 154 (75) with SAT (only 54 with IC)

bull Independent predictors SAT

ndash Center-related factors Hospital lt 800 beds (OR 29) organ transplant activity (OR26)

use fluoroquinolones (OR23) use SAT unresolved sepsis (OR19 22 20)

ndash Patient related factors Candida colonization (OR 124) severe sepsis and septic shock (OR47)

emergency surgery (OR 24) hematologic malignancies (OR71)

bull Trend greater impact SAT on survival when CS = 4 or 5

SAT Systemic Antifungal Treatment

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

Crit Care Med 201240813-22

Impact SAT on 28-d mortality according CS

Crit Care Med 201240813-22

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 12: Recordant L Àngels - academia.cat

Fungal colonization andor infection in non-neutropenic critically ill patients

results of the EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J Jordaacute R Saavedra P Palomar M and

EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

bull Prospective cohort observational multicenter study

bull Adult non-neutropenic pts 73 ICUs MS (70 hospitals)

bull 9 months (May 1998-January 1999)

bull Underlying diseases comorbidities reasons for ICU admission RF (presence and duration)

bull 7 days of ICU admission Once a week APACHE II Clinical situation microbiological

screening (TA pharyngeal exudates gastric aspirates and urine)

bull Antifungal treatment and outcome

bull 1765 patients age 579 y APACHE II ICU admission 18 5

bull Overall mortality 435 Intra ICU 338

bull No CI (785) Colonized (883) infected (97)

bull 18385 samples 13849 (surveillance) and 4536 (optional)

bull C albicans 721 (screening) and 697 (optional)

Economic Impact of Candida Colonization and Candida Infection in the

Critically Ill Patient Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor MA

and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

bull Prospective cohort observational multicenter study

bull 1765 adult non-neutropenic pts 73 ICUs mixed (70 hospitals)

bull 9 months (May 1998-January 1999)

bull 7 days of ICU admission Once a week APACHE II SOFA Clinical situation

and microbiological screening

bull No CI Colonized Infected Comorbidities and RF ATF therapy Outcome

Cost (2000)

ICU 1153 E

Hospit 406 E

Direct Cost (1 day)

- Candida colonization 8000

- Candida infection 16000

1

1

1

2

Courtesy by J Mensa

Score gt 25 Sensitivity 81

Specificity 74

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in

nonneutropenic critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro Saavedra Benito Almirante Juan Nolla-Salas

Francisco Aacutelvarez-Lerma Joseacute Garnacho-Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group

Crit Care Med 2006 34730-37

Score gt 25

1

1

1

2

probability of Candida infection

x 775

Courtesy byJ Mensa

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in

nonneutropenic critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro Saavedra Benito Almirante Juan Nolla-Salas

Francisco Aacutelvarez-Lerma Joseacute Garnacho-Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group

Crit Care Med 2006 34730-37

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

bull Prospective cohort observational multicenter study

bull Adult non-neutropenic pts 36 ICUs MS (32 hospitals)

bull 14 months (April 2006-June 2007)

bull Underlying diseases comorbidities reasons for ICU admission RF (presence and duration)

bull Antifungal treatment and outcome

bull 7 days of ICU admission Once a week APACHE II SOFA Clinical situation and microbiological

screening (5) TA pharyngeal exudatesgastric aspirates urine perirectal swab skin and optional

samples

bull1107 patients age 60 y ICU admission APACHE II 184 SOFA 7 (median)

bull No CI (215) Colonized (834) infected (58)

bull Overall mortality 305 Intra ICU 217

bull ATFT 49 (844) patients Time between ICU admission and administration of ATFT 173 days

bull 240 patients with Candida species colonization or IC (18) (1ndash3)-beta-D-glucan serum levels

Candida Score lt 3 = 3 gt 3

IC rate medical surgical

patients (n = 1107) 23 59

115

(51 - 178)

IC rate Abdominal Surgery

(n = 182) 23 125

303

(192 - 414)

Abdominal Surgery IC rates according CS

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash1633

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash33

Candiduria in critically ill patients admitted to intensive care medical units

Francisco Aacutelvarez-Lerma Juan Nolla-Salas Cristobal Leon Mercedes Palomar Ricard

Jorda Nieves Carrasco Felipe Bobillo (EPCAN Study Group)

Intensive Care Med 2003291069ndash76

bull 1765 adult non-neutropenic pts (lt 7 days) Candiduria 389 patients (22)

bull Age 61 y Apache II 19

bull Incidence density 95 episodes1000 days

bull Length of ICU stay since presence of candiduria 16 days

bull Risk factor associated age over 65 y female gender LOS in hospital

before ICU admission diabetes TPN MV previous use of antibiotics

(C no albicans)

bull C albicans 266 (684) C glabrata 32 (82) C tropicalis 14 (36)

bull Candiduria is a risk factor for ICUhospital mortality (OR 158)

Jordaacute Marcos R Alvarez-Lerma F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C

and EPCAN Study Group Mycoses 200750302-10

Risk factors for candidaemia in critically ill patients a prospective

surveillance study

bull 1765 adult non-neutropenic pts (lt 7 days) Candidemia 63 pts

bull Age 63 y Apache II 18 ICUhospital stay 2848 Surgical 29 (46) Medical 26 (413 )

bull ATF treatment 4863 (76)

- FCNZ 32 (667) AFBD 8 (16) LAFB 5 (104) AFBLC 3 (63)

bull ICUhospital Mortality 34 (54)-39 (73)

Assessment of candidemia-attributable mortality in critically ill patients using

propensity score matching analysis Francisco J Gonzaacutelez de Molina Cristoacutebal Leoacuten Sergio Ruiz-Santana and Pedro Saavedra for the

CAVA I Study Group

Crit Care 201216 R105

Critical Care 2012 16R105

bull The use of propensity score matching analysis to control for all potential confounding

variables allowed the assessment of candidemia-attributable mortality in critically ill

patients

bull Candidemia was not associated with an increase in either ICU or hospital

mortality

bull Earlier treatment of bloodstream infection and better monitoring (surveillance sampling

weekly) resulting in appropriate antifungal agent may contribute to increased survival

bull APACHE II at the time of diagnosis of candidemia was the only predictor of death in

patients with candidemia

bull 1107 pts 38 (34) candidemias Propensity score matching analysis

(Candidemia 70 no 35 yes)

Multicenter observational prospective

C Score biomarkers amp IC

18 ICUs n = 176 (SAC) 4 wks Study 2009-10

ICU gt 7 days

C Score BG CAGTA others Weekly (x 2) screening

Optional Samples related clinical situation follow up

Variables demographics APACHE II SOFA (admission weekly x 2 starting antifungals) comorbid

diseases risk factors antifungal therapy and outcome

Adult patients admitted ICU ge 7 days SAC = Severe Abdominal Conditions

CAGTA = Candida albicans germ-tube antibody

1st 2nd 3rd 4th 3d

Intensive Care Med 2012 381315-25

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating between

Candida colonization and invasive candidiasis in patients with severe abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J Aacutelvarez L

Utande A Farintildeas O and the Study Group Cava II

- Patients with Candida colonization A model for IC prediction was obtained

using Classification And Regression Trees (CART)

- Variables used maximum values biomarkers before during development IC or highest value when IC did not

developed (Apache-II BG CAGTA)

- CART through a process of binary recursive spliting of the datasets based on rules of the form if-then-else identifies

a set of predictors of IC estimating the probabilities of IC according to the values of predictors

- The discriminate value of the probabilities of IC obtained by the CART was evaluated by the receiver characteristic

operating (ROC) curve

- Predictive rule identify patients have an IC risk when probability to develop

IC is ge 30(cut-off chosen by CART algorithm to minimize error measurement = deviance)

- Obtained rule estimated Sensitivity Specificity PPV NPV

- Data analysis carried out using R-package

CART prediction rule model

Breiman L et al (1984) Classfication and regression trees

Belmont CA Wadsworth International

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

n = 115 pts

IC = 31 (27 )

n = 27 pts

IC = 16 (599)

n = 88 pts

IC = 15 (170)

n = 49 pts

IC = 3 (61 )

n = 39 pts

IC = 12 (308 )

B-glucan ge 259 pgml

CAGTA positive B-glucan lt 329 pgml

B-glucan lt 259 pgml

CAGTA negative

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

Diagnostic accuracy of CART-derived prediction rule BG (cut-off

gt 259 pgmL) CAGTA (cutt-off positive) and CS for IC diagnosis

Area under

ROC curve

(95 CI)

Sensitivity

(95 CI)

Specificity

(95 CI)

Predictive value

Positive

(95 CI)

Negative

(95 CI)

CART analysis

078

(076-081)

903

(751-966)

547

(441-650)

424

(312-544)

939

(835-979)

BG

067

(059-074)

516

(348-680)

869

(780-925)

593

(407-755)

830

(738-894)

CAGTA

067

(063-070)

710

(534-839)

573

(465-675)

386

(271-516)

839

(722-913)

CS 062

(058-066)

935

(792-982)

181

(113-277)

299

(217-396)

882

(65-7-967)

CART classification and regression tree analysis BG beta-D-glucan CAGTA Candida albicans germ tube antibody Total number of patients with

Candida spp colonization = 115

Usefulness of the (13)--D-Glucan and Candida albicans germ tube antibody in the

Diagnosis of Invasive Candidiasis in Non-neutropenic Critically Ill Patients (non selected)

201112 One ICU (HUV) 105 NNCIP non selected gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida colonization

cultures (rectal swabs tracheal pharyngeal or gastric aspirates and urine) and serum

BG and CAGTA Were collected factors can interfere with the levels of BG (RRT AC

PT use of blood transfusions surgeryhellip)

NCNI

(n = 42)

Colonized

(n = 52)

Candidemia

(n = 6)

Peritonitis

(n =5)

P

value

Age years mean (range) 66 (50-73) 63 (54-76) 68 (62-78) 67 (62-70) 0820

Malefemale patients 3210 2527 42 50 0007

BG pgmL

Median (IQR)

Maximum (IQR)

44 (31-102)

77 (31-140)

40 (31-140)

150 (47-500)

72 ( 31-300)

194 (120-300)

31 (31-31)

50 (31-80)

0527

0037

CAGTA positives n () 13 (310) 26 (500) 3 (500) 1 (200) 0203

Instituto Salud Carlos III Madrid Spain (FIS PI 1002110) ICAAC 2013 (M-1380)

Conclusions

Patients with candidemia and Candida spp colonization showed significantly higher values

of serum BG than neither colonized or infected patients

NCNI neither colonized nor infected BG B-D- glucan IQR interquartile range (25th-75th percentile) CAGTA Candida albicans germ

tube antibodies Significant differences as compared with the NCNI group

CAVA FIS PROJECT

Prospective cohort observational multicenter study

201214 12 ICUs NNCIP selected (SAC) gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida

colonization cultures (rectal swabs tracheal pharyngeal urine) and serum (BG and

CAGTA)

Preliminary data (October 2013) 215 pts included 117 CC 26 IC AFT 94 (446)

Invasive Candidiasis in the critically ill patients Diagnostic utility of 1-3-Beta-D-

Glucan(BDG) anti-mycelium antibodies (CAGTA) mannanantimannan antibodies

(MAA) and detection of Candida DNA (PCR)rdquo CAVA TREM PROJECT

Candida DNA detection (PCR)

To evaluate CS performance ICU patients developing hospital-acquired severe sepsis or septic shock

Prospective multicenter (5 ICUs France) cohort study

n = 94 recruited (IC = 5 53 )

IC rates CS = 2 or 3 0 CS = 4 176 CS = 5 50 (p lt 00001)

CS gt 3 Benefit early SAT

Evaluation of ldquoCandida scorerdquo in critically ill patients a prospective multicenter

observational cohort study Leroy G Lamblotte F Thevenin D Lemaire C Parmentier E Devos P Leroy O

Ann Intens Care 2011150

bull To determine nordm patients w o documented IC received SAT

bull 1-day cross-sectional cohort study 169 ICUs France Belgium

bull n = 2047 recruited

bull n = 154 (75) with SAT (only 54 with IC)

bull Independent predictors SAT

ndash Center-related factors Hospital lt 800 beds (OR 29) organ transplant activity (OR26)

use fluoroquinolones (OR23) use SAT unresolved sepsis (OR19 22 20)

ndash Patient related factors Candida colonization (OR 124) severe sepsis and septic shock (OR47)

emergency surgery (OR 24) hematologic malignancies (OR71)

bull Trend greater impact SAT on survival when CS = 4 or 5

SAT Systemic Antifungal Treatment

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

Crit Care Med 201240813-22

Impact SAT on 28-d mortality according CS

Crit Care Med 201240813-22

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 13: Recordant L Àngels - academia.cat

Economic Impact of Candida Colonization and Candida Infection in the

Critically Ill Patient Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor MA

and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

bull Prospective cohort observational multicenter study

bull 1765 adult non-neutropenic pts 73 ICUs mixed (70 hospitals)

bull 9 months (May 1998-January 1999)

bull 7 days of ICU admission Once a week APACHE II SOFA Clinical situation

and microbiological screening

bull No CI Colonized Infected Comorbidities and RF ATF therapy Outcome

Cost (2000)

ICU 1153 E

Hospit 406 E

Direct Cost (1 day)

- Candida colonization 8000

- Candida infection 16000

1

1

1

2

Courtesy by J Mensa

Score gt 25 Sensitivity 81

Specificity 74

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in

nonneutropenic critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro Saavedra Benito Almirante Juan Nolla-Salas

Francisco Aacutelvarez-Lerma Joseacute Garnacho-Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group

Crit Care Med 2006 34730-37

Score gt 25

1

1

1

2

probability of Candida infection

x 775

Courtesy byJ Mensa

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in

nonneutropenic critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro Saavedra Benito Almirante Juan Nolla-Salas

Francisco Aacutelvarez-Lerma Joseacute Garnacho-Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group

Crit Care Med 2006 34730-37

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

bull Prospective cohort observational multicenter study

bull Adult non-neutropenic pts 36 ICUs MS (32 hospitals)

bull 14 months (April 2006-June 2007)

bull Underlying diseases comorbidities reasons for ICU admission RF (presence and duration)

bull Antifungal treatment and outcome

bull 7 days of ICU admission Once a week APACHE II SOFA Clinical situation and microbiological

screening (5) TA pharyngeal exudatesgastric aspirates urine perirectal swab skin and optional

samples

bull1107 patients age 60 y ICU admission APACHE II 184 SOFA 7 (median)

bull No CI (215) Colonized (834) infected (58)

bull Overall mortality 305 Intra ICU 217

bull ATFT 49 (844) patients Time between ICU admission and administration of ATFT 173 days

bull 240 patients with Candida species colonization or IC (18) (1ndash3)-beta-D-glucan serum levels

Candida Score lt 3 = 3 gt 3

IC rate medical surgical

patients (n = 1107) 23 59

115

(51 - 178)

IC rate Abdominal Surgery

(n = 182) 23 125

303

(192 - 414)

Abdominal Surgery IC rates according CS

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash1633

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash33

Candiduria in critically ill patients admitted to intensive care medical units

Francisco Aacutelvarez-Lerma Juan Nolla-Salas Cristobal Leon Mercedes Palomar Ricard

Jorda Nieves Carrasco Felipe Bobillo (EPCAN Study Group)

Intensive Care Med 2003291069ndash76

bull 1765 adult non-neutropenic pts (lt 7 days) Candiduria 389 patients (22)

bull Age 61 y Apache II 19

bull Incidence density 95 episodes1000 days

bull Length of ICU stay since presence of candiduria 16 days

bull Risk factor associated age over 65 y female gender LOS in hospital

before ICU admission diabetes TPN MV previous use of antibiotics

(C no albicans)

bull C albicans 266 (684) C glabrata 32 (82) C tropicalis 14 (36)

bull Candiduria is a risk factor for ICUhospital mortality (OR 158)

Jordaacute Marcos R Alvarez-Lerma F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C

and EPCAN Study Group Mycoses 200750302-10

Risk factors for candidaemia in critically ill patients a prospective

surveillance study

bull 1765 adult non-neutropenic pts (lt 7 days) Candidemia 63 pts

bull Age 63 y Apache II 18 ICUhospital stay 2848 Surgical 29 (46) Medical 26 (413 )

bull ATF treatment 4863 (76)

- FCNZ 32 (667) AFBD 8 (16) LAFB 5 (104) AFBLC 3 (63)

bull ICUhospital Mortality 34 (54)-39 (73)

Assessment of candidemia-attributable mortality in critically ill patients using

propensity score matching analysis Francisco J Gonzaacutelez de Molina Cristoacutebal Leoacuten Sergio Ruiz-Santana and Pedro Saavedra for the

CAVA I Study Group

Crit Care 201216 R105

Critical Care 2012 16R105

bull The use of propensity score matching analysis to control for all potential confounding

variables allowed the assessment of candidemia-attributable mortality in critically ill

patients

bull Candidemia was not associated with an increase in either ICU or hospital

mortality

bull Earlier treatment of bloodstream infection and better monitoring (surveillance sampling

weekly) resulting in appropriate antifungal agent may contribute to increased survival

bull APACHE II at the time of diagnosis of candidemia was the only predictor of death in

patients with candidemia

bull 1107 pts 38 (34) candidemias Propensity score matching analysis

(Candidemia 70 no 35 yes)

Multicenter observational prospective

C Score biomarkers amp IC

18 ICUs n = 176 (SAC) 4 wks Study 2009-10

ICU gt 7 days

C Score BG CAGTA others Weekly (x 2) screening

Optional Samples related clinical situation follow up

Variables demographics APACHE II SOFA (admission weekly x 2 starting antifungals) comorbid

diseases risk factors antifungal therapy and outcome

Adult patients admitted ICU ge 7 days SAC = Severe Abdominal Conditions

CAGTA = Candida albicans germ-tube antibody

1st 2nd 3rd 4th 3d

Intensive Care Med 2012 381315-25

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating between

Candida colonization and invasive candidiasis in patients with severe abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J Aacutelvarez L

Utande A Farintildeas O and the Study Group Cava II

- Patients with Candida colonization A model for IC prediction was obtained

using Classification And Regression Trees (CART)

- Variables used maximum values biomarkers before during development IC or highest value when IC did not

developed (Apache-II BG CAGTA)

- CART through a process of binary recursive spliting of the datasets based on rules of the form if-then-else identifies

a set of predictors of IC estimating the probabilities of IC according to the values of predictors

- The discriminate value of the probabilities of IC obtained by the CART was evaluated by the receiver characteristic

operating (ROC) curve

- Predictive rule identify patients have an IC risk when probability to develop

IC is ge 30(cut-off chosen by CART algorithm to minimize error measurement = deviance)

- Obtained rule estimated Sensitivity Specificity PPV NPV

- Data analysis carried out using R-package

CART prediction rule model

Breiman L et al (1984) Classfication and regression trees

Belmont CA Wadsworth International

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

n = 115 pts

IC = 31 (27 )

n = 27 pts

IC = 16 (599)

n = 88 pts

IC = 15 (170)

n = 49 pts

IC = 3 (61 )

n = 39 pts

IC = 12 (308 )

B-glucan ge 259 pgml

CAGTA positive B-glucan lt 329 pgml

B-glucan lt 259 pgml

CAGTA negative

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

Diagnostic accuracy of CART-derived prediction rule BG (cut-off

gt 259 pgmL) CAGTA (cutt-off positive) and CS for IC diagnosis

Area under

ROC curve

(95 CI)

Sensitivity

(95 CI)

Specificity

(95 CI)

Predictive value

Positive

(95 CI)

Negative

(95 CI)

CART analysis

078

(076-081)

903

(751-966)

547

(441-650)

424

(312-544)

939

(835-979)

BG

067

(059-074)

516

(348-680)

869

(780-925)

593

(407-755)

830

(738-894)

CAGTA

067

(063-070)

710

(534-839)

573

(465-675)

386

(271-516)

839

(722-913)

CS 062

(058-066)

935

(792-982)

181

(113-277)

299

(217-396)

882

(65-7-967)

CART classification and regression tree analysis BG beta-D-glucan CAGTA Candida albicans germ tube antibody Total number of patients with

Candida spp colonization = 115

Usefulness of the (13)--D-Glucan and Candida albicans germ tube antibody in the

Diagnosis of Invasive Candidiasis in Non-neutropenic Critically Ill Patients (non selected)

201112 One ICU (HUV) 105 NNCIP non selected gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida colonization

cultures (rectal swabs tracheal pharyngeal or gastric aspirates and urine) and serum

BG and CAGTA Were collected factors can interfere with the levels of BG (RRT AC

PT use of blood transfusions surgeryhellip)

NCNI

(n = 42)

Colonized

(n = 52)

Candidemia

(n = 6)

Peritonitis

(n =5)

P

value

Age years mean (range) 66 (50-73) 63 (54-76) 68 (62-78) 67 (62-70) 0820

Malefemale patients 3210 2527 42 50 0007

BG pgmL

Median (IQR)

Maximum (IQR)

44 (31-102)

77 (31-140)

40 (31-140)

150 (47-500)

72 ( 31-300)

194 (120-300)

31 (31-31)

50 (31-80)

0527

0037

CAGTA positives n () 13 (310) 26 (500) 3 (500) 1 (200) 0203

Instituto Salud Carlos III Madrid Spain (FIS PI 1002110) ICAAC 2013 (M-1380)

Conclusions

Patients with candidemia and Candida spp colonization showed significantly higher values

of serum BG than neither colonized or infected patients

NCNI neither colonized nor infected BG B-D- glucan IQR interquartile range (25th-75th percentile) CAGTA Candida albicans germ

tube antibodies Significant differences as compared with the NCNI group

CAVA FIS PROJECT

Prospective cohort observational multicenter study

201214 12 ICUs NNCIP selected (SAC) gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida

colonization cultures (rectal swabs tracheal pharyngeal urine) and serum (BG and

CAGTA)

Preliminary data (October 2013) 215 pts included 117 CC 26 IC AFT 94 (446)

Invasive Candidiasis in the critically ill patients Diagnostic utility of 1-3-Beta-D-

Glucan(BDG) anti-mycelium antibodies (CAGTA) mannanantimannan antibodies

(MAA) and detection of Candida DNA (PCR)rdquo CAVA TREM PROJECT

Candida DNA detection (PCR)

To evaluate CS performance ICU patients developing hospital-acquired severe sepsis or septic shock

Prospective multicenter (5 ICUs France) cohort study

n = 94 recruited (IC = 5 53 )

IC rates CS = 2 or 3 0 CS = 4 176 CS = 5 50 (p lt 00001)

CS gt 3 Benefit early SAT

Evaluation of ldquoCandida scorerdquo in critically ill patients a prospective multicenter

observational cohort study Leroy G Lamblotte F Thevenin D Lemaire C Parmentier E Devos P Leroy O

Ann Intens Care 2011150

bull To determine nordm patients w o documented IC received SAT

bull 1-day cross-sectional cohort study 169 ICUs France Belgium

bull n = 2047 recruited

bull n = 154 (75) with SAT (only 54 with IC)

bull Independent predictors SAT

ndash Center-related factors Hospital lt 800 beds (OR 29) organ transplant activity (OR26)

use fluoroquinolones (OR23) use SAT unresolved sepsis (OR19 22 20)

ndash Patient related factors Candida colonization (OR 124) severe sepsis and septic shock (OR47)

emergency surgery (OR 24) hematologic malignancies (OR71)

bull Trend greater impact SAT on survival when CS = 4 or 5

SAT Systemic Antifungal Treatment

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

Crit Care Med 201240813-22

Impact SAT on 28-d mortality according CS

Crit Care Med 201240813-22

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 14: Recordant L Àngels - academia.cat

1

1

1

2

Courtesy by J Mensa

Score gt 25 Sensitivity 81

Specificity 74

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in

nonneutropenic critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro Saavedra Benito Almirante Juan Nolla-Salas

Francisco Aacutelvarez-Lerma Joseacute Garnacho-Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group

Crit Care Med 2006 34730-37

Score gt 25

1

1

1

2

probability of Candida infection

x 775

Courtesy byJ Mensa

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in

nonneutropenic critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro Saavedra Benito Almirante Juan Nolla-Salas

Francisco Aacutelvarez-Lerma Joseacute Garnacho-Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group

Crit Care Med 2006 34730-37

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

bull Prospective cohort observational multicenter study

bull Adult non-neutropenic pts 36 ICUs MS (32 hospitals)

bull 14 months (April 2006-June 2007)

bull Underlying diseases comorbidities reasons for ICU admission RF (presence and duration)

bull Antifungal treatment and outcome

bull 7 days of ICU admission Once a week APACHE II SOFA Clinical situation and microbiological

screening (5) TA pharyngeal exudatesgastric aspirates urine perirectal swab skin and optional

samples

bull1107 patients age 60 y ICU admission APACHE II 184 SOFA 7 (median)

bull No CI (215) Colonized (834) infected (58)

bull Overall mortality 305 Intra ICU 217

bull ATFT 49 (844) patients Time between ICU admission and administration of ATFT 173 days

bull 240 patients with Candida species colonization or IC (18) (1ndash3)-beta-D-glucan serum levels

Candida Score lt 3 = 3 gt 3

IC rate medical surgical

patients (n = 1107) 23 59

115

(51 - 178)

IC rate Abdominal Surgery

(n = 182) 23 125

303

(192 - 414)

Abdominal Surgery IC rates according CS

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash1633

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash33

Candiduria in critically ill patients admitted to intensive care medical units

Francisco Aacutelvarez-Lerma Juan Nolla-Salas Cristobal Leon Mercedes Palomar Ricard

Jorda Nieves Carrasco Felipe Bobillo (EPCAN Study Group)

Intensive Care Med 2003291069ndash76

bull 1765 adult non-neutropenic pts (lt 7 days) Candiduria 389 patients (22)

bull Age 61 y Apache II 19

bull Incidence density 95 episodes1000 days

bull Length of ICU stay since presence of candiduria 16 days

bull Risk factor associated age over 65 y female gender LOS in hospital

before ICU admission diabetes TPN MV previous use of antibiotics

(C no albicans)

bull C albicans 266 (684) C glabrata 32 (82) C tropicalis 14 (36)

bull Candiduria is a risk factor for ICUhospital mortality (OR 158)

Jordaacute Marcos R Alvarez-Lerma F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C

and EPCAN Study Group Mycoses 200750302-10

Risk factors for candidaemia in critically ill patients a prospective

surveillance study

bull 1765 adult non-neutropenic pts (lt 7 days) Candidemia 63 pts

bull Age 63 y Apache II 18 ICUhospital stay 2848 Surgical 29 (46) Medical 26 (413 )

bull ATF treatment 4863 (76)

- FCNZ 32 (667) AFBD 8 (16) LAFB 5 (104) AFBLC 3 (63)

bull ICUhospital Mortality 34 (54)-39 (73)

Assessment of candidemia-attributable mortality in critically ill patients using

propensity score matching analysis Francisco J Gonzaacutelez de Molina Cristoacutebal Leoacuten Sergio Ruiz-Santana and Pedro Saavedra for the

CAVA I Study Group

Crit Care 201216 R105

Critical Care 2012 16R105

bull The use of propensity score matching analysis to control for all potential confounding

variables allowed the assessment of candidemia-attributable mortality in critically ill

patients

bull Candidemia was not associated with an increase in either ICU or hospital

mortality

bull Earlier treatment of bloodstream infection and better monitoring (surveillance sampling

weekly) resulting in appropriate antifungal agent may contribute to increased survival

bull APACHE II at the time of diagnosis of candidemia was the only predictor of death in

patients with candidemia

bull 1107 pts 38 (34) candidemias Propensity score matching analysis

(Candidemia 70 no 35 yes)

Multicenter observational prospective

C Score biomarkers amp IC

18 ICUs n = 176 (SAC) 4 wks Study 2009-10

ICU gt 7 days

C Score BG CAGTA others Weekly (x 2) screening

Optional Samples related clinical situation follow up

Variables demographics APACHE II SOFA (admission weekly x 2 starting antifungals) comorbid

diseases risk factors antifungal therapy and outcome

Adult patients admitted ICU ge 7 days SAC = Severe Abdominal Conditions

CAGTA = Candida albicans germ-tube antibody

1st 2nd 3rd 4th 3d

Intensive Care Med 2012 381315-25

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating between

Candida colonization and invasive candidiasis in patients with severe abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J Aacutelvarez L

Utande A Farintildeas O and the Study Group Cava II

- Patients with Candida colonization A model for IC prediction was obtained

using Classification And Regression Trees (CART)

- Variables used maximum values biomarkers before during development IC or highest value when IC did not

developed (Apache-II BG CAGTA)

- CART through a process of binary recursive spliting of the datasets based on rules of the form if-then-else identifies

a set of predictors of IC estimating the probabilities of IC according to the values of predictors

- The discriminate value of the probabilities of IC obtained by the CART was evaluated by the receiver characteristic

operating (ROC) curve

- Predictive rule identify patients have an IC risk when probability to develop

IC is ge 30(cut-off chosen by CART algorithm to minimize error measurement = deviance)

- Obtained rule estimated Sensitivity Specificity PPV NPV

- Data analysis carried out using R-package

CART prediction rule model

Breiman L et al (1984) Classfication and regression trees

Belmont CA Wadsworth International

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

n = 115 pts

IC = 31 (27 )

n = 27 pts

IC = 16 (599)

n = 88 pts

IC = 15 (170)

n = 49 pts

IC = 3 (61 )

n = 39 pts

IC = 12 (308 )

B-glucan ge 259 pgml

CAGTA positive B-glucan lt 329 pgml

B-glucan lt 259 pgml

CAGTA negative

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

Diagnostic accuracy of CART-derived prediction rule BG (cut-off

gt 259 pgmL) CAGTA (cutt-off positive) and CS for IC diagnosis

Area under

ROC curve

(95 CI)

Sensitivity

(95 CI)

Specificity

(95 CI)

Predictive value

Positive

(95 CI)

Negative

(95 CI)

CART analysis

078

(076-081)

903

(751-966)

547

(441-650)

424

(312-544)

939

(835-979)

BG

067

(059-074)

516

(348-680)

869

(780-925)

593

(407-755)

830

(738-894)

CAGTA

067

(063-070)

710

(534-839)

573

(465-675)

386

(271-516)

839

(722-913)

CS 062

(058-066)

935

(792-982)

181

(113-277)

299

(217-396)

882

(65-7-967)

CART classification and regression tree analysis BG beta-D-glucan CAGTA Candida albicans germ tube antibody Total number of patients with

Candida spp colonization = 115

Usefulness of the (13)--D-Glucan and Candida albicans germ tube antibody in the

Diagnosis of Invasive Candidiasis in Non-neutropenic Critically Ill Patients (non selected)

201112 One ICU (HUV) 105 NNCIP non selected gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida colonization

cultures (rectal swabs tracheal pharyngeal or gastric aspirates and urine) and serum

BG and CAGTA Were collected factors can interfere with the levels of BG (RRT AC

PT use of blood transfusions surgeryhellip)

NCNI

(n = 42)

Colonized

(n = 52)

Candidemia

(n = 6)

Peritonitis

(n =5)

P

value

Age years mean (range) 66 (50-73) 63 (54-76) 68 (62-78) 67 (62-70) 0820

Malefemale patients 3210 2527 42 50 0007

BG pgmL

Median (IQR)

Maximum (IQR)

44 (31-102)

77 (31-140)

40 (31-140)

150 (47-500)

72 ( 31-300)

194 (120-300)

31 (31-31)

50 (31-80)

0527

0037

CAGTA positives n () 13 (310) 26 (500) 3 (500) 1 (200) 0203

Instituto Salud Carlos III Madrid Spain (FIS PI 1002110) ICAAC 2013 (M-1380)

Conclusions

Patients with candidemia and Candida spp colonization showed significantly higher values

of serum BG than neither colonized or infected patients

NCNI neither colonized nor infected BG B-D- glucan IQR interquartile range (25th-75th percentile) CAGTA Candida albicans germ

tube antibodies Significant differences as compared with the NCNI group

CAVA FIS PROJECT

Prospective cohort observational multicenter study

201214 12 ICUs NNCIP selected (SAC) gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida

colonization cultures (rectal swabs tracheal pharyngeal urine) and serum (BG and

CAGTA)

Preliminary data (October 2013) 215 pts included 117 CC 26 IC AFT 94 (446)

Invasive Candidiasis in the critically ill patients Diagnostic utility of 1-3-Beta-D-

Glucan(BDG) anti-mycelium antibodies (CAGTA) mannanantimannan antibodies

(MAA) and detection of Candida DNA (PCR)rdquo CAVA TREM PROJECT

Candida DNA detection (PCR)

To evaluate CS performance ICU patients developing hospital-acquired severe sepsis or septic shock

Prospective multicenter (5 ICUs France) cohort study

n = 94 recruited (IC = 5 53 )

IC rates CS = 2 or 3 0 CS = 4 176 CS = 5 50 (p lt 00001)

CS gt 3 Benefit early SAT

Evaluation of ldquoCandida scorerdquo in critically ill patients a prospective multicenter

observational cohort study Leroy G Lamblotte F Thevenin D Lemaire C Parmentier E Devos P Leroy O

Ann Intens Care 2011150

bull To determine nordm patients w o documented IC received SAT

bull 1-day cross-sectional cohort study 169 ICUs France Belgium

bull n = 2047 recruited

bull n = 154 (75) with SAT (only 54 with IC)

bull Independent predictors SAT

ndash Center-related factors Hospital lt 800 beds (OR 29) organ transplant activity (OR26)

use fluoroquinolones (OR23) use SAT unresolved sepsis (OR19 22 20)

ndash Patient related factors Candida colonization (OR 124) severe sepsis and septic shock (OR47)

emergency surgery (OR 24) hematologic malignancies (OR71)

bull Trend greater impact SAT on survival when CS = 4 or 5

SAT Systemic Antifungal Treatment

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

Crit Care Med 201240813-22

Impact SAT on 28-d mortality according CS

Crit Care Med 201240813-22

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 15: Recordant L Àngels - academia.cat

Score gt 25

1

1

1

2

probability of Candida infection

x 775

Courtesy byJ Mensa

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in

nonneutropenic critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro Saavedra Benito Almirante Juan Nolla-Salas

Francisco Aacutelvarez-Lerma Joseacute Garnacho-Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group

Crit Care Med 2006 34730-37

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

bull Prospective cohort observational multicenter study

bull Adult non-neutropenic pts 36 ICUs MS (32 hospitals)

bull 14 months (April 2006-June 2007)

bull Underlying diseases comorbidities reasons for ICU admission RF (presence and duration)

bull Antifungal treatment and outcome

bull 7 days of ICU admission Once a week APACHE II SOFA Clinical situation and microbiological

screening (5) TA pharyngeal exudatesgastric aspirates urine perirectal swab skin and optional

samples

bull1107 patients age 60 y ICU admission APACHE II 184 SOFA 7 (median)

bull No CI (215) Colonized (834) infected (58)

bull Overall mortality 305 Intra ICU 217

bull ATFT 49 (844) patients Time between ICU admission and administration of ATFT 173 days

bull 240 patients with Candida species colonization or IC (18) (1ndash3)-beta-D-glucan serum levels

Candida Score lt 3 = 3 gt 3

IC rate medical surgical

patients (n = 1107) 23 59

115

(51 - 178)

IC rate Abdominal Surgery

(n = 182) 23 125

303

(192 - 414)

Abdominal Surgery IC rates according CS

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash1633

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash33

Candiduria in critically ill patients admitted to intensive care medical units

Francisco Aacutelvarez-Lerma Juan Nolla-Salas Cristobal Leon Mercedes Palomar Ricard

Jorda Nieves Carrasco Felipe Bobillo (EPCAN Study Group)

Intensive Care Med 2003291069ndash76

bull 1765 adult non-neutropenic pts (lt 7 days) Candiduria 389 patients (22)

bull Age 61 y Apache II 19

bull Incidence density 95 episodes1000 days

bull Length of ICU stay since presence of candiduria 16 days

bull Risk factor associated age over 65 y female gender LOS in hospital

before ICU admission diabetes TPN MV previous use of antibiotics

(C no albicans)

bull C albicans 266 (684) C glabrata 32 (82) C tropicalis 14 (36)

bull Candiduria is a risk factor for ICUhospital mortality (OR 158)

Jordaacute Marcos R Alvarez-Lerma F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C

and EPCAN Study Group Mycoses 200750302-10

Risk factors for candidaemia in critically ill patients a prospective

surveillance study

bull 1765 adult non-neutropenic pts (lt 7 days) Candidemia 63 pts

bull Age 63 y Apache II 18 ICUhospital stay 2848 Surgical 29 (46) Medical 26 (413 )

bull ATF treatment 4863 (76)

- FCNZ 32 (667) AFBD 8 (16) LAFB 5 (104) AFBLC 3 (63)

bull ICUhospital Mortality 34 (54)-39 (73)

Assessment of candidemia-attributable mortality in critically ill patients using

propensity score matching analysis Francisco J Gonzaacutelez de Molina Cristoacutebal Leoacuten Sergio Ruiz-Santana and Pedro Saavedra for the

CAVA I Study Group

Crit Care 201216 R105

Critical Care 2012 16R105

bull The use of propensity score matching analysis to control for all potential confounding

variables allowed the assessment of candidemia-attributable mortality in critically ill

patients

bull Candidemia was not associated with an increase in either ICU or hospital

mortality

bull Earlier treatment of bloodstream infection and better monitoring (surveillance sampling

weekly) resulting in appropriate antifungal agent may contribute to increased survival

bull APACHE II at the time of diagnosis of candidemia was the only predictor of death in

patients with candidemia

bull 1107 pts 38 (34) candidemias Propensity score matching analysis

(Candidemia 70 no 35 yes)

Multicenter observational prospective

C Score biomarkers amp IC

18 ICUs n = 176 (SAC) 4 wks Study 2009-10

ICU gt 7 days

C Score BG CAGTA others Weekly (x 2) screening

Optional Samples related clinical situation follow up

Variables demographics APACHE II SOFA (admission weekly x 2 starting antifungals) comorbid

diseases risk factors antifungal therapy and outcome

Adult patients admitted ICU ge 7 days SAC = Severe Abdominal Conditions

CAGTA = Candida albicans germ-tube antibody

1st 2nd 3rd 4th 3d

Intensive Care Med 2012 381315-25

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating between

Candida colonization and invasive candidiasis in patients with severe abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J Aacutelvarez L

Utande A Farintildeas O and the Study Group Cava II

- Patients with Candida colonization A model for IC prediction was obtained

using Classification And Regression Trees (CART)

- Variables used maximum values biomarkers before during development IC or highest value when IC did not

developed (Apache-II BG CAGTA)

- CART through a process of binary recursive spliting of the datasets based on rules of the form if-then-else identifies

a set of predictors of IC estimating the probabilities of IC according to the values of predictors

- The discriminate value of the probabilities of IC obtained by the CART was evaluated by the receiver characteristic

operating (ROC) curve

- Predictive rule identify patients have an IC risk when probability to develop

IC is ge 30(cut-off chosen by CART algorithm to minimize error measurement = deviance)

- Obtained rule estimated Sensitivity Specificity PPV NPV

- Data analysis carried out using R-package

CART prediction rule model

Breiman L et al (1984) Classfication and regression trees

Belmont CA Wadsworth International

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

n = 115 pts

IC = 31 (27 )

n = 27 pts

IC = 16 (599)

n = 88 pts

IC = 15 (170)

n = 49 pts

IC = 3 (61 )

n = 39 pts

IC = 12 (308 )

B-glucan ge 259 pgml

CAGTA positive B-glucan lt 329 pgml

B-glucan lt 259 pgml

CAGTA negative

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

Diagnostic accuracy of CART-derived prediction rule BG (cut-off

gt 259 pgmL) CAGTA (cutt-off positive) and CS for IC diagnosis

Area under

ROC curve

(95 CI)

Sensitivity

(95 CI)

Specificity

(95 CI)

Predictive value

Positive

(95 CI)

Negative

(95 CI)

CART analysis

078

(076-081)

903

(751-966)

547

(441-650)

424

(312-544)

939

(835-979)

BG

067

(059-074)

516

(348-680)

869

(780-925)

593

(407-755)

830

(738-894)

CAGTA

067

(063-070)

710

(534-839)

573

(465-675)

386

(271-516)

839

(722-913)

CS 062

(058-066)

935

(792-982)

181

(113-277)

299

(217-396)

882

(65-7-967)

CART classification and regression tree analysis BG beta-D-glucan CAGTA Candida albicans germ tube antibody Total number of patients with

Candida spp colonization = 115

Usefulness of the (13)--D-Glucan and Candida albicans germ tube antibody in the

Diagnosis of Invasive Candidiasis in Non-neutropenic Critically Ill Patients (non selected)

201112 One ICU (HUV) 105 NNCIP non selected gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida colonization

cultures (rectal swabs tracheal pharyngeal or gastric aspirates and urine) and serum

BG and CAGTA Were collected factors can interfere with the levels of BG (RRT AC

PT use of blood transfusions surgeryhellip)

NCNI

(n = 42)

Colonized

(n = 52)

Candidemia

(n = 6)

Peritonitis

(n =5)

P

value

Age years mean (range) 66 (50-73) 63 (54-76) 68 (62-78) 67 (62-70) 0820

Malefemale patients 3210 2527 42 50 0007

BG pgmL

Median (IQR)

Maximum (IQR)

44 (31-102)

77 (31-140)

40 (31-140)

150 (47-500)

72 ( 31-300)

194 (120-300)

31 (31-31)

50 (31-80)

0527

0037

CAGTA positives n () 13 (310) 26 (500) 3 (500) 1 (200) 0203

Instituto Salud Carlos III Madrid Spain (FIS PI 1002110) ICAAC 2013 (M-1380)

Conclusions

Patients with candidemia and Candida spp colonization showed significantly higher values

of serum BG than neither colonized or infected patients

NCNI neither colonized nor infected BG B-D- glucan IQR interquartile range (25th-75th percentile) CAGTA Candida albicans germ

tube antibodies Significant differences as compared with the NCNI group

CAVA FIS PROJECT

Prospective cohort observational multicenter study

201214 12 ICUs NNCIP selected (SAC) gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida

colonization cultures (rectal swabs tracheal pharyngeal urine) and serum (BG and

CAGTA)

Preliminary data (October 2013) 215 pts included 117 CC 26 IC AFT 94 (446)

Invasive Candidiasis in the critically ill patients Diagnostic utility of 1-3-Beta-D-

Glucan(BDG) anti-mycelium antibodies (CAGTA) mannanantimannan antibodies

(MAA) and detection of Candida DNA (PCR)rdquo CAVA TREM PROJECT

Candida DNA detection (PCR)

To evaluate CS performance ICU patients developing hospital-acquired severe sepsis or septic shock

Prospective multicenter (5 ICUs France) cohort study

n = 94 recruited (IC = 5 53 )

IC rates CS = 2 or 3 0 CS = 4 176 CS = 5 50 (p lt 00001)

CS gt 3 Benefit early SAT

Evaluation of ldquoCandida scorerdquo in critically ill patients a prospective multicenter

observational cohort study Leroy G Lamblotte F Thevenin D Lemaire C Parmentier E Devos P Leroy O

Ann Intens Care 2011150

bull To determine nordm patients w o documented IC received SAT

bull 1-day cross-sectional cohort study 169 ICUs France Belgium

bull n = 2047 recruited

bull n = 154 (75) with SAT (only 54 with IC)

bull Independent predictors SAT

ndash Center-related factors Hospital lt 800 beds (OR 29) organ transplant activity (OR26)

use fluoroquinolones (OR23) use SAT unresolved sepsis (OR19 22 20)

ndash Patient related factors Candida colonization (OR 124) severe sepsis and septic shock (OR47)

emergency surgery (OR 24) hematologic malignancies (OR71)

bull Trend greater impact SAT on survival when CS = 4 or 5

SAT Systemic Antifungal Treatment

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

Crit Care Med 201240813-22

Impact SAT on 28-d mortality according CS

Crit Care Med 201240813-22

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 16: Recordant L Àngels - academia.cat

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

bull Prospective cohort observational multicenter study

bull Adult non-neutropenic pts 36 ICUs MS (32 hospitals)

bull 14 months (April 2006-June 2007)

bull Underlying diseases comorbidities reasons for ICU admission RF (presence and duration)

bull Antifungal treatment and outcome

bull 7 days of ICU admission Once a week APACHE II SOFA Clinical situation and microbiological

screening (5) TA pharyngeal exudatesgastric aspirates urine perirectal swab skin and optional

samples

bull1107 patients age 60 y ICU admission APACHE II 184 SOFA 7 (median)

bull No CI (215) Colonized (834) infected (58)

bull Overall mortality 305 Intra ICU 217

bull ATFT 49 (844) patients Time between ICU admission and administration of ATFT 173 days

bull 240 patients with Candida species colonization or IC (18) (1ndash3)-beta-D-glucan serum levels

Candida Score lt 3 = 3 gt 3

IC rate medical surgical

patients (n = 1107) 23 59

115

(51 - 178)

IC rate Abdominal Surgery

(n = 182) 23 125

303

(192 - 414)

Abdominal Surgery IC rates according CS

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash1633

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash33

Candiduria in critically ill patients admitted to intensive care medical units

Francisco Aacutelvarez-Lerma Juan Nolla-Salas Cristobal Leon Mercedes Palomar Ricard

Jorda Nieves Carrasco Felipe Bobillo (EPCAN Study Group)

Intensive Care Med 2003291069ndash76

bull 1765 adult non-neutropenic pts (lt 7 days) Candiduria 389 patients (22)

bull Age 61 y Apache II 19

bull Incidence density 95 episodes1000 days

bull Length of ICU stay since presence of candiduria 16 days

bull Risk factor associated age over 65 y female gender LOS in hospital

before ICU admission diabetes TPN MV previous use of antibiotics

(C no albicans)

bull C albicans 266 (684) C glabrata 32 (82) C tropicalis 14 (36)

bull Candiduria is a risk factor for ICUhospital mortality (OR 158)

Jordaacute Marcos R Alvarez-Lerma F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C

and EPCAN Study Group Mycoses 200750302-10

Risk factors for candidaemia in critically ill patients a prospective

surveillance study

bull 1765 adult non-neutropenic pts (lt 7 days) Candidemia 63 pts

bull Age 63 y Apache II 18 ICUhospital stay 2848 Surgical 29 (46) Medical 26 (413 )

bull ATF treatment 4863 (76)

- FCNZ 32 (667) AFBD 8 (16) LAFB 5 (104) AFBLC 3 (63)

bull ICUhospital Mortality 34 (54)-39 (73)

Assessment of candidemia-attributable mortality in critically ill patients using

propensity score matching analysis Francisco J Gonzaacutelez de Molina Cristoacutebal Leoacuten Sergio Ruiz-Santana and Pedro Saavedra for the

CAVA I Study Group

Crit Care 201216 R105

Critical Care 2012 16R105

bull The use of propensity score matching analysis to control for all potential confounding

variables allowed the assessment of candidemia-attributable mortality in critically ill

patients

bull Candidemia was not associated with an increase in either ICU or hospital

mortality

bull Earlier treatment of bloodstream infection and better monitoring (surveillance sampling

weekly) resulting in appropriate antifungal agent may contribute to increased survival

bull APACHE II at the time of diagnosis of candidemia was the only predictor of death in

patients with candidemia

bull 1107 pts 38 (34) candidemias Propensity score matching analysis

(Candidemia 70 no 35 yes)

Multicenter observational prospective

C Score biomarkers amp IC

18 ICUs n = 176 (SAC) 4 wks Study 2009-10

ICU gt 7 days

C Score BG CAGTA others Weekly (x 2) screening

Optional Samples related clinical situation follow up

Variables demographics APACHE II SOFA (admission weekly x 2 starting antifungals) comorbid

diseases risk factors antifungal therapy and outcome

Adult patients admitted ICU ge 7 days SAC = Severe Abdominal Conditions

CAGTA = Candida albicans germ-tube antibody

1st 2nd 3rd 4th 3d

Intensive Care Med 2012 381315-25

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating between

Candida colonization and invasive candidiasis in patients with severe abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J Aacutelvarez L

Utande A Farintildeas O and the Study Group Cava II

- Patients with Candida colonization A model for IC prediction was obtained

using Classification And Regression Trees (CART)

- Variables used maximum values biomarkers before during development IC or highest value when IC did not

developed (Apache-II BG CAGTA)

- CART through a process of binary recursive spliting of the datasets based on rules of the form if-then-else identifies

a set of predictors of IC estimating the probabilities of IC according to the values of predictors

- The discriminate value of the probabilities of IC obtained by the CART was evaluated by the receiver characteristic

operating (ROC) curve

- Predictive rule identify patients have an IC risk when probability to develop

IC is ge 30(cut-off chosen by CART algorithm to minimize error measurement = deviance)

- Obtained rule estimated Sensitivity Specificity PPV NPV

- Data analysis carried out using R-package

CART prediction rule model

Breiman L et al (1984) Classfication and regression trees

Belmont CA Wadsworth International

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

n = 115 pts

IC = 31 (27 )

n = 27 pts

IC = 16 (599)

n = 88 pts

IC = 15 (170)

n = 49 pts

IC = 3 (61 )

n = 39 pts

IC = 12 (308 )

B-glucan ge 259 pgml

CAGTA positive B-glucan lt 329 pgml

B-glucan lt 259 pgml

CAGTA negative

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

Diagnostic accuracy of CART-derived prediction rule BG (cut-off

gt 259 pgmL) CAGTA (cutt-off positive) and CS for IC diagnosis

Area under

ROC curve

(95 CI)

Sensitivity

(95 CI)

Specificity

(95 CI)

Predictive value

Positive

(95 CI)

Negative

(95 CI)

CART analysis

078

(076-081)

903

(751-966)

547

(441-650)

424

(312-544)

939

(835-979)

BG

067

(059-074)

516

(348-680)

869

(780-925)

593

(407-755)

830

(738-894)

CAGTA

067

(063-070)

710

(534-839)

573

(465-675)

386

(271-516)

839

(722-913)

CS 062

(058-066)

935

(792-982)

181

(113-277)

299

(217-396)

882

(65-7-967)

CART classification and regression tree analysis BG beta-D-glucan CAGTA Candida albicans germ tube antibody Total number of patients with

Candida spp colonization = 115

Usefulness of the (13)--D-Glucan and Candida albicans germ tube antibody in the

Diagnosis of Invasive Candidiasis in Non-neutropenic Critically Ill Patients (non selected)

201112 One ICU (HUV) 105 NNCIP non selected gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida colonization

cultures (rectal swabs tracheal pharyngeal or gastric aspirates and urine) and serum

BG and CAGTA Were collected factors can interfere with the levels of BG (RRT AC

PT use of blood transfusions surgeryhellip)

NCNI

(n = 42)

Colonized

(n = 52)

Candidemia

(n = 6)

Peritonitis

(n =5)

P

value

Age years mean (range) 66 (50-73) 63 (54-76) 68 (62-78) 67 (62-70) 0820

Malefemale patients 3210 2527 42 50 0007

BG pgmL

Median (IQR)

Maximum (IQR)

44 (31-102)

77 (31-140)

40 (31-140)

150 (47-500)

72 ( 31-300)

194 (120-300)

31 (31-31)

50 (31-80)

0527

0037

CAGTA positives n () 13 (310) 26 (500) 3 (500) 1 (200) 0203

Instituto Salud Carlos III Madrid Spain (FIS PI 1002110) ICAAC 2013 (M-1380)

Conclusions

Patients with candidemia and Candida spp colonization showed significantly higher values

of serum BG than neither colonized or infected patients

NCNI neither colonized nor infected BG B-D- glucan IQR interquartile range (25th-75th percentile) CAGTA Candida albicans germ

tube antibodies Significant differences as compared with the NCNI group

CAVA FIS PROJECT

Prospective cohort observational multicenter study

201214 12 ICUs NNCIP selected (SAC) gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida

colonization cultures (rectal swabs tracheal pharyngeal urine) and serum (BG and

CAGTA)

Preliminary data (October 2013) 215 pts included 117 CC 26 IC AFT 94 (446)

Invasive Candidiasis in the critically ill patients Diagnostic utility of 1-3-Beta-D-

Glucan(BDG) anti-mycelium antibodies (CAGTA) mannanantimannan antibodies

(MAA) and detection of Candida DNA (PCR)rdquo CAVA TREM PROJECT

Candida DNA detection (PCR)

To evaluate CS performance ICU patients developing hospital-acquired severe sepsis or septic shock

Prospective multicenter (5 ICUs France) cohort study

n = 94 recruited (IC = 5 53 )

IC rates CS = 2 or 3 0 CS = 4 176 CS = 5 50 (p lt 00001)

CS gt 3 Benefit early SAT

Evaluation of ldquoCandida scorerdquo in critically ill patients a prospective multicenter

observational cohort study Leroy G Lamblotte F Thevenin D Lemaire C Parmentier E Devos P Leroy O

Ann Intens Care 2011150

bull To determine nordm patients w o documented IC received SAT

bull 1-day cross-sectional cohort study 169 ICUs France Belgium

bull n = 2047 recruited

bull n = 154 (75) with SAT (only 54 with IC)

bull Independent predictors SAT

ndash Center-related factors Hospital lt 800 beds (OR 29) organ transplant activity (OR26)

use fluoroquinolones (OR23) use SAT unresolved sepsis (OR19 22 20)

ndash Patient related factors Candida colonization (OR 124) severe sepsis and septic shock (OR47)

emergency surgery (OR 24) hematologic malignancies (OR71)

bull Trend greater impact SAT on survival when CS = 4 or 5

SAT Systemic Antifungal Treatment

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

Crit Care Med 201240813-22

Impact SAT on 28-d mortality according CS

Crit Care Med 201240813-22

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 17: Recordant L Àngels - academia.cat

Candida Score lt 3 = 3 gt 3

IC rate medical surgical

patients (n = 1107) 23 59

115

(51 - 178)

IC rate Abdominal Surgery

(n = 182) 23 125

303

(192 - 414)

Abdominal Surgery IC rates according CS

Values in parentheses 95 CI

Crit Care Med 2009 371624 ndash33

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash1633

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash33

Candiduria in critically ill patients admitted to intensive care medical units

Francisco Aacutelvarez-Lerma Juan Nolla-Salas Cristobal Leon Mercedes Palomar Ricard

Jorda Nieves Carrasco Felipe Bobillo (EPCAN Study Group)

Intensive Care Med 2003291069ndash76

bull 1765 adult non-neutropenic pts (lt 7 days) Candiduria 389 patients (22)

bull Age 61 y Apache II 19

bull Incidence density 95 episodes1000 days

bull Length of ICU stay since presence of candiduria 16 days

bull Risk factor associated age over 65 y female gender LOS in hospital

before ICU admission diabetes TPN MV previous use of antibiotics

(C no albicans)

bull C albicans 266 (684) C glabrata 32 (82) C tropicalis 14 (36)

bull Candiduria is a risk factor for ICUhospital mortality (OR 158)

Jordaacute Marcos R Alvarez-Lerma F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C

and EPCAN Study Group Mycoses 200750302-10

Risk factors for candidaemia in critically ill patients a prospective

surveillance study

bull 1765 adult non-neutropenic pts (lt 7 days) Candidemia 63 pts

bull Age 63 y Apache II 18 ICUhospital stay 2848 Surgical 29 (46) Medical 26 (413 )

bull ATF treatment 4863 (76)

- FCNZ 32 (667) AFBD 8 (16) LAFB 5 (104) AFBLC 3 (63)

bull ICUhospital Mortality 34 (54)-39 (73)

Assessment of candidemia-attributable mortality in critically ill patients using

propensity score matching analysis Francisco J Gonzaacutelez de Molina Cristoacutebal Leoacuten Sergio Ruiz-Santana and Pedro Saavedra for the

CAVA I Study Group

Crit Care 201216 R105

Critical Care 2012 16R105

bull The use of propensity score matching analysis to control for all potential confounding

variables allowed the assessment of candidemia-attributable mortality in critically ill

patients

bull Candidemia was not associated with an increase in either ICU or hospital

mortality

bull Earlier treatment of bloodstream infection and better monitoring (surveillance sampling

weekly) resulting in appropriate antifungal agent may contribute to increased survival

bull APACHE II at the time of diagnosis of candidemia was the only predictor of death in

patients with candidemia

bull 1107 pts 38 (34) candidemias Propensity score matching analysis

(Candidemia 70 no 35 yes)

Multicenter observational prospective

C Score biomarkers amp IC

18 ICUs n = 176 (SAC) 4 wks Study 2009-10

ICU gt 7 days

C Score BG CAGTA others Weekly (x 2) screening

Optional Samples related clinical situation follow up

Variables demographics APACHE II SOFA (admission weekly x 2 starting antifungals) comorbid

diseases risk factors antifungal therapy and outcome

Adult patients admitted ICU ge 7 days SAC = Severe Abdominal Conditions

CAGTA = Candida albicans germ-tube antibody

1st 2nd 3rd 4th 3d

Intensive Care Med 2012 381315-25

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating between

Candida colonization and invasive candidiasis in patients with severe abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J Aacutelvarez L

Utande A Farintildeas O and the Study Group Cava II

- Patients with Candida colonization A model for IC prediction was obtained

using Classification And Regression Trees (CART)

- Variables used maximum values biomarkers before during development IC or highest value when IC did not

developed (Apache-II BG CAGTA)

- CART through a process of binary recursive spliting of the datasets based on rules of the form if-then-else identifies

a set of predictors of IC estimating the probabilities of IC according to the values of predictors

- The discriminate value of the probabilities of IC obtained by the CART was evaluated by the receiver characteristic

operating (ROC) curve

- Predictive rule identify patients have an IC risk when probability to develop

IC is ge 30(cut-off chosen by CART algorithm to minimize error measurement = deviance)

- Obtained rule estimated Sensitivity Specificity PPV NPV

- Data analysis carried out using R-package

CART prediction rule model

Breiman L et al (1984) Classfication and regression trees

Belmont CA Wadsworth International

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

n = 115 pts

IC = 31 (27 )

n = 27 pts

IC = 16 (599)

n = 88 pts

IC = 15 (170)

n = 49 pts

IC = 3 (61 )

n = 39 pts

IC = 12 (308 )

B-glucan ge 259 pgml

CAGTA positive B-glucan lt 329 pgml

B-glucan lt 259 pgml

CAGTA negative

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

Diagnostic accuracy of CART-derived prediction rule BG (cut-off

gt 259 pgmL) CAGTA (cutt-off positive) and CS for IC diagnosis

Area under

ROC curve

(95 CI)

Sensitivity

(95 CI)

Specificity

(95 CI)

Predictive value

Positive

(95 CI)

Negative

(95 CI)

CART analysis

078

(076-081)

903

(751-966)

547

(441-650)

424

(312-544)

939

(835-979)

BG

067

(059-074)

516

(348-680)

869

(780-925)

593

(407-755)

830

(738-894)

CAGTA

067

(063-070)

710

(534-839)

573

(465-675)

386

(271-516)

839

(722-913)

CS 062

(058-066)

935

(792-982)

181

(113-277)

299

(217-396)

882

(65-7-967)

CART classification and regression tree analysis BG beta-D-glucan CAGTA Candida albicans germ tube antibody Total number of patients with

Candida spp colonization = 115

Usefulness of the (13)--D-Glucan and Candida albicans germ tube antibody in the

Diagnosis of Invasive Candidiasis in Non-neutropenic Critically Ill Patients (non selected)

201112 One ICU (HUV) 105 NNCIP non selected gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida colonization

cultures (rectal swabs tracheal pharyngeal or gastric aspirates and urine) and serum

BG and CAGTA Were collected factors can interfere with the levels of BG (RRT AC

PT use of blood transfusions surgeryhellip)

NCNI

(n = 42)

Colonized

(n = 52)

Candidemia

(n = 6)

Peritonitis

(n =5)

P

value

Age years mean (range) 66 (50-73) 63 (54-76) 68 (62-78) 67 (62-70) 0820

Malefemale patients 3210 2527 42 50 0007

BG pgmL

Median (IQR)

Maximum (IQR)

44 (31-102)

77 (31-140)

40 (31-140)

150 (47-500)

72 ( 31-300)

194 (120-300)

31 (31-31)

50 (31-80)

0527

0037

CAGTA positives n () 13 (310) 26 (500) 3 (500) 1 (200) 0203

Instituto Salud Carlos III Madrid Spain (FIS PI 1002110) ICAAC 2013 (M-1380)

Conclusions

Patients with candidemia and Candida spp colonization showed significantly higher values

of serum BG than neither colonized or infected patients

NCNI neither colonized nor infected BG B-D- glucan IQR interquartile range (25th-75th percentile) CAGTA Candida albicans germ

tube antibodies Significant differences as compared with the NCNI group

CAVA FIS PROJECT

Prospective cohort observational multicenter study

201214 12 ICUs NNCIP selected (SAC) gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida

colonization cultures (rectal swabs tracheal pharyngeal urine) and serum (BG and

CAGTA)

Preliminary data (October 2013) 215 pts included 117 CC 26 IC AFT 94 (446)

Invasive Candidiasis in the critically ill patients Diagnostic utility of 1-3-Beta-D-

Glucan(BDG) anti-mycelium antibodies (CAGTA) mannanantimannan antibodies

(MAA) and detection of Candida DNA (PCR)rdquo CAVA TREM PROJECT

Candida DNA detection (PCR)

To evaluate CS performance ICU patients developing hospital-acquired severe sepsis or septic shock

Prospective multicenter (5 ICUs France) cohort study

n = 94 recruited (IC = 5 53 )

IC rates CS = 2 or 3 0 CS = 4 176 CS = 5 50 (p lt 00001)

CS gt 3 Benefit early SAT

Evaluation of ldquoCandida scorerdquo in critically ill patients a prospective multicenter

observational cohort study Leroy G Lamblotte F Thevenin D Lemaire C Parmentier E Devos P Leroy O

Ann Intens Care 2011150

bull To determine nordm patients w o documented IC received SAT

bull 1-day cross-sectional cohort study 169 ICUs France Belgium

bull n = 2047 recruited

bull n = 154 (75) with SAT (only 54 with IC)

bull Independent predictors SAT

ndash Center-related factors Hospital lt 800 beds (OR 29) organ transplant activity (OR26)

use fluoroquinolones (OR23) use SAT unresolved sepsis (OR19 22 20)

ndash Patient related factors Candida colonization (OR 124) severe sepsis and septic shock (OR47)

emergency surgery (OR 24) hematologic malignancies (OR71)

bull Trend greater impact SAT on survival when CS = 4 or 5

SAT Systemic Antifungal Treatment

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

Crit Care Med 201240813-22

Impact SAT on 28-d mortality according CS

Crit Care Med 201240813-22

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 18: Recordant L Àngels - academia.cat

Crit Care Med 2009 371624 ndash1633

Usefulness of the ldquoCandida scorerdquo for discriminating beween Candida

colonization and invasive candidiasis in non-neutropenic critically ill patients

A prospective multicenter study

C Leoacuten S Ruiz-Santana P Saavedra B Galvaacuten A Blanco C Balasini A Utande FJ Gonzaacutelez MA

Blasco MJ Loacutepez PE Charles A Hernaacutendez and Cava I Study Group

Crit Care Med 2009 371624 ndash33

Candiduria in critically ill patients admitted to intensive care medical units

Francisco Aacutelvarez-Lerma Juan Nolla-Salas Cristobal Leon Mercedes Palomar Ricard

Jorda Nieves Carrasco Felipe Bobillo (EPCAN Study Group)

Intensive Care Med 2003291069ndash76

bull 1765 adult non-neutropenic pts (lt 7 days) Candiduria 389 patients (22)

bull Age 61 y Apache II 19

bull Incidence density 95 episodes1000 days

bull Length of ICU stay since presence of candiduria 16 days

bull Risk factor associated age over 65 y female gender LOS in hospital

before ICU admission diabetes TPN MV previous use of antibiotics

(C no albicans)

bull C albicans 266 (684) C glabrata 32 (82) C tropicalis 14 (36)

bull Candiduria is a risk factor for ICUhospital mortality (OR 158)

Jordaacute Marcos R Alvarez-Lerma F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C

and EPCAN Study Group Mycoses 200750302-10

Risk factors for candidaemia in critically ill patients a prospective

surveillance study

bull 1765 adult non-neutropenic pts (lt 7 days) Candidemia 63 pts

bull Age 63 y Apache II 18 ICUhospital stay 2848 Surgical 29 (46) Medical 26 (413 )

bull ATF treatment 4863 (76)

- FCNZ 32 (667) AFBD 8 (16) LAFB 5 (104) AFBLC 3 (63)

bull ICUhospital Mortality 34 (54)-39 (73)

Assessment of candidemia-attributable mortality in critically ill patients using

propensity score matching analysis Francisco J Gonzaacutelez de Molina Cristoacutebal Leoacuten Sergio Ruiz-Santana and Pedro Saavedra for the

CAVA I Study Group

Crit Care 201216 R105

Critical Care 2012 16R105

bull The use of propensity score matching analysis to control for all potential confounding

variables allowed the assessment of candidemia-attributable mortality in critically ill

patients

bull Candidemia was not associated with an increase in either ICU or hospital

mortality

bull Earlier treatment of bloodstream infection and better monitoring (surveillance sampling

weekly) resulting in appropriate antifungal agent may contribute to increased survival

bull APACHE II at the time of diagnosis of candidemia was the only predictor of death in

patients with candidemia

bull 1107 pts 38 (34) candidemias Propensity score matching analysis

(Candidemia 70 no 35 yes)

Multicenter observational prospective

C Score biomarkers amp IC

18 ICUs n = 176 (SAC) 4 wks Study 2009-10

ICU gt 7 days

C Score BG CAGTA others Weekly (x 2) screening

Optional Samples related clinical situation follow up

Variables demographics APACHE II SOFA (admission weekly x 2 starting antifungals) comorbid

diseases risk factors antifungal therapy and outcome

Adult patients admitted ICU ge 7 days SAC = Severe Abdominal Conditions

CAGTA = Candida albicans germ-tube antibody

1st 2nd 3rd 4th 3d

Intensive Care Med 2012 381315-25

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating between

Candida colonization and invasive candidiasis in patients with severe abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J Aacutelvarez L

Utande A Farintildeas O and the Study Group Cava II

- Patients with Candida colonization A model for IC prediction was obtained

using Classification And Regression Trees (CART)

- Variables used maximum values biomarkers before during development IC or highest value when IC did not

developed (Apache-II BG CAGTA)

- CART through a process of binary recursive spliting of the datasets based on rules of the form if-then-else identifies

a set of predictors of IC estimating the probabilities of IC according to the values of predictors

- The discriminate value of the probabilities of IC obtained by the CART was evaluated by the receiver characteristic

operating (ROC) curve

- Predictive rule identify patients have an IC risk when probability to develop

IC is ge 30(cut-off chosen by CART algorithm to minimize error measurement = deviance)

- Obtained rule estimated Sensitivity Specificity PPV NPV

- Data analysis carried out using R-package

CART prediction rule model

Breiman L et al (1984) Classfication and regression trees

Belmont CA Wadsworth International

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

n = 115 pts

IC = 31 (27 )

n = 27 pts

IC = 16 (599)

n = 88 pts

IC = 15 (170)

n = 49 pts

IC = 3 (61 )

n = 39 pts

IC = 12 (308 )

B-glucan ge 259 pgml

CAGTA positive B-glucan lt 329 pgml

B-glucan lt 259 pgml

CAGTA negative

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

Diagnostic accuracy of CART-derived prediction rule BG (cut-off

gt 259 pgmL) CAGTA (cutt-off positive) and CS for IC diagnosis

Area under

ROC curve

(95 CI)

Sensitivity

(95 CI)

Specificity

(95 CI)

Predictive value

Positive

(95 CI)

Negative

(95 CI)

CART analysis

078

(076-081)

903

(751-966)

547

(441-650)

424

(312-544)

939

(835-979)

BG

067

(059-074)

516

(348-680)

869

(780-925)

593

(407-755)

830

(738-894)

CAGTA

067

(063-070)

710

(534-839)

573

(465-675)

386

(271-516)

839

(722-913)

CS 062

(058-066)

935

(792-982)

181

(113-277)

299

(217-396)

882

(65-7-967)

CART classification and regression tree analysis BG beta-D-glucan CAGTA Candida albicans germ tube antibody Total number of patients with

Candida spp colonization = 115

Usefulness of the (13)--D-Glucan and Candida albicans germ tube antibody in the

Diagnosis of Invasive Candidiasis in Non-neutropenic Critically Ill Patients (non selected)

201112 One ICU (HUV) 105 NNCIP non selected gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida colonization

cultures (rectal swabs tracheal pharyngeal or gastric aspirates and urine) and serum

BG and CAGTA Were collected factors can interfere with the levels of BG (RRT AC

PT use of blood transfusions surgeryhellip)

NCNI

(n = 42)

Colonized

(n = 52)

Candidemia

(n = 6)

Peritonitis

(n =5)

P

value

Age years mean (range) 66 (50-73) 63 (54-76) 68 (62-78) 67 (62-70) 0820

Malefemale patients 3210 2527 42 50 0007

BG pgmL

Median (IQR)

Maximum (IQR)

44 (31-102)

77 (31-140)

40 (31-140)

150 (47-500)

72 ( 31-300)

194 (120-300)

31 (31-31)

50 (31-80)

0527

0037

CAGTA positives n () 13 (310) 26 (500) 3 (500) 1 (200) 0203

Instituto Salud Carlos III Madrid Spain (FIS PI 1002110) ICAAC 2013 (M-1380)

Conclusions

Patients with candidemia and Candida spp colonization showed significantly higher values

of serum BG than neither colonized or infected patients

NCNI neither colonized nor infected BG B-D- glucan IQR interquartile range (25th-75th percentile) CAGTA Candida albicans germ

tube antibodies Significant differences as compared with the NCNI group

CAVA FIS PROJECT

Prospective cohort observational multicenter study

201214 12 ICUs NNCIP selected (SAC) gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida

colonization cultures (rectal swabs tracheal pharyngeal urine) and serum (BG and

CAGTA)

Preliminary data (October 2013) 215 pts included 117 CC 26 IC AFT 94 (446)

Invasive Candidiasis in the critically ill patients Diagnostic utility of 1-3-Beta-D-

Glucan(BDG) anti-mycelium antibodies (CAGTA) mannanantimannan antibodies

(MAA) and detection of Candida DNA (PCR)rdquo CAVA TREM PROJECT

Candida DNA detection (PCR)

To evaluate CS performance ICU patients developing hospital-acquired severe sepsis or septic shock

Prospective multicenter (5 ICUs France) cohort study

n = 94 recruited (IC = 5 53 )

IC rates CS = 2 or 3 0 CS = 4 176 CS = 5 50 (p lt 00001)

CS gt 3 Benefit early SAT

Evaluation of ldquoCandida scorerdquo in critically ill patients a prospective multicenter

observational cohort study Leroy G Lamblotte F Thevenin D Lemaire C Parmentier E Devos P Leroy O

Ann Intens Care 2011150

bull To determine nordm patients w o documented IC received SAT

bull 1-day cross-sectional cohort study 169 ICUs France Belgium

bull n = 2047 recruited

bull n = 154 (75) with SAT (only 54 with IC)

bull Independent predictors SAT

ndash Center-related factors Hospital lt 800 beds (OR 29) organ transplant activity (OR26)

use fluoroquinolones (OR23) use SAT unresolved sepsis (OR19 22 20)

ndash Patient related factors Candida colonization (OR 124) severe sepsis and septic shock (OR47)

emergency surgery (OR 24) hematologic malignancies (OR71)

bull Trend greater impact SAT on survival when CS = 4 or 5

SAT Systemic Antifungal Treatment

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

Crit Care Med 201240813-22

Impact SAT on 28-d mortality according CS

Crit Care Med 201240813-22

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 19: Recordant L Àngels - academia.cat

Candiduria in critically ill patients admitted to intensive care medical units

Francisco Aacutelvarez-Lerma Juan Nolla-Salas Cristobal Leon Mercedes Palomar Ricard

Jorda Nieves Carrasco Felipe Bobillo (EPCAN Study Group)

Intensive Care Med 2003291069ndash76

bull 1765 adult non-neutropenic pts (lt 7 days) Candiduria 389 patients (22)

bull Age 61 y Apache II 19

bull Incidence density 95 episodes1000 days

bull Length of ICU stay since presence of candiduria 16 days

bull Risk factor associated age over 65 y female gender LOS in hospital

before ICU admission diabetes TPN MV previous use of antibiotics

(C no albicans)

bull C albicans 266 (684) C glabrata 32 (82) C tropicalis 14 (36)

bull Candiduria is a risk factor for ICUhospital mortality (OR 158)

Jordaacute Marcos R Alvarez-Lerma F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C

and EPCAN Study Group Mycoses 200750302-10

Risk factors for candidaemia in critically ill patients a prospective

surveillance study

bull 1765 adult non-neutropenic pts (lt 7 days) Candidemia 63 pts

bull Age 63 y Apache II 18 ICUhospital stay 2848 Surgical 29 (46) Medical 26 (413 )

bull ATF treatment 4863 (76)

- FCNZ 32 (667) AFBD 8 (16) LAFB 5 (104) AFBLC 3 (63)

bull ICUhospital Mortality 34 (54)-39 (73)

Assessment of candidemia-attributable mortality in critically ill patients using

propensity score matching analysis Francisco J Gonzaacutelez de Molina Cristoacutebal Leoacuten Sergio Ruiz-Santana and Pedro Saavedra for the

CAVA I Study Group

Crit Care 201216 R105

Critical Care 2012 16R105

bull The use of propensity score matching analysis to control for all potential confounding

variables allowed the assessment of candidemia-attributable mortality in critically ill

patients

bull Candidemia was not associated with an increase in either ICU or hospital

mortality

bull Earlier treatment of bloodstream infection and better monitoring (surveillance sampling

weekly) resulting in appropriate antifungal agent may contribute to increased survival

bull APACHE II at the time of diagnosis of candidemia was the only predictor of death in

patients with candidemia

bull 1107 pts 38 (34) candidemias Propensity score matching analysis

(Candidemia 70 no 35 yes)

Multicenter observational prospective

C Score biomarkers amp IC

18 ICUs n = 176 (SAC) 4 wks Study 2009-10

ICU gt 7 days

C Score BG CAGTA others Weekly (x 2) screening

Optional Samples related clinical situation follow up

Variables demographics APACHE II SOFA (admission weekly x 2 starting antifungals) comorbid

diseases risk factors antifungal therapy and outcome

Adult patients admitted ICU ge 7 days SAC = Severe Abdominal Conditions

CAGTA = Candida albicans germ-tube antibody

1st 2nd 3rd 4th 3d

Intensive Care Med 2012 381315-25

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating between

Candida colonization and invasive candidiasis in patients with severe abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J Aacutelvarez L

Utande A Farintildeas O and the Study Group Cava II

- Patients with Candida colonization A model for IC prediction was obtained

using Classification And Regression Trees (CART)

- Variables used maximum values biomarkers before during development IC or highest value when IC did not

developed (Apache-II BG CAGTA)

- CART through a process of binary recursive spliting of the datasets based on rules of the form if-then-else identifies

a set of predictors of IC estimating the probabilities of IC according to the values of predictors

- The discriminate value of the probabilities of IC obtained by the CART was evaluated by the receiver characteristic

operating (ROC) curve

- Predictive rule identify patients have an IC risk when probability to develop

IC is ge 30(cut-off chosen by CART algorithm to minimize error measurement = deviance)

- Obtained rule estimated Sensitivity Specificity PPV NPV

- Data analysis carried out using R-package

CART prediction rule model

Breiman L et al (1984) Classfication and regression trees

Belmont CA Wadsworth International

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

n = 115 pts

IC = 31 (27 )

n = 27 pts

IC = 16 (599)

n = 88 pts

IC = 15 (170)

n = 49 pts

IC = 3 (61 )

n = 39 pts

IC = 12 (308 )

B-glucan ge 259 pgml

CAGTA positive B-glucan lt 329 pgml

B-glucan lt 259 pgml

CAGTA negative

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

Diagnostic accuracy of CART-derived prediction rule BG (cut-off

gt 259 pgmL) CAGTA (cutt-off positive) and CS for IC diagnosis

Area under

ROC curve

(95 CI)

Sensitivity

(95 CI)

Specificity

(95 CI)

Predictive value

Positive

(95 CI)

Negative

(95 CI)

CART analysis

078

(076-081)

903

(751-966)

547

(441-650)

424

(312-544)

939

(835-979)

BG

067

(059-074)

516

(348-680)

869

(780-925)

593

(407-755)

830

(738-894)

CAGTA

067

(063-070)

710

(534-839)

573

(465-675)

386

(271-516)

839

(722-913)

CS 062

(058-066)

935

(792-982)

181

(113-277)

299

(217-396)

882

(65-7-967)

CART classification and regression tree analysis BG beta-D-glucan CAGTA Candida albicans germ tube antibody Total number of patients with

Candida spp colonization = 115

Usefulness of the (13)--D-Glucan and Candida albicans germ tube antibody in the

Diagnosis of Invasive Candidiasis in Non-neutropenic Critically Ill Patients (non selected)

201112 One ICU (HUV) 105 NNCIP non selected gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida colonization

cultures (rectal swabs tracheal pharyngeal or gastric aspirates and urine) and serum

BG and CAGTA Were collected factors can interfere with the levels of BG (RRT AC

PT use of blood transfusions surgeryhellip)

NCNI

(n = 42)

Colonized

(n = 52)

Candidemia

(n = 6)

Peritonitis

(n =5)

P

value

Age years mean (range) 66 (50-73) 63 (54-76) 68 (62-78) 67 (62-70) 0820

Malefemale patients 3210 2527 42 50 0007

BG pgmL

Median (IQR)

Maximum (IQR)

44 (31-102)

77 (31-140)

40 (31-140)

150 (47-500)

72 ( 31-300)

194 (120-300)

31 (31-31)

50 (31-80)

0527

0037

CAGTA positives n () 13 (310) 26 (500) 3 (500) 1 (200) 0203

Instituto Salud Carlos III Madrid Spain (FIS PI 1002110) ICAAC 2013 (M-1380)

Conclusions

Patients with candidemia and Candida spp colonization showed significantly higher values

of serum BG than neither colonized or infected patients

NCNI neither colonized nor infected BG B-D- glucan IQR interquartile range (25th-75th percentile) CAGTA Candida albicans germ

tube antibodies Significant differences as compared with the NCNI group

CAVA FIS PROJECT

Prospective cohort observational multicenter study

201214 12 ICUs NNCIP selected (SAC) gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida

colonization cultures (rectal swabs tracheal pharyngeal urine) and serum (BG and

CAGTA)

Preliminary data (October 2013) 215 pts included 117 CC 26 IC AFT 94 (446)

Invasive Candidiasis in the critically ill patients Diagnostic utility of 1-3-Beta-D-

Glucan(BDG) anti-mycelium antibodies (CAGTA) mannanantimannan antibodies

(MAA) and detection of Candida DNA (PCR)rdquo CAVA TREM PROJECT

Candida DNA detection (PCR)

To evaluate CS performance ICU patients developing hospital-acquired severe sepsis or septic shock

Prospective multicenter (5 ICUs France) cohort study

n = 94 recruited (IC = 5 53 )

IC rates CS = 2 or 3 0 CS = 4 176 CS = 5 50 (p lt 00001)

CS gt 3 Benefit early SAT

Evaluation of ldquoCandida scorerdquo in critically ill patients a prospective multicenter

observational cohort study Leroy G Lamblotte F Thevenin D Lemaire C Parmentier E Devos P Leroy O

Ann Intens Care 2011150

bull To determine nordm patients w o documented IC received SAT

bull 1-day cross-sectional cohort study 169 ICUs France Belgium

bull n = 2047 recruited

bull n = 154 (75) with SAT (only 54 with IC)

bull Independent predictors SAT

ndash Center-related factors Hospital lt 800 beds (OR 29) organ transplant activity (OR26)

use fluoroquinolones (OR23) use SAT unresolved sepsis (OR19 22 20)

ndash Patient related factors Candida colonization (OR 124) severe sepsis and septic shock (OR47)

emergency surgery (OR 24) hematologic malignancies (OR71)

bull Trend greater impact SAT on survival when CS = 4 or 5

SAT Systemic Antifungal Treatment

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

Crit Care Med 201240813-22

Impact SAT on 28-d mortality according CS

Crit Care Med 201240813-22

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 20: Recordant L Àngels - academia.cat

Jordaacute Marcos R Alvarez-Lerma F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C

and EPCAN Study Group Mycoses 200750302-10

Risk factors for candidaemia in critically ill patients a prospective

surveillance study

bull 1765 adult non-neutropenic pts (lt 7 days) Candidemia 63 pts

bull Age 63 y Apache II 18 ICUhospital stay 2848 Surgical 29 (46) Medical 26 (413 )

bull ATF treatment 4863 (76)

- FCNZ 32 (667) AFBD 8 (16) LAFB 5 (104) AFBLC 3 (63)

bull ICUhospital Mortality 34 (54)-39 (73)

Assessment of candidemia-attributable mortality in critically ill patients using

propensity score matching analysis Francisco J Gonzaacutelez de Molina Cristoacutebal Leoacuten Sergio Ruiz-Santana and Pedro Saavedra for the

CAVA I Study Group

Crit Care 201216 R105

Critical Care 2012 16R105

bull The use of propensity score matching analysis to control for all potential confounding

variables allowed the assessment of candidemia-attributable mortality in critically ill

patients

bull Candidemia was not associated with an increase in either ICU or hospital

mortality

bull Earlier treatment of bloodstream infection and better monitoring (surveillance sampling

weekly) resulting in appropriate antifungal agent may contribute to increased survival

bull APACHE II at the time of diagnosis of candidemia was the only predictor of death in

patients with candidemia

bull 1107 pts 38 (34) candidemias Propensity score matching analysis

(Candidemia 70 no 35 yes)

Multicenter observational prospective

C Score biomarkers amp IC

18 ICUs n = 176 (SAC) 4 wks Study 2009-10

ICU gt 7 days

C Score BG CAGTA others Weekly (x 2) screening

Optional Samples related clinical situation follow up

Variables demographics APACHE II SOFA (admission weekly x 2 starting antifungals) comorbid

diseases risk factors antifungal therapy and outcome

Adult patients admitted ICU ge 7 days SAC = Severe Abdominal Conditions

CAGTA = Candida albicans germ-tube antibody

1st 2nd 3rd 4th 3d

Intensive Care Med 2012 381315-25

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating between

Candida colonization and invasive candidiasis in patients with severe abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J Aacutelvarez L

Utande A Farintildeas O and the Study Group Cava II

- Patients with Candida colonization A model for IC prediction was obtained

using Classification And Regression Trees (CART)

- Variables used maximum values biomarkers before during development IC or highest value when IC did not

developed (Apache-II BG CAGTA)

- CART through a process of binary recursive spliting of the datasets based on rules of the form if-then-else identifies

a set of predictors of IC estimating the probabilities of IC according to the values of predictors

- The discriminate value of the probabilities of IC obtained by the CART was evaluated by the receiver characteristic

operating (ROC) curve

- Predictive rule identify patients have an IC risk when probability to develop

IC is ge 30(cut-off chosen by CART algorithm to minimize error measurement = deviance)

- Obtained rule estimated Sensitivity Specificity PPV NPV

- Data analysis carried out using R-package

CART prediction rule model

Breiman L et al (1984) Classfication and regression trees

Belmont CA Wadsworth International

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

n = 115 pts

IC = 31 (27 )

n = 27 pts

IC = 16 (599)

n = 88 pts

IC = 15 (170)

n = 49 pts

IC = 3 (61 )

n = 39 pts

IC = 12 (308 )

B-glucan ge 259 pgml

CAGTA positive B-glucan lt 329 pgml

B-glucan lt 259 pgml

CAGTA negative

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

Diagnostic accuracy of CART-derived prediction rule BG (cut-off

gt 259 pgmL) CAGTA (cutt-off positive) and CS for IC diagnosis

Area under

ROC curve

(95 CI)

Sensitivity

(95 CI)

Specificity

(95 CI)

Predictive value

Positive

(95 CI)

Negative

(95 CI)

CART analysis

078

(076-081)

903

(751-966)

547

(441-650)

424

(312-544)

939

(835-979)

BG

067

(059-074)

516

(348-680)

869

(780-925)

593

(407-755)

830

(738-894)

CAGTA

067

(063-070)

710

(534-839)

573

(465-675)

386

(271-516)

839

(722-913)

CS 062

(058-066)

935

(792-982)

181

(113-277)

299

(217-396)

882

(65-7-967)

CART classification and regression tree analysis BG beta-D-glucan CAGTA Candida albicans germ tube antibody Total number of patients with

Candida spp colonization = 115

Usefulness of the (13)--D-Glucan and Candida albicans germ tube antibody in the

Diagnosis of Invasive Candidiasis in Non-neutropenic Critically Ill Patients (non selected)

201112 One ICU (HUV) 105 NNCIP non selected gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida colonization

cultures (rectal swabs tracheal pharyngeal or gastric aspirates and urine) and serum

BG and CAGTA Were collected factors can interfere with the levels of BG (RRT AC

PT use of blood transfusions surgeryhellip)

NCNI

(n = 42)

Colonized

(n = 52)

Candidemia

(n = 6)

Peritonitis

(n =5)

P

value

Age years mean (range) 66 (50-73) 63 (54-76) 68 (62-78) 67 (62-70) 0820

Malefemale patients 3210 2527 42 50 0007

BG pgmL

Median (IQR)

Maximum (IQR)

44 (31-102)

77 (31-140)

40 (31-140)

150 (47-500)

72 ( 31-300)

194 (120-300)

31 (31-31)

50 (31-80)

0527

0037

CAGTA positives n () 13 (310) 26 (500) 3 (500) 1 (200) 0203

Instituto Salud Carlos III Madrid Spain (FIS PI 1002110) ICAAC 2013 (M-1380)

Conclusions

Patients with candidemia and Candida spp colonization showed significantly higher values

of serum BG than neither colonized or infected patients

NCNI neither colonized nor infected BG B-D- glucan IQR interquartile range (25th-75th percentile) CAGTA Candida albicans germ

tube antibodies Significant differences as compared with the NCNI group

CAVA FIS PROJECT

Prospective cohort observational multicenter study

201214 12 ICUs NNCIP selected (SAC) gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida

colonization cultures (rectal swabs tracheal pharyngeal urine) and serum (BG and

CAGTA)

Preliminary data (October 2013) 215 pts included 117 CC 26 IC AFT 94 (446)

Invasive Candidiasis in the critically ill patients Diagnostic utility of 1-3-Beta-D-

Glucan(BDG) anti-mycelium antibodies (CAGTA) mannanantimannan antibodies

(MAA) and detection of Candida DNA (PCR)rdquo CAVA TREM PROJECT

Candida DNA detection (PCR)

To evaluate CS performance ICU patients developing hospital-acquired severe sepsis or septic shock

Prospective multicenter (5 ICUs France) cohort study

n = 94 recruited (IC = 5 53 )

IC rates CS = 2 or 3 0 CS = 4 176 CS = 5 50 (p lt 00001)

CS gt 3 Benefit early SAT

Evaluation of ldquoCandida scorerdquo in critically ill patients a prospective multicenter

observational cohort study Leroy G Lamblotte F Thevenin D Lemaire C Parmentier E Devos P Leroy O

Ann Intens Care 2011150

bull To determine nordm patients w o documented IC received SAT

bull 1-day cross-sectional cohort study 169 ICUs France Belgium

bull n = 2047 recruited

bull n = 154 (75) with SAT (only 54 with IC)

bull Independent predictors SAT

ndash Center-related factors Hospital lt 800 beds (OR 29) organ transplant activity (OR26)

use fluoroquinolones (OR23) use SAT unresolved sepsis (OR19 22 20)

ndash Patient related factors Candida colonization (OR 124) severe sepsis and septic shock (OR47)

emergency surgery (OR 24) hematologic malignancies (OR71)

bull Trend greater impact SAT on survival when CS = 4 or 5

SAT Systemic Antifungal Treatment

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

Crit Care Med 201240813-22

Impact SAT on 28-d mortality according CS

Crit Care Med 201240813-22

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 21: Recordant L Àngels - academia.cat

Assessment of candidemia-attributable mortality in critically ill patients using

propensity score matching analysis Francisco J Gonzaacutelez de Molina Cristoacutebal Leoacuten Sergio Ruiz-Santana and Pedro Saavedra for the

CAVA I Study Group

Crit Care 201216 R105

Critical Care 2012 16R105

bull The use of propensity score matching analysis to control for all potential confounding

variables allowed the assessment of candidemia-attributable mortality in critically ill

patients

bull Candidemia was not associated with an increase in either ICU or hospital

mortality

bull Earlier treatment of bloodstream infection and better monitoring (surveillance sampling

weekly) resulting in appropriate antifungal agent may contribute to increased survival

bull APACHE II at the time of diagnosis of candidemia was the only predictor of death in

patients with candidemia

bull 1107 pts 38 (34) candidemias Propensity score matching analysis

(Candidemia 70 no 35 yes)

Multicenter observational prospective

C Score biomarkers amp IC

18 ICUs n = 176 (SAC) 4 wks Study 2009-10

ICU gt 7 days

C Score BG CAGTA others Weekly (x 2) screening

Optional Samples related clinical situation follow up

Variables demographics APACHE II SOFA (admission weekly x 2 starting antifungals) comorbid

diseases risk factors antifungal therapy and outcome

Adult patients admitted ICU ge 7 days SAC = Severe Abdominal Conditions

CAGTA = Candida albicans germ-tube antibody

1st 2nd 3rd 4th 3d

Intensive Care Med 2012 381315-25

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating between

Candida colonization and invasive candidiasis in patients with severe abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J Aacutelvarez L

Utande A Farintildeas O and the Study Group Cava II

- Patients with Candida colonization A model for IC prediction was obtained

using Classification And Regression Trees (CART)

- Variables used maximum values biomarkers before during development IC or highest value when IC did not

developed (Apache-II BG CAGTA)

- CART through a process of binary recursive spliting of the datasets based on rules of the form if-then-else identifies

a set of predictors of IC estimating the probabilities of IC according to the values of predictors

- The discriminate value of the probabilities of IC obtained by the CART was evaluated by the receiver characteristic

operating (ROC) curve

- Predictive rule identify patients have an IC risk when probability to develop

IC is ge 30(cut-off chosen by CART algorithm to minimize error measurement = deviance)

- Obtained rule estimated Sensitivity Specificity PPV NPV

- Data analysis carried out using R-package

CART prediction rule model

Breiman L et al (1984) Classfication and regression trees

Belmont CA Wadsworth International

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

n = 115 pts

IC = 31 (27 )

n = 27 pts

IC = 16 (599)

n = 88 pts

IC = 15 (170)

n = 49 pts

IC = 3 (61 )

n = 39 pts

IC = 12 (308 )

B-glucan ge 259 pgml

CAGTA positive B-glucan lt 329 pgml

B-glucan lt 259 pgml

CAGTA negative

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

Diagnostic accuracy of CART-derived prediction rule BG (cut-off

gt 259 pgmL) CAGTA (cutt-off positive) and CS for IC diagnosis

Area under

ROC curve

(95 CI)

Sensitivity

(95 CI)

Specificity

(95 CI)

Predictive value

Positive

(95 CI)

Negative

(95 CI)

CART analysis

078

(076-081)

903

(751-966)

547

(441-650)

424

(312-544)

939

(835-979)

BG

067

(059-074)

516

(348-680)

869

(780-925)

593

(407-755)

830

(738-894)

CAGTA

067

(063-070)

710

(534-839)

573

(465-675)

386

(271-516)

839

(722-913)

CS 062

(058-066)

935

(792-982)

181

(113-277)

299

(217-396)

882

(65-7-967)

CART classification and regression tree analysis BG beta-D-glucan CAGTA Candida albicans germ tube antibody Total number of patients with

Candida spp colonization = 115

Usefulness of the (13)--D-Glucan and Candida albicans germ tube antibody in the

Diagnosis of Invasive Candidiasis in Non-neutropenic Critically Ill Patients (non selected)

201112 One ICU (HUV) 105 NNCIP non selected gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida colonization

cultures (rectal swabs tracheal pharyngeal or gastric aspirates and urine) and serum

BG and CAGTA Were collected factors can interfere with the levels of BG (RRT AC

PT use of blood transfusions surgeryhellip)

NCNI

(n = 42)

Colonized

(n = 52)

Candidemia

(n = 6)

Peritonitis

(n =5)

P

value

Age years mean (range) 66 (50-73) 63 (54-76) 68 (62-78) 67 (62-70) 0820

Malefemale patients 3210 2527 42 50 0007

BG pgmL

Median (IQR)

Maximum (IQR)

44 (31-102)

77 (31-140)

40 (31-140)

150 (47-500)

72 ( 31-300)

194 (120-300)

31 (31-31)

50 (31-80)

0527

0037

CAGTA positives n () 13 (310) 26 (500) 3 (500) 1 (200) 0203

Instituto Salud Carlos III Madrid Spain (FIS PI 1002110) ICAAC 2013 (M-1380)

Conclusions

Patients with candidemia and Candida spp colonization showed significantly higher values

of serum BG than neither colonized or infected patients

NCNI neither colonized nor infected BG B-D- glucan IQR interquartile range (25th-75th percentile) CAGTA Candida albicans germ

tube antibodies Significant differences as compared with the NCNI group

CAVA FIS PROJECT

Prospective cohort observational multicenter study

201214 12 ICUs NNCIP selected (SAC) gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida

colonization cultures (rectal swabs tracheal pharyngeal urine) and serum (BG and

CAGTA)

Preliminary data (October 2013) 215 pts included 117 CC 26 IC AFT 94 (446)

Invasive Candidiasis in the critically ill patients Diagnostic utility of 1-3-Beta-D-

Glucan(BDG) anti-mycelium antibodies (CAGTA) mannanantimannan antibodies

(MAA) and detection of Candida DNA (PCR)rdquo CAVA TREM PROJECT

Candida DNA detection (PCR)

To evaluate CS performance ICU patients developing hospital-acquired severe sepsis or septic shock

Prospective multicenter (5 ICUs France) cohort study

n = 94 recruited (IC = 5 53 )

IC rates CS = 2 or 3 0 CS = 4 176 CS = 5 50 (p lt 00001)

CS gt 3 Benefit early SAT

Evaluation of ldquoCandida scorerdquo in critically ill patients a prospective multicenter

observational cohort study Leroy G Lamblotte F Thevenin D Lemaire C Parmentier E Devos P Leroy O

Ann Intens Care 2011150

bull To determine nordm patients w o documented IC received SAT

bull 1-day cross-sectional cohort study 169 ICUs France Belgium

bull n = 2047 recruited

bull n = 154 (75) with SAT (only 54 with IC)

bull Independent predictors SAT

ndash Center-related factors Hospital lt 800 beds (OR 29) organ transplant activity (OR26)

use fluoroquinolones (OR23) use SAT unresolved sepsis (OR19 22 20)

ndash Patient related factors Candida colonization (OR 124) severe sepsis and septic shock (OR47)

emergency surgery (OR 24) hematologic malignancies (OR71)

bull Trend greater impact SAT on survival when CS = 4 or 5

SAT Systemic Antifungal Treatment

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

Crit Care Med 201240813-22

Impact SAT on 28-d mortality according CS

Crit Care Med 201240813-22

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 22: Recordant L Àngels - academia.cat

Multicenter observational prospective

C Score biomarkers amp IC

18 ICUs n = 176 (SAC) 4 wks Study 2009-10

ICU gt 7 days

C Score BG CAGTA others Weekly (x 2) screening

Optional Samples related clinical situation follow up

Variables demographics APACHE II SOFA (admission weekly x 2 starting antifungals) comorbid

diseases risk factors antifungal therapy and outcome

Adult patients admitted ICU ge 7 days SAC = Severe Abdominal Conditions

CAGTA = Candida albicans germ-tube antibody

1st 2nd 3rd 4th 3d

Intensive Care Med 2012 381315-25

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating between

Candida colonization and invasive candidiasis in patients with severe abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J Aacutelvarez L

Utande A Farintildeas O and the Study Group Cava II

- Patients with Candida colonization A model for IC prediction was obtained

using Classification And Regression Trees (CART)

- Variables used maximum values biomarkers before during development IC or highest value when IC did not

developed (Apache-II BG CAGTA)

- CART through a process of binary recursive spliting of the datasets based on rules of the form if-then-else identifies

a set of predictors of IC estimating the probabilities of IC according to the values of predictors

- The discriminate value of the probabilities of IC obtained by the CART was evaluated by the receiver characteristic

operating (ROC) curve

- Predictive rule identify patients have an IC risk when probability to develop

IC is ge 30(cut-off chosen by CART algorithm to minimize error measurement = deviance)

- Obtained rule estimated Sensitivity Specificity PPV NPV

- Data analysis carried out using R-package

CART prediction rule model

Breiman L et al (1984) Classfication and regression trees

Belmont CA Wadsworth International

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

n = 115 pts

IC = 31 (27 )

n = 27 pts

IC = 16 (599)

n = 88 pts

IC = 15 (170)

n = 49 pts

IC = 3 (61 )

n = 39 pts

IC = 12 (308 )

B-glucan ge 259 pgml

CAGTA positive B-glucan lt 329 pgml

B-glucan lt 259 pgml

CAGTA negative

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

Diagnostic accuracy of CART-derived prediction rule BG (cut-off

gt 259 pgmL) CAGTA (cutt-off positive) and CS for IC diagnosis

Area under

ROC curve

(95 CI)

Sensitivity

(95 CI)

Specificity

(95 CI)

Predictive value

Positive

(95 CI)

Negative

(95 CI)

CART analysis

078

(076-081)

903

(751-966)

547

(441-650)

424

(312-544)

939

(835-979)

BG

067

(059-074)

516

(348-680)

869

(780-925)

593

(407-755)

830

(738-894)

CAGTA

067

(063-070)

710

(534-839)

573

(465-675)

386

(271-516)

839

(722-913)

CS 062

(058-066)

935

(792-982)

181

(113-277)

299

(217-396)

882

(65-7-967)

CART classification and regression tree analysis BG beta-D-glucan CAGTA Candida albicans germ tube antibody Total number of patients with

Candida spp colonization = 115

Usefulness of the (13)--D-Glucan and Candida albicans germ tube antibody in the

Diagnosis of Invasive Candidiasis in Non-neutropenic Critically Ill Patients (non selected)

201112 One ICU (HUV) 105 NNCIP non selected gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida colonization

cultures (rectal swabs tracheal pharyngeal or gastric aspirates and urine) and serum

BG and CAGTA Were collected factors can interfere with the levels of BG (RRT AC

PT use of blood transfusions surgeryhellip)

NCNI

(n = 42)

Colonized

(n = 52)

Candidemia

(n = 6)

Peritonitis

(n =5)

P

value

Age years mean (range) 66 (50-73) 63 (54-76) 68 (62-78) 67 (62-70) 0820

Malefemale patients 3210 2527 42 50 0007

BG pgmL

Median (IQR)

Maximum (IQR)

44 (31-102)

77 (31-140)

40 (31-140)

150 (47-500)

72 ( 31-300)

194 (120-300)

31 (31-31)

50 (31-80)

0527

0037

CAGTA positives n () 13 (310) 26 (500) 3 (500) 1 (200) 0203

Instituto Salud Carlos III Madrid Spain (FIS PI 1002110) ICAAC 2013 (M-1380)

Conclusions

Patients with candidemia and Candida spp colonization showed significantly higher values

of serum BG than neither colonized or infected patients

NCNI neither colonized nor infected BG B-D- glucan IQR interquartile range (25th-75th percentile) CAGTA Candida albicans germ

tube antibodies Significant differences as compared with the NCNI group

CAVA FIS PROJECT

Prospective cohort observational multicenter study

201214 12 ICUs NNCIP selected (SAC) gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida

colonization cultures (rectal swabs tracheal pharyngeal urine) and serum (BG and

CAGTA)

Preliminary data (October 2013) 215 pts included 117 CC 26 IC AFT 94 (446)

Invasive Candidiasis in the critically ill patients Diagnostic utility of 1-3-Beta-D-

Glucan(BDG) anti-mycelium antibodies (CAGTA) mannanantimannan antibodies

(MAA) and detection of Candida DNA (PCR)rdquo CAVA TREM PROJECT

Candida DNA detection (PCR)

To evaluate CS performance ICU patients developing hospital-acquired severe sepsis or septic shock

Prospective multicenter (5 ICUs France) cohort study

n = 94 recruited (IC = 5 53 )

IC rates CS = 2 or 3 0 CS = 4 176 CS = 5 50 (p lt 00001)

CS gt 3 Benefit early SAT

Evaluation of ldquoCandida scorerdquo in critically ill patients a prospective multicenter

observational cohort study Leroy G Lamblotte F Thevenin D Lemaire C Parmentier E Devos P Leroy O

Ann Intens Care 2011150

bull To determine nordm patients w o documented IC received SAT

bull 1-day cross-sectional cohort study 169 ICUs France Belgium

bull n = 2047 recruited

bull n = 154 (75) with SAT (only 54 with IC)

bull Independent predictors SAT

ndash Center-related factors Hospital lt 800 beds (OR 29) organ transplant activity (OR26)

use fluoroquinolones (OR23) use SAT unresolved sepsis (OR19 22 20)

ndash Patient related factors Candida colonization (OR 124) severe sepsis and septic shock (OR47)

emergency surgery (OR 24) hematologic malignancies (OR71)

bull Trend greater impact SAT on survival when CS = 4 or 5

SAT Systemic Antifungal Treatment

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

Crit Care Med 201240813-22

Impact SAT on 28-d mortality according CS

Crit Care Med 201240813-22

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 23: Recordant L Àngels - academia.cat

- Patients with Candida colonization A model for IC prediction was obtained

using Classification And Regression Trees (CART)

- Variables used maximum values biomarkers before during development IC or highest value when IC did not

developed (Apache-II BG CAGTA)

- CART through a process of binary recursive spliting of the datasets based on rules of the form if-then-else identifies

a set of predictors of IC estimating the probabilities of IC according to the values of predictors

- The discriminate value of the probabilities of IC obtained by the CART was evaluated by the receiver characteristic

operating (ROC) curve

- Predictive rule identify patients have an IC risk when probability to develop

IC is ge 30(cut-off chosen by CART algorithm to minimize error measurement = deviance)

- Obtained rule estimated Sensitivity Specificity PPV NPV

- Data analysis carried out using R-package

CART prediction rule model

Breiman L et al (1984) Classfication and regression trees

Belmont CA Wadsworth International

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions

Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

n = 115 pts

IC = 31 (27 )

n = 27 pts

IC = 16 (599)

n = 88 pts

IC = 15 (170)

n = 49 pts

IC = 3 (61 )

n = 39 pts

IC = 12 (308 )

B-glucan ge 259 pgml

CAGTA positive B-glucan lt 329 pgml

B-glucan lt 259 pgml

CAGTA negative

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

Diagnostic accuracy of CART-derived prediction rule BG (cut-off

gt 259 pgmL) CAGTA (cutt-off positive) and CS for IC diagnosis

Area under

ROC curve

(95 CI)

Sensitivity

(95 CI)

Specificity

(95 CI)

Predictive value

Positive

(95 CI)

Negative

(95 CI)

CART analysis

078

(076-081)

903

(751-966)

547

(441-650)

424

(312-544)

939

(835-979)

BG

067

(059-074)

516

(348-680)

869

(780-925)

593

(407-755)

830

(738-894)

CAGTA

067

(063-070)

710

(534-839)

573

(465-675)

386

(271-516)

839

(722-913)

CS 062

(058-066)

935

(792-982)

181

(113-277)

299

(217-396)

882

(65-7-967)

CART classification and regression tree analysis BG beta-D-glucan CAGTA Candida albicans germ tube antibody Total number of patients with

Candida spp colonization = 115

Usefulness of the (13)--D-Glucan and Candida albicans germ tube antibody in the

Diagnosis of Invasive Candidiasis in Non-neutropenic Critically Ill Patients (non selected)

201112 One ICU (HUV) 105 NNCIP non selected gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida colonization

cultures (rectal swabs tracheal pharyngeal or gastric aspirates and urine) and serum

BG and CAGTA Were collected factors can interfere with the levels of BG (RRT AC

PT use of blood transfusions surgeryhellip)

NCNI

(n = 42)

Colonized

(n = 52)

Candidemia

(n = 6)

Peritonitis

(n =5)

P

value

Age years mean (range) 66 (50-73) 63 (54-76) 68 (62-78) 67 (62-70) 0820

Malefemale patients 3210 2527 42 50 0007

BG pgmL

Median (IQR)

Maximum (IQR)

44 (31-102)

77 (31-140)

40 (31-140)

150 (47-500)

72 ( 31-300)

194 (120-300)

31 (31-31)

50 (31-80)

0527

0037

CAGTA positives n () 13 (310) 26 (500) 3 (500) 1 (200) 0203

Instituto Salud Carlos III Madrid Spain (FIS PI 1002110) ICAAC 2013 (M-1380)

Conclusions

Patients with candidemia and Candida spp colonization showed significantly higher values

of serum BG than neither colonized or infected patients

NCNI neither colonized nor infected BG B-D- glucan IQR interquartile range (25th-75th percentile) CAGTA Candida albicans germ

tube antibodies Significant differences as compared with the NCNI group

CAVA FIS PROJECT

Prospective cohort observational multicenter study

201214 12 ICUs NNCIP selected (SAC) gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida

colonization cultures (rectal swabs tracheal pharyngeal urine) and serum (BG and

CAGTA)

Preliminary data (October 2013) 215 pts included 117 CC 26 IC AFT 94 (446)

Invasive Candidiasis in the critically ill patients Diagnostic utility of 1-3-Beta-D-

Glucan(BDG) anti-mycelium antibodies (CAGTA) mannanantimannan antibodies

(MAA) and detection of Candida DNA (PCR)rdquo CAVA TREM PROJECT

Candida DNA detection (PCR)

To evaluate CS performance ICU patients developing hospital-acquired severe sepsis or septic shock

Prospective multicenter (5 ICUs France) cohort study

n = 94 recruited (IC = 5 53 )

IC rates CS = 2 or 3 0 CS = 4 176 CS = 5 50 (p lt 00001)

CS gt 3 Benefit early SAT

Evaluation of ldquoCandida scorerdquo in critically ill patients a prospective multicenter

observational cohort study Leroy G Lamblotte F Thevenin D Lemaire C Parmentier E Devos P Leroy O

Ann Intens Care 2011150

bull To determine nordm patients w o documented IC received SAT

bull 1-day cross-sectional cohort study 169 ICUs France Belgium

bull n = 2047 recruited

bull n = 154 (75) with SAT (only 54 with IC)

bull Independent predictors SAT

ndash Center-related factors Hospital lt 800 beds (OR 29) organ transplant activity (OR26)

use fluoroquinolones (OR23) use SAT unresolved sepsis (OR19 22 20)

ndash Patient related factors Candida colonization (OR 124) severe sepsis and septic shock (OR47)

emergency surgery (OR 24) hematologic malignancies (OR71)

bull Trend greater impact SAT on survival when CS = 4 or 5

SAT Systemic Antifungal Treatment

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

Crit Care Med 201240813-22

Impact SAT on 28-d mortality according CS

Crit Care Med 201240813-22

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 24: Recordant L Àngels - academia.cat

n = 115 pts

IC = 31 (27 )

n = 27 pts

IC = 16 (599)

n = 88 pts

IC = 15 (170)

n = 49 pts

IC = 3 (61 )

n = 39 pts

IC = 12 (308 )

B-glucan ge 259 pgml

CAGTA positive B-glucan lt 329 pgml

B-glucan lt 259 pgml

CAGTA negative

Value of B-D-glucan and Candida albicans germ tube antibody for discriminating

between Candida colonization and invasive candidiasis in patients with severe

abdominal conditions Leoacuten C Ruiz-Santana Saavedra P Castro C Uacutebeda A Loza A Martin E Blanco A Jerez V Balluacutes J

Aacutelvarez L Utande A Farintildeas O and the Study Group Cava II

Intensive Care Med 2012 381315-25

Diagnostic accuracy of CART-derived prediction rule BG (cut-off

gt 259 pgmL) CAGTA (cutt-off positive) and CS for IC diagnosis

Area under

ROC curve

(95 CI)

Sensitivity

(95 CI)

Specificity

(95 CI)

Predictive value

Positive

(95 CI)

Negative

(95 CI)

CART analysis

078

(076-081)

903

(751-966)

547

(441-650)

424

(312-544)

939

(835-979)

BG

067

(059-074)

516

(348-680)

869

(780-925)

593

(407-755)

830

(738-894)

CAGTA

067

(063-070)

710

(534-839)

573

(465-675)

386

(271-516)

839

(722-913)

CS 062

(058-066)

935

(792-982)

181

(113-277)

299

(217-396)

882

(65-7-967)

CART classification and regression tree analysis BG beta-D-glucan CAGTA Candida albicans germ tube antibody Total number of patients with

Candida spp colonization = 115

Usefulness of the (13)--D-Glucan and Candida albicans germ tube antibody in the

Diagnosis of Invasive Candidiasis in Non-neutropenic Critically Ill Patients (non selected)

201112 One ICU (HUV) 105 NNCIP non selected gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida colonization

cultures (rectal swabs tracheal pharyngeal or gastric aspirates and urine) and serum

BG and CAGTA Were collected factors can interfere with the levels of BG (RRT AC

PT use of blood transfusions surgeryhellip)

NCNI

(n = 42)

Colonized

(n = 52)

Candidemia

(n = 6)

Peritonitis

(n =5)

P

value

Age years mean (range) 66 (50-73) 63 (54-76) 68 (62-78) 67 (62-70) 0820

Malefemale patients 3210 2527 42 50 0007

BG pgmL

Median (IQR)

Maximum (IQR)

44 (31-102)

77 (31-140)

40 (31-140)

150 (47-500)

72 ( 31-300)

194 (120-300)

31 (31-31)

50 (31-80)

0527

0037

CAGTA positives n () 13 (310) 26 (500) 3 (500) 1 (200) 0203

Instituto Salud Carlos III Madrid Spain (FIS PI 1002110) ICAAC 2013 (M-1380)

Conclusions

Patients with candidemia and Candida spp colonization showed significantly higher values

of serum BG than neither colonized or infected patients

NCNI neither colonized nor infected BG B-D- glucan IQR interquartile range (25th-75th percentile) CAGTA Candida albicans germ

tube antibodies Significant differences as compared with the NCNI group

CAVA FIS PROJECT

Prospective cohort observational multicenter study

201214 12 ICUs NNCIP selected (SAC) gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida

colonization cultures (rectal swabs tracheal pharyngeal urine) and serum (BG and

CAGTA)

Preliminary data (October 2013) 215 pts included 117 CC 26 IC AFT 94 (446)

Invasive Candidiasis in the critically ill patients Diagnostic utility of 1-3-Beta-D-

Glucan(BDG) anti-mycelium antibodies (CAGTA) mannanantimannan antibodies

(MAA) and detection of Candida DNA (PCR)rdquo CAVA TREM PROJECT

Candida DNA detection (PCR)

To evaluate CS performance ICU patients developing hospital-acquired severe sepsis or septic shock

Prospective multicenter (5 ICUs France) cohort study

n = 94 recruited (IC = 5 53 )

IC rates CS = 2 or 3 0 CS = 4 176 CS = 5 50 (p lt 00001)

CS gt 3 Benefit early SAT

Evaluation of ldquoCandida scorerdquo in critically ill patients a prospective multicenter

observational cohort study Leroy G Lamblotte F Thevenin D Lemaire C Parmentier E Devos P Leroy O

Ann Intens Care 2011150

bull To determine nordm patients w o documented IC received SAT

bull 1-day cross-sectional cohort study 169 ICUs France Belgium

bull n = 2047 recruited

bull n = 154 (75) with SAT (only 54 with IC)

bull Independent predictors SAT

ndash Center-related factors Hospital lt 800 beds (OR 29) organ transplant activity (OR26)

use fluoroquinolones (OR23) use SAT unresolved sepsis (OR19 22 20)

ndash Patient related factors Candida colonization (OR 124) severe sepsis and septic shock (OR47)

emergency surgery (OR 24) hematologic malignancies (OR71)

bull Trend greater impact SAT on survival when CS = 4 or 5

SAT Systemic Antifungal Treatment

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

Crit Care Med 201240813-22

Impact SAT on 28-d mortality according CS

Crit Care Med 201240813-22

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 25: Recordant L Àngels - academia.cat

Diagnostic accuracy of CART-derived prediction rule BG (cut-off

gt 259 pgmL) CAGTA (cutt-off positive) and CS for IC diagnosis

Area under

ROC curve

(95 CI)

Sensitivity

(95 CI)

Specificity

(95 CI)

Predictive value

Positive

(95 CI)

Negative

(95 CI)

CART analysis

078

(076-081)

903

(751-966)

547

(441-650)

424

(312-544)

939

(835-979)

BG

067

(059-074)

516

(348-680)

869

(780-925)

593

(407-755)

830

(738-894)

CAGTA

067

(063-070)

710

(534-839)

573

(465-675)

386

(271-516)

839

(722-913)

CS 062

(058-066)

935

(792-982)

181

(113-277)

299

(217-396)

882

(65-7-967)

CART classification and regression tree analysis BG beta-D-glucan CAGTA Candida albicans germ tube antibody Total number of patients with

Candida spp colonization = 115

Usefulness of the (13)--D-Glucan and Candida albicans germ tube antibody in the

Diagnosis of Invasive Candidiasis in Non-neutropenic Critically Ill Patients (non selected)

201112 One ICU (HUV) 105 NNCIP non selected gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida colonization

cultures (rectal swabs tracheal pharyngeal or gastric aspirates and urine) and serum

BG and CAGTA Were collected factors can interfere with the levels of BG (RRT AC

PT use of blood transfusions surgeryhellip)

NCNI

(n = 42)

Colonized

(n = 52)

Candidemia

(n = 6)

Peritonitis

(n =5)

P

value

Age years mean (range) 66 (50-73) 63 (54-76) 68 (62-78) 67 (62-70) 0820

Malefemale patients 3210 2527 42 50 0007

BG pgmL

Median (IQR)

Maximum (IQR)

44 (31-102)

77 (31-140)

40 (31-140)

150 (47-500)

72 ( 31-300)

194 (120-300)

31 (31-31)

50 (31-80)

0527

0037

CAGTA positives n () 13 (310) 26 (500) 3 (500) 1 (200) 0203

Instituto Salud Carlos III Madrid Spain (FIS PI 1002110) ICAAC 2013 (M-1380)

Conclusions

Patients with candidemia and Candida spp colonization showed significantly higher values

of serum BG than neither colonized or infected patients

NCNI neither colonized nor infected BG B-D- glucan IQR interquartile range (25th-75th percentile) CAGTA Candida albicans germ

tube antibodies Significant differences as compared with the NCNI group

CAVA FIS PROJECT

Prospective cohort observational multicenter study

201214 12 ICUs NNCIP selected (SAC) gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida

colonization cultures (rectal swabs tracheal pharyngeal urine) and serum (BG and

CAGTA)

Preliminary data (October 2013) 215 pts included 117 CC 26 IC AFT 94 (446)

Invasive Candidiasis in the critically ill patients Diagnostic utility of 1-3-Beta-D-

Glucan(BDG) anti-mycelium antibodies (CAGTA) mannanantimannan antibodies

(MAA) and detection of Candida DNA (PCR)rdquo CAVA TREM PROJECT

Candida DNA detection (PCR)

To evaluate CS performance ICU patients developing hospital-acquired severe sepsis or septic shock

Prospective multicenter (5 ICUs France) cohort study

n = 94 recruited (IC = 5 53 )

IC rates CS = 2 or 3 0 CS = 4 176 CS = 5 50 (p lt 00001)

CS gt 3 Benefit early SAT

Evaluation of ldquoCandida scorerdquo in critically ill patients a prospective multicenter

observational cohort study Leroy G Lamblotte F Thevenin D Lemaire C Parmentier E Devos P Leroy O

Ann Intens Care 2011150

bull To determine nordm patients w o documented IC received SAT

bull 1-day cross-sectional cohort study 169 ICUs France Belgium

bull n = 2047 recruited

bull n = 154 (75) with SAT (only 54 with IC)

bull Independent predictors SAT

ndash Center-related factors Hospital lt 800 beds (OR 29) organ transplant activity (OR26)

use fluoroquinolones (OR23) use SAT unresolved sepsis (OR19 22 20)

ndash Patient related factors Candida colonization (OR 124) severe sepsis and septic shock (OR47)

emergency surgery (OR 24) hematologic malignancies (OR71)

bull Trend greater impact SAT on survival when CS = 4 or 5

SAT Systemic Antifungal Treatment

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

Crit Care Med 201240813-22

Impact SAT on 28-d mortality according CS

Crit Care Med 201240813-22

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 26: Recordant L Àngels - academia.cat

Usefulness of the (13)--D-Glucan and Candida albicans germ tube antibody in the

Diagnosis of Invasive Candidiasis in Non-neutropenic Critically Ill Patients (non selected)

201112 One ICU (HUV) 105 NNCIP non selected gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida colonization

cultures (rectal swabs tracheal pharyngeal or gastric aspirates and urine) and serum

BG and CAGTA Were collected factors can interfere with the levels of BG (RRT AC

PT use of blood transfusions surgeryhellip)

NCNI

(n = 42)

Colonized

(n = 52)

Candidemia

(n = 6)

Peritonitis

(n =5)

P

value

Age years mean (range) 66 (50-73) 63 (54-76) 68 (62-78) 67 (62-70) 0820

Malefemale patients 3210 2527 42 50 0007

BG pgmL

Median (IQR)

Maximum (IQR)

44 (31-102)

77 (31-140)

40 (31-140)

150 (47-500)

72 ( 31-300)

194 (120-300)

31 (31-31)

50 (31-80)

0527

0037

CAGTA positives n () 13 (310) 26 (500) 3 (500) 1 (200) 0203

Instituto Salud Carlos III Madrid Spain (FIS PI 1002110) ICAAC 2013 (M-1380)

Conclusions

Patients with candidemia and Candida spp colonization showed significantly higher values

of serum BG than neither colonized or infected patients

NCNI neither colonized nor infected BG B-D- glucan IQR interquartile range (25th-75th percentile) CAGTA Candida albicans germ

tube antibodies Significant differences as compared with the NCNI group

CAVA FIS PROJECT

Prospective cohort observational multicenter study

201214 12 ICUs NNCIP selected (SAC) gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida

colonization cultures (rectal swabs tracheal pharyngeal urine) and serum (BG and

CAGTA)

Preliminary data (October 2013) 215 pts included 117 CC 26 IC AFT 94 (446)

Invasive Candidiasis in the critically ill patients Diagnostic utility of 1-3-Beta-D-

Glucan(BDG) anti-mycelium antibodies (CAGTA) mannanantimannan antibodies

(MAA) and detection of Candida DNA (PCR)rdquo CAVA TREM PROJECT

Candida DNA detection (PCR)

To evaluate CS performance ICU patients developing hospital-acquired severe sepsis or septic shock

Prospective multicenter (5 ICUs France) cohort study

n = 94 recruited (IC = 5 53 )

IC rates CS = 2 or 3 0 CS = 4 176 CS = 5 50 (p lt 00001)

CS gt 3 Benefit early SAT

Evaluation of ldquoCandida scorerdquo in critically ill patients a prospective multicenter

observational cohort study Leroy G Lamblotte F Thevenin D Lemaire C Parmentier E Devos P Leroy O

Ann Intens Care 2011150

bull To determine nordm patients w o documented IC received SAT

bull 1-day cross-sectional cohort study 169 ICUs France Belgium

bull n = 2047 recruited

bull n = 154 (75) with SAT (only 54 with IC)

bull Independent predictors SAT

ndash Center-related factors Hospital lt 800 beds (OR 29) organ transplant activity (OR26)

use fluoroquinolones (OR23) use SAT unresolved sepsis (OR19 22 20)

ndash Patient related factors Candida colonization (OR 124) severe sepsis and septic shock (OR47)

emergency surgery (OR 24) hematologic malignancies (OR71)

bull Trend greater impact SAT on survival when CS = 4 or 5

SAT Systemic Antifungal Treatment

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

Crit Care Med 201240813-22

Impact SAT on 28-d mortality according CS

Crit Care Med 201240813-22

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 27: Recordant L Àngels - academia.cat

Prospective cohort observational multicenter study

201214 12 ICUs NNCIP selected (SAC) gt 7 days

Twice a week Clinical status APACHE II SOFA and Candida score candida

colonization cultures (rectal swabs tracheal pharyngeal urine) and serum (BG and

CAGTA)

Preliminary data (October 2013) 215 pts included 117 CC 26 IC AFT 94 (446)

Invasive Candidiasis in the critically ill patients Diagnostic utility of 1-3-Beta-D-

Glucan(BDG) anti-mycelium antibodies (CAGTA) mannanantimannan antibodies

(MAA) and detection of Candida DNA (PCR)rdquo CAVA TREM PROJECT

Candida DNA detection (PCR)

To evaluate CS performance ICU patients developing hospital-acquired severe sepsis or septic shock

Prospective multicenter (5 ICUs France) cohort study

n = 94 recruited (IC = 5 53 )

IC rates CS = 2 or 3 0 CS = 4 176 CS = 5 50 (p lt 00001)

CS gt 3 Benefit early SAT

Evaluation of ldquoCandida scorerdquo in critically ill patients a prospective multicenter

observational cohort study Leroy G Lamblotte F Thevenin D Lemaire C Parmentier E Devos P Leroy O

Ann Intens Care 2011150

bull To determine nordm patients w o documented IC received SAT

bull 1-day cross-sectional cohort study 169 ICUs France Belgium

bull n = 2047 recruited

bull n = 154 (75) with SAT (only 54 with IC)

bull Independent predictors SAT

ndash Center-related factors Hospital lt 800 beds (OR 29) organ transplant activity (OR26)

use fluoroquinolones (OR23) use SAT unresolved sepsis (OR19 22 20)

ndash Patient related factors Candida colonization (OR 124) severe sepsis and septic shock (OR47)

emergency surgery (OR 24) hematologic malignancies (OR71)

bull Trend greater impact SAT on survival when CS = 4 or 5

SAT Systemic Antifungal Treatment

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

Crit Care Med 201240813-22

Impact SAT on 28-d mortality according CS

Crit Care Med 201240813-22

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 28: Recordant L Àngels - academia.cat

To evaluate CS performance ICU patients developing hospital-acquired severe sepsis or septic shock

Prospective multicenter (5 ICUs France) cohort study

n = 94 recruited (IC = 5 53 )

IC rates CS = 2 or 3 0 CS = 4 176 CS = 5 50 (p lt 00001)

CS gt 3 Benefit early SAT

Evaluation of ldquoCandida scorerdquo in critically ill patients a prospective multicenter

observational cohort study Leroy G Lamblotte F Thevenin D Lemaire C Parmentier E Devos P Leroy O

Ann Intens Care 2011150

bull To determine nordm patients w o documented IC received SAT

bull 1-day cross-sectional cohort study 169 ICUs France Belgium

bull n = 2047 recruited

bull n = 154 (75) with SAT (only 54 with IC)

bull Independent predictors SAT

ndash Center-related factors Hospital lt 800 beds (OR 29) organ transplant activity (OR26)

use fluoroquinolones (OR23) use SAT unresolved sepsis (OR19 22 20)

ndash Patient related factors Candida colonization (OR 124) severe sepsis and septic shock (OR47)

emergency surgery (OR 24) hematologic malignancies (OR71)

bull Trend greater impact SAT on survival when CS = 4 or 5

SAT Systemic Antifungal Treatment

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

Crit Care Med 201240813-22

Impact SAT on 28-d mortality according CS

Crit Care Med 201240813-22

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 29: Recordant L Àngels - academia.cat

bull To determine nordm patients w o documented IC received SAT

bull 1-day cross-sectional cohort study 169 ICUs France Belgium

bull n = 2047 recruited

bull n = 154 (75) with SAT (only 54 with IC)

bull Independent predictors SAT

ndash Center-related factors Hospital lt 800 beds (OR 29) organ transplant activity (OR26)

use fluoroquinolones (OR23) use SAT unresolved sepsis (OR19 22 20)

ndash Patient related factors Candida colonization (OR 124) severe sepsis and septic shock (OR47)

emergency surgery (OR 24) hematologic malignancies (OR71)

bull Trend greater impact SAT on survival when CS = 4 or 5

SAT Systemic Antifungal Treatment

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

Crit Care Med 201240813-22

Impact SAT on 28-d mortality according CS

Crit Care Med 201240813-22

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 30: Recordant L Àngels - academia.cat

Impact SAT on 28-d mortality according CS

Crit Care Med 201240813-22

Systemic antifungal therapy in critically ill patients without invasive fungal

Infections Azoulay E Dupont H Tabak A Lortholary O Stahl JP Francais A Martin C et al

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 31: Recordant L Àngels - academia.cat

bull Prospective single center observational study

bull To compare diagnostic value BG CS CI ICU patients risk IC

bull n = 95 (LOS gt 5 days) clinical sepsis onset BG blood cultures

bull Clinical data surveillance cultures

bull Of 14 IC patients13 candidemias

bull Combination positive BG and CS ge 3 improved IC diagnosis

Sensitivity [100 (95 CI 768 to 100)]

NPV [100 (95 CI 946 to 100)] vs 929 and 987 for

BG test alone

Posteraro et al Critical Care 2011 15R249

Early diagnosis of candidemia in intensive care unit patients with sepsis a

prospective comparison of (1- 3)-B-D-glucan assay Candida score and

colonization index Posteraro B De Pascale G Tumbarello M Torelli R Pennisi MA Bello G Maviglia R Fadda G

Sanguinetti M Antonelli M

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 32: Recordant L Àngels - academia.cat

ndash Prospective cohort study (FUNGINOS)

ndash 89 (205) 434 patients high-risk IAC studied (ICU stay ge72h) 29 IAC + negative blood culture (2729)

ndash BG preceded microbiological documentation IAC and start SAT by five six days (median) respectively

ndash Conclusion BG is superior to cultures CS CI CCI for anticipating diagnosis of blood-culture-negative post-surgical IAC

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Sensit

(95CI)

Specif

(95CI)

PPV

(95CI)

NPV

(95CI)

BG ge 80 pgml 1 x

083

(064 -094)

040

(026-057)

049

(034-064)

077

(055-092)

BG ge 80 pgml 2 x

065

(046-062)

078

(063-090)

068

(048-084)

077

(061-068)

CS ge 3

086

(068-096)

038

(023-054)

049

(035-063)

080

(056-094)

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 33: Recordant L Àngels - academia.cat

Beta-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intra-Abdominal Candidiasis Tissot F Lamoth F Hauser PM et al

Am J Respir Crit Care Med 2013 Jun 19 [Epub ahead of print )

Individual BG kinetics in IAC patients receiving antifungal therapy (n=26)

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 34: Recordant L Àngels - academia.cat

Comparison of BDG test findings in non-neutropenic critically ill adult patients

Author year Patientacutes

type

Number

Ptssamples

(mean)

IC

Type Cut-off

Sensit()

(95 CI)

Spec()

(95 CI)

PPV ()

(95 CI)

NPV ()

(95 CI)

Proven IC

BG

(median)

Tissot 2013 Surgical

Pancreatitis 89921 (9) IAC ge 80

65

(46-82)

78

(63-93)

68

(52-88)

77

63-89) 253

Leoacuten 2012 SAC 176766 (43) C IAC ge 80 516

(34-69)

869

(78-92)

593

(40-75)

830

(73-89) 259

Del Bono 2011 Surgical 152152 (1) C ge 80 62 98 984 573 324

Posteraro 2011 Medical 95130 (13) C ge 80 929

(66-99)

937

(85-90)

722

(46-90)

987

(92-99) 500

Mohr 2011 MedSurg 57239 (41) C ge 80 100 59 NDA NDA 171

Presterl 2009 MedSurg 197 NDA C IAC

HC ge 40

522

(31-76)

759

(62-85)

462

27-66)

80

(66-89) 44

Two consecutive BG determinations pgmL CI Confidence intervals

SAC severe abdominal conditionsIC Invasive Candidiasis C Candidemia IAC Intra-abdominal Candidiasis

HC Hepatic Candidiasis NDA No data available

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 35: Recordant L Àngels - academia.cat

Abdominal Surgery and BG in discriminating between Candida colonization and IC in non-

neutropenic critically ill patients - Prospective multicenter observational cohort studies (Cava I Cava II Cava Fis)

- 435 patients high-risk IC (ICU ge 7 days) medical surgical (177 with abdominal surgery)

- 371 CC 64 IC (IAC 35 Candidemia 28 Chorioretinitis1)

- Twice a week surveillance cultures Candida score and BG

435 pts with CC

Colonized 371 (853)

IAC 35 (80)

Candidemia 29 (67)

258 pts

Colonized 240 (93)

IAC 4 (16)

Candidemia 14 (54)

177 pts

Colonized 131 (74)

IAC 31 (175)

Candidemia 15 ( 85)

136 pts

Colonized 109 (801)

IAC 22 (162)

Candidemia 5 (37)

41 pts

Colonized 22 (537)

IAC 9 (220)

Candidemia 10 (243)

No abdominal surgery Abdominal surgery

RR 95 CI = 372 (226 - 620)

B-glucan ge 329 pgml RR 95 CI = 233 (146-374) B-glucan lt 329 pgml

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 36: Recordant L Àngels - academia.cat

Diagnostic accuracy of CART-derived prediction rule for IC diagnosis

in abdominal surgery patients

Risk of IC among patients with abdominal surgery (n=177)

1-3- β-D- glucan IC RR (95 CI)

le 80 (n = 74) 203 1

gt 80 (n = 103) 301 148 (087255)

lt 329 (n = 136) 199 1

ge 329 (n = 41) 463 233 (146 374)

pgml

pgml

Area Under

ROC Curve Sensitivity

(95 CI) Specificity

(95 CI) PPV

(95 CI) NPV

(95 CI)

0713 718

(598 - 814) 646

(597 - 693) 259

(200 - 329) 930

(892 - 955)

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 37: Recordant L Àngels - academia.cat

Num Tituloautoresrevista Citas

1

A bedside scoring system (ldquoCandida scorerdquo) for early antifungal treatment in nonneutropenic

critically ill patients with Candida Colonization Cristoacutebal Leoacuten Sergio Ruiz-Santana Pedro

Saavedra Benito Almirante Juan Nolla-Salas Francisco Aacutelvarez-Lerma Joseacute Garnacho-

Montero Mariacutea Aacutengeles Leoacuten and EPCAN Study Group Crit Care Med 2006 34730-37

307

2

Candidemia in non-neutropenic critically ill patients analysis of prognostic factors and

assessment of systemic antifungal therapy J Nolla-Salas A Sitges-Serra C Leoacuten-Gil J

Martiacutenez-Gonzaacutelez MA Leoacuten-Regidor P Ibantildeez-Luciacutea JM Torres-Rodriacuteguez Study Group

of Fungal Infection in the ICU Intensive Care Med 1997 2323-30

227

3

Economic Impact of Candida Colonization and Candida Infection in the Critically Ill Patient

Olaechea PM Palomar M Leoacuten-Gil C Aacutelvarez-Lerma F Jordaacute R Nolla-Salas J Leoacuten-Regidor

MA and EPCAN Study Group Eur J Clin Microbiol Infect Dis 200423323-30

100

4

Risk factors for candidaemia in critically ill patients a prospective surveillance study Jordaacute R

Alvarez F Jurado M Palomar M Nolla-Salas J Leoacuten MA Leoacuten C and EPCAN Study Group

Mycoses 200750302-10

48

5

Fungal colonization andor infection in non-neutropenic critically ill patients results of the

EPCAN observational study Leoacuten C Aacutelvarez-Lerma F Ruiz-Santana S Leoacuten MA Nolla J

Jordaacute R Saavedra P Palomar M and EPCAN Study Group

Eur J Clin Microbiol Infect Dis 200928233-42

33

6

Ibantildeez-Nolla J Torres-Rodriguez JM Nolla M Leoacuten MA Mendez R Soria G Diaz RM

Marrugat J The utility of serology in diagnosing candidosis in non-neutropenic critically ill

patients Mycoses 20014447-53

17

Citaciones

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 38: Recordant L Àngels - academia.cat

1- Fraser VJ et al CID 1992

Barnes Hospital 1988-89 (20-fold increase in incidence)

Mortality 63 (in patients without AFT)

2- Rex JH et al NEJM 1996

FCNZ is as effective as AFBD

3- Mora-Duarte J et al NEJM 2002

Caspofungin and AFB

4- Andes DR et al CID 2012

Review 1915 patients (7 randomized clinical trials)

Echinocandin use is associated with improved survival and greater clinical

success than azoles or AFB

The end of an era in defining the optimal treatment of invasIve candidiasis Clancy CJ Nguyen NH

CID 2012541123-5

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 39: Recordant L Àngels - academia.cat

Invasive candidiasis in critically ill patients does progressing knowledge

improve clinical management and outcome Marchetti O Eggimann P Calandra T

Current Opin Crit Care 201016442ndash4

ldquoIn summary major advances in our understanding of the pathogenesis of

Candida infections and recent improvements regarding diagnosis clinical

assessment and therapy of invasive candidiasis have opened new

perspectives for better prevention and treatment of invasive candidiasis in

critically ill patientsrdquo

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 40: Recordant L Àngels - academia.cat

1 Epidemiological aspects Candida spp rate of CCIC date of

appearance time (CCIC) etc

2 Practical consequences Mortality (attributable) ATFT (over)

3 Clinical scenario surgical patients (abdominal)

4 IC prediction rules (better stratification)

- Colonization index Ostrosky rule Candida Score

5 Candida Score amp clinical use

6 Candida Score amp biomarkers

7 Candida DNA detection (RT- in house PCR)

3 What this studyproject adds to our knowledge

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 41: Recordant L Àngels - academia.cat

1- Neither Candida colonizationinfection

2- Candida colonization

- Low grade

- High grade (heavy)

3- Candida infection

- Candidemia

- Candidemia primary

- Catheter-related Candidemia

- Deep - seated infection

- Intra-abdominal candidiasis

- Others

- Pleural candidiasis

- Ocular candidiasis

- Candida meningitis

- Candida endocarditis

Categorization of Candida colonization infection in ICU

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 42: Recordant L Àngels - academia.cat

TargetedIC documented

EmpiricalClinical symptoms

Pre-emptivePrediction rules + risk factors

Prophylaxis High risk for Candida infection

EARLYPrediction rules + clinical

symptoms + biomarkersCandida DNA

detection

Systemic Antifungal Treatment Modalities

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 43: Recordant L Àngels - academia.cat

4 How this is relevant to clinical practice

High Risk of IC (Clinical Prediction Rules)

Biomarkers (combination)Candida DNA detection

ATF therapy

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 44: Recordant L Àngels - academia.cat

Future

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 45: Recordant L Àngels - academia.cat

Neely LA et al Science Translat Med 20135182ra54

This study shows that the nanoparticle- and T2MR- based detection method is

rapid and amenable to automation and offers clinicians the opportunity to detect

and identify multiple human pathogens within hours(3) of sample collection

Gracias por su atencioacuten

Page 46: Recordant L Àngels - academia.cat

Gracias por su atencioacuten

Page 47: Recordant L Àngels - academia.cat