Invasive Candida Infections in the ICU

B. GueryLille

Infectious Diseases Summit: Fungal Series

Invasive Candida infections in the ICU

Epidemiology and pathophysiology Diagnosis The molecules Key studies Available guidelines

Nosocomial infections

29%

17%30%

24%

P. aeruginosaCandida sppS. aureusOthers

Vincent et al, JAMA 1995

Incidence (/1000)

Beck JID 1993

Candida infections

Invasive Candidiasis 10

Documented colonisations 200 ?

Unknown colonisations 800?

Candidemia 1

Increasing rate of candidiasis in the US

Martin et al, NEJM 2003;348:1546

+300%

+300%

+600%

Viridans streptococci

E. coli

S. aureus

Coag neg staph

P. aeruginosa

Enterobacter spp

Candida spp

Klebsiella spp

Enterocci

Serratia spp

0 5 10 15 20 25

22,5 days

Edmond et al, Clin Inf Dis 1999

Epidemiology of candidemia

Tortorano Trick Diekema Richet Pfaller Marchetti

(n=569) (n=2759) (n=254) (n=377) (n=1134) (n=1137)

J Hosp Infect CID J Clin Microbiol CMI J Clin Microbiol CID

2002 2002 2002 2002 2002 2004

C.albicans 58,50% 59% 58% 53% 55% 66%

C.glabrata 12,80% 12% 20% 11% 15% 15%

C.parapsilosis 14,60% 11% 7% 16% 15% 1%

C.tropicalis 6,10% 10% 11% 9% 9% 9%

C.krusei 0,90% 1,20% 2% 4% 1% 2%

Miscellaneous 7,10% 7% 2% 6% 1% 7%

Evolution of the distribution

Marchetti, Clin Infect Dis 2004.

300 patients with proven invasive candida infection

Main risks factors of invasive candidiasis

Colonisation Abdominal (Solomkin, Surgery 1980) Independant risk factor(Wey, Pittet, Karabinis,…) 5-15% patients colonized on admission, 50-86% if

prolonged LOS, 5-30% develop a candidemia Antibiotics

Major risk factor (Wey, Arch Intern Med 1989) Wide spectrum, increase with time (Pittet, Ann Surg 1994)

Neutropenia Venous access:

Candidemia directly related to the IVL in 35-80% of the cases (Luzzati, Eur J Clin Microb Inf Dis 2002)

ICU, surgery, ARF, steroids, anti-H2, high Apache score…

Physiopathology

12 may

16 may

21 may

25 may

Blood culture

27 mayendogenous >> exogenous

Pittet Am J Med 1991 / Ann Surg 1994 / Nucci & Anaissie CID 2001

Invasive Candida infections in the ICU

Epidemiology and pathophysiology Diagnosis The molecules Key studies Available guidelines

Colonisation/Infection

1,0

0,8

0,6

0,4

0,2

0,00 20 40 60 140

Length of colonisation (d)

Colonisation IndexInfectedColonized • Prospective cohort study in the ICU

• 5,3 distincts sites /patient

• Colonisation Index : Prospectively definedMeasured 3 times/we

nb distincts colonized sites nb distincts sampled sites

(Pittet et al, Ann Surg 94 ; 220 : 751-8)

(Pittet et al, Ann Surg 94 ; 220 : 751-8)(Pittet et al, Ann Surg 94 ; 220 : 751-8)

Se Se SpSp PPV PPV NPVNPV

>2 colonized sites >2 colonized sites 100100 2222 44 44 100 100

≥≥3 colonized sites 3 colonized sites 4545 7272 50 50 68 68

Index >0,5Index >0,5 100100 6969 66 66 100 100

Prediction rules

IMV: Invasive mechanical ventilation

CPB: cardiopulmonary bypass duration

Prediction rules

Se: 81%Sp: 74%

Prediction rules

The CS - total parenteral nutrition 1- surgery 1, - multifocal Candida colonization 1 - severe sepsis 2

Prediction rules

In this cohort of colonized patients staying >7 days, with a CS <3 and not receiving antifungal treatment, the rate of IC was <5%. Therefore, IC is highly improbable if a Candida-colonized non-neutropenic critically ill patient has a CS <3.

Diagnosis

Positive blood culture or isolation from a normaly sterile site (except urine)

Surrogate markers 1,3 D glucan Mannans Germ tube antibody Hyphal wall protein 1 PCR

Invasive Candida infections in the ICU

Epidemiology and pathophysiology Diagnosis The molecules Key studies Available guidelines

Mecanisms of action

Amphotericin B

Lipid complexes AMBLiposomal AMB

AMB deoxycholate

Fluconazole Good oral absorption CNS diffusion Half life 25-30 h Side effects

Nausea, vomiting Rash Liver toxicity (lower compared to other

azoles)

Voriconazole

Oral and IV Large distribution volume Half life 6h (200mg) CSF concentration ≈ 50% serum

Side effects: Photopsia, abdominal pain, rash, nausea, diarrhea, Liver toxicity

Johnson et al, Clin Infect Dis 2003

Echinocandins

Only intravenously Fungicidal 3 molecules

Caspofugin Anidulafungin Micafungin

Different metabolisms

AnidulafunginCaspofungin MicafunginGlarea lozoyensis Aspergillus nidulansColeophoma empetri

Adapted from Micafungin US Prescribing Information; Anidulafungin US Prescribing Information; Debono M, Gordee RS. Annu Rev Microbiol. 1994;48:471–497; Debono M et al. J Med Chem. 1995;38:3271–3281.

Echinocandins

N O

O

O

NH

O

H

HH H

OH

CH3

O

O

H2N

OH

NHHO

H2N

HO NHHN

OH

OH

HN OH

NH

HO

H3CCH3 CH3

O

O

ON

O

O

HN

NO

O

O

O

ON

O

H3C

SOO

HO

OHHO

HO

OH

HN

NH

NHH3CH2N

HOHO

OH

NH

OH

OH

CH3O

ON

H3C

O

NO

O

O

O

O

HO

HO

HO

OH

HN

NH

OH

HOHO OH

NH

HN

CH3

OH

NH

H3C

H3C

• Side chains are key determinants of lipophilicity, solubility, antifungal activity, and toxicity

Pharmacology: Metabolism, Elimination, Bioavailability, and Protein Binding

Caspofungin Micafungin Anidulafungin

Metabolism Hepatic metabolism by hydrolysis and

N-acetylation

Spontaneous nonhepatic chemical degeneration

Hepatic metabolism by arylsulfatase and

catechol-O-methyltransferase

Nonhepatic chemical degradation

Elimination/excretion Urine 41%Feces 34%

Urine + feces 82.5%Feces 71%

Urine <1%Feces ≈30%

Protein Binding 97% >99% >99%

Oral Bioavailability <5% <5% <5%

Dialyzable No No No

Adapted from Micafungin US Prescribing Information; Anidulafungin US Prescribing Information; Dodds Ashley ES et al. Clin Infect Dis. 2006;43:S28–S39.

Pfaller et al, JCM 2008

No evidence of emerging resistance

Invasive Candida infections in the ICU

Epidemiology and pathophysiology Diagnosis The molecules Key studies Available guidelines

Caspofungin

Mora-Duarte J et al. N Engl J Med 2002

*°

* p=0.03° p=0.05

224 patientsNon inferiority

Primary analysis (ITTm*)Success at 12 weeks

Kullberg BJ et al, Lancet 2005

Su

cess

rate

Voriconazole

VoriconazolVoriconazolee

(n = 248)(n = 248)

AmB fluconazol

e(n = 122)

p

End of treatment

70 % (173)70 % (173) 74 % (90)0,42 ;

NS

2 weeks after EOT

52 % (130)52 % (130) 53 % (64)0,99 ;

NS

6 weeks after EOT

44 % (110)44 % (110) 46 % (56)0,78 ;

NS

Kullberg BJ et al, Lancet 2005

Secondary Analysis (ITTm*)

on inferiority

Voriconazole

Amphotericin B/Fluconazole

Caspofungin

Note: Data on file. Pfizer. Adapted from Kullberg BJ, et al. N Engl J Med. In pressSources: Candidemia 1 (Rex, 1994); Candidemia 2 (Rex, 2003); Caspofungin (Mora-Duarte, 2002); Itraconazole (Tuil, 2003; ISICEM); Global Candidemia Study

Pro

bab

ilit

y o

f P

osi

tive

Cu

ltu

re

0 2520151054321 6 987 11 141312 16 191817 21 2423220.0

0.2

1.0

0.8

0.6

0.4

Time to First Negative Blood Culture

Investigator-Assessed Responses

Improved at EOT

Success at2 Weeks

Success at6 Weeks

Success at12 Weeks

72%

50%

42% 42%

72%

51%45%

42%

73%

51%

43%

Voriconazole

Amphotericin B Fluconazole

Cancidas

NA

Reboli et al, NEJM 2007Etude de non infériorité

Invasive Candida infections in the ICU

Epidemiology and pathophysiology Diagnosis The molecules Key studies Available guidelines

Nonneutropenic patients Transition to

fluconazole Isolates likely to be

susceptible and stable Glabrata:

echinocandin preferred

Parapsilosis: fluconazole preferred

Catheter removal Duration: 2 wk post

clearance

Neutropenic patients

Glabrata: echinocandin preferred

Parapsilosis: fluconazole preferred

Catheter removal Duration: 2 wk post

clearance

Conclusion

Epidemiology and pathophysiology Increased rate of non albicans

Diagnosis Remains difficult

The molecules Echinocandins have a proeminent place

Available guidelines Association?