invasive fungal dis 2012
DESCRIPTION
invasive fungal infection updates 2012TRANSCRIPT
ذنب لكل أستغفرك إني ذنب اللهم لكل أستغفرك إني اللهممددت.. .. أو برجلي إليه مددت.. .. خطوت أو برجلي إليه خطوت
يدي يدي إليه إليهأصغيت.. .. أو ببصري تأملته أصغيت.. .. أو أو ببصري تأملته أو
بأذني بأذني إليه إليه
Invasive Fungal Infections Management
Updates Ahmed Saad MD. FACP.
Ass Prof .Cairo university
Review
• Different types of Invasive fungi
• Changing local epidemiology
• Risk factors
• Clinical picture
• Diagnosis
• Treatment & prophylaxis
Incidence of Systemic Infections: Bacterial vs Fungal
Martin GS, et al. N Engl J Med. 2003;348(16):1546-1554.
No.
of C
ases
of S
epsi
s
1991 1993 1995 1997 1999 2001
225,000
150,000
75,000
25,000
15,000
10,000
5000
0
Gram-positive bacteriaGram-negative bacteriaFungi
Year
Nosocomial Bloodstream Infections in US Hospitals: 1995-2002
CoNS, coagulase-negative staphylococci; BSI, blood stream infection.Surveillance and Control of Pathogens of Epidemiological Importance (SCOPE) study.Wisplinghoff H, et al. Clin Infect Dis. 2004;39:309-317.
9
Patients withcandidal bloodstream
infections
Adapted from Edmond MB et al Clin Infect Dis 1999;29:239–244.
0
5
10
15
20
25
30
35
40
45
40%
25%
Perc
ent o
f P
atie
nts
Patients with bacterial (non-candidal)
bloodstream infections
Invasive Candidiasis
Mortality Associated with Candidemia
Impact of delayed treatment on mortalityImpact of delayed treatment on mortality
Morrell M, Fraser VJ, Kollef MH. Delaying the empiric treatment of Candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality. Antimicrob Agents Chemother 2005;49: 3640–5.
Epidemiology of Invasive Mycosis
Pfaller & Diekema, 2007, Clin. Micro. Rev. 20:133-163
Review
• Different types of Invasive fungi
• Changing epidemiology
• Clinical picture
• Risk factors
• Diagnosis
• Treatment & prophylaxis
Infections Caused by Non-Infections Caused by Non-albicans Candidaalbicans Candida Are IncreasingAre Increasing
Pfaller MA, et al. Clin Microbiol Rev. 2007;20(1):133-163.
0
10
20
30
40
50
60
70
80
90
100
1997-1998 1999 2000 2001 2002 2003
C. kruseiC. parapsilosis
C. tropicalisC. glabrataC. albicansOther
Neither C. glabrata nor C. krusei showed a consistent increase or decrease in isolation rates overall Increased rates of isolation of C. tropicalis (4.2% to 7.5% increase) and C. parapsilosis (4.6% to 7.3% increase)
were observed between 1997 and 2003 over 134,000 consecutive isolates of Candida from cases of invasive candidiasis at 127 medical centers
in 39 countries
Candida Species:Incidence vs Mortality
%
Candida Species
Incidence of Candida albicans, 45.6%; incidence of non-albicans Candida, 54.4%*
*This study is based on data for the 2019 patients (pediatric and adult) enrolled from July 1, 2004 through March 5, 2008 from 23North American centers who received a diagnosis of proven candidemia, including 2.1% other non-albicans Candida [C. lusitaniae,C. dubliniensis, C. guilliermondii, other (not specified), and unknown].
Horn DL, et al. Clin Infect Dis. 2009;48(12):1695-1703.
Invasive Fungal Infections
Aspergillus Candida
Kidney & liver 1.4–14% 0–10% 90–100%
Heart 5–20% 77–91% 8–23%
Lungs/Heart-Lungs 15–35% 25–50% 43–72%
Small Intestine 40–59% 0–3.6% 80–100%
Gabardi S. et al. Transplant Int 2007;20:993–1015, Singh N. Clin Infect Dis 2000:31;545–53.
Incidence of Fungal Infections after SOT
Denning Denning DWDW
Clin Infect Clin Infect DisDis
till 1995till 1995
Paterson DL, Paterson DL, Singh NSingh NMedicineMedicine
1987-19971987-1997
Lin QYLin QYClin Infect Clin Infect
DisDis1995-19991995-1999
Bone marrowBone marrow 90 % 92 % 86.7 %
AIDS/HIVAIDS/HIV 81 % - 85.7 %
Liver Liver transplant.transplant.
93 %93 % 87 %87 % 67.6 %67.6 %
Kidney Kidney transplant.transplant.
70 % 75 % 62.5 %
Lung Lung Transplant.Transplant.
77 % 55 % 62.5 %
Heart Heart transplant.transplant.
50 % 78 % 43.6 %
Pancreas Pancreas transplanttransplant
100 % -
Invasive Aspergillose : Mortality
Review
• Different types of Invasive fungi
• Our local data
• Clinical picture
• Risk factors
• Diagnosis
• Treatment & prophylaxis
Our local data For Candida fungogram for Candida Isolates (In-patient) March 2011- June 2012
CandidaAlbicans
Candida Tropicalis
CandidaGlabrata
CandicaParapsilosis
Candica Krusei
CandidaLusitaniae
Candida Dubliniensis
No. of Isolates 73 23 7 5 2 1 5Caspufugen 100 100 100 100 100 100 100Amphotericin B 96 98 100 100 100 100 100Flucytosine 97 100 100 100 50 100 66Fluconazole 97 89 66 100 0 100 100Voriconazole 100 100 66 100 100 100 100Caspofungin 100 100 100 100 100 100 100
Dr Erfan & Bagedo Hospital Data 2010
• Aspergillus +ve in 3 sputum samples & 24 environmental samples
sample Candida Parapsiliosis
Candida
Albicans
Candida Tropicalis
Candida
Glabrata
Candida
Krusie
Blood 8 6 6 1 1
BAL 9 1
Sputum 4
Urine 1 1
No of Candidal isolates (115) in 18 monthes
Candida albicans63.5%
Candida tropicalis20.0%
Candida glabrata6.1%
Candida parapsilosis4.3%
Candida krusei1.7%
Candida dublinensis4.3%
Candida Albicans
Amph
oter
icin
B
Flucyto
sine
Flucon
azole
Vorico
nazo
le
Caspo
fung
in0
20
40
60
80
100
120
Candida tropicalis
0
20
40
60
80
100
120
Candida Glabrata
Amph
oter
icin
B
Flucyto
sine
Flucon
azole
Vorico
nazo
le
Caspo
fung
in0
20
40
60
80
100
120
Candida parapsislosis
Amph
oter
icin
B
Flucyto
sine
Flucon
azole
Vorico
nazo
le
Caspo
fung
in0
20
40
60
80
100
120
Candida Krusei
0
20
40
60
80
100
120
Candida Dubliniensis
Amph
oter
icin
B
Flucyto
sine
Flucon
azole
Vorico
nazo
le
Caspo
fung
in0
20
40
60
80
100
120
Review
• Different types of Invasive fungi
• Epidemiology
• Risk factors
• Clinical picture
• Diagnosis
• Treatment & prophylaxis
Risk Factors for Invasive Candidiasis In ICU
3 antibiotics• Antibiotics 4 d• Time 4 d in ICU• Mechanical vent >48• Major Abd surgery• CVP• TPN
• Neutropenia• Immunosuppression• Concomitant infection• Diabetes mellitus• Candida coloniz 2 sites• Candiduria (>100,000
colonies)
Pappas PG et al. Clin Infect Dis 2004;38:161-189; Ostrosky-Zeichner L et al. Crit Care Med 2006;34:857-63
Invasive Aspergillosis: Risk factors Post liver transplant
Early IA < 3 months
OR (95% CI)p
Renal failure after SOT 4.9(2.4 -9.8) < 0.0001
Hemodialysis after SOT 3.2(1.3 - 8.1) 0.014
> 1 episode of bacterial infection
3.2(3.2 - 17.4) < 0.006
CMV disease 2.3(1.1 - 4.9) < 0.029
Gavaldà J et al, Clin Inf Dis 2005; 41:52-9
Reintervention is also risk factor
• High doses or prolonged duration of corticosteroids
• Graft failure requiring Hemodialysis
• Potent immunosuppressive therapy for rejection
Risk factors of IA after Renal transplantation
Singh N et al, Am J Transplant 2009, 9, S180-S191 .
• Isolation of Aspergillus from respiratory tract cultures
• Reintervention
• CMV disease
• Hemodialysis
Risk factors of IA after Heart transplantation
Munoz P et al, Curr Opin Infect Dis 2006; 19: 365-370 Singh N et al, Am J Transplant 2009, 9, S180-S191 .
Fungal Infection Post Biologics
Fungal Infection Post Biologics
Fungal Infection Post Biologics
• Till 2007 ,281 reports of invasive fungal infections (IFIs) associated with the 3 anti-TNF- alpha agents, ie, infliximab, etanercept, and adalimumab
• 226 (80%) were associated with infliximab, 44 (16%) with etanercept, and 11 (4%) with adalimumab
• Histoplasmosis (n=84 [30%]), candidiasis (n=64 [23%]), and aspergillosis (n equals 64 [23%]).
• Infliximab induces apoptosis memory T cells, whereas etanercept is antiapoptotic
Review
• Different types of Invasive fungi
• Epidemiology
• Clinical picture
• Risk factors
• Diagnosis
• Treatment & prophylaxis
SPECTRUM OF INVASIVE CANDIDA INFECTIONS
SPECTRUM OF INVASIVE CANDIDA INFECTIONS
candidemiacandidemia
organ infectionorgan infection
candidemia candidemia acuteacute
disseminateddisseminated candidiasis candidiasis
‘ ‘hepato-hepato- splenic’splenic’
candidiasis candidiasis
Candida: Infection sites
C. parapsilosisC. parapsilosisC. parapsilosisC. parapsilosis C. tropicalisC. tropicalisC. tropicalisC. tropicalis
C. albicansC. albicansC. albicansC. albicans
C. kruseiC. kruseiC. kruseiC. krusei
C. glabrataC. glabrataC. glabrataC. glabrata
Candida: Hepatosplenic candidiasis
FEVERFEVER
ALKALINE PHOSPHATASEALKALINE PHOSPHATASE
NEUTROPHILSNEUTROPHILS
DISSEMINATIONDISSEMINATION MICROCOLONIESMICROCOLONIES ‘BULLS EYE’‘BULLS EYE’
Renal candidiasis
Baseline After caspofunginCourtesy of John Rex, MD
Esophageal Candidiasis
Candida Retinitis
Candida Endocarditis
Interaction of Interaction of AspergillusAspergillus with the host with the host
A unique microbial-host interactionA unique microbial-host interaction
Immune dysfunction
Frequency
of a
sperg
illosis
Immune hyperactivity
Frequency
of
asp
erg
illosi
s
Acute IA
Subacute IA
AspergillomaChronic cavitaryChronic fibrosing
ABPAAllergic sinusitis
. www.aspergillus.man.ac.ukwww.aspergillus.man.ac.uk
TimeframesTimeframes
IPA days/1-4 weeks
Subacute IPA weeks/2-3 months
CCPA months/years
Aspergilloma months/years
AspergillomaAspergilloma
Patient RTDecember 2002
Cough (mild) &tired
Wythenshawe Hospital
Aspergilloma – may be mobile in the Aspergilloma – may be mobile in the cavitycavity
Upright Prone
Severo on www.aspergillus.man.ac.uk
AspergillomaAspergilloma
Severo on www.aspergillus.man.ac.uk
Fungal Sinusitis
Fungal Sinusitis
Aspergillus Endocarditis
Zygomycosis in SOT
• Rhinocerebral form
• 76% diabetes and corticosteroids
• 56% mortality
Review
• Different types of Invasive fungi
• Epidemiology
• Clinical picture
• Risk factors
• Diagnosis
• Treatment & prophylaxis
Invasive aspergillosis diagnosis
• Radiology: chest X-ray and CT• Microbiology
– Respiratory secretions: BAL/biopsy• Direct microscopy• culture
• PCR
Ergin et al. Transplant International 2003; 16: 280-286
IA in solid-organ transplant recipients
Diagnosis of Pulmonary Aspergillosis
•Pulmonary Infection
– Peripheral infiltrates
– "halo" sign on chest CT scan
– Broncho-alveolar lavage ++
• Direct exam, Culture, Ag, PCR
Halo sign ??
Fungal Pneumonia
Serology
• 1,3-,D-glucan is a component of fungal
cell walls that can be detected by serology
• One way to effectively use the 1,3-,D-glucan or galactomannan assays may be to serially screen patients who are at high risk for IFIs and/or use them to monitor response to therapy .
Review
• Different types of Invasive fungi
• Epidemiology
• Clinical picture
• Risk factors
• Diagnosis
• Treatment & prophylaxis
Antifungal Agents
Cell Membrane Active Antifungals
Cell membrane • Polyene antibiotics - Amphotericin B, lipid formulations
• Azole antifungals - Ketoconazole - Itraconazole - Fluconazole - Voriconazole -Posaconazole
DNA/RNA synthesis Inhibitors Cell membrane • Polyene antibiotics • Azole antifungals
DNA/RNA synthesis • Pyrimidine analogues - Flucytosine
Cell wall • Echinocandins -Caspofungin acetate (Cancidas)
Cell Wall Active Antifungals
Cell membrane • Polyene antibiotics • Azole antifungals
DNA/RNA synthesis • Pyrimidine analogues - Flucytosine
Cell wall • Echinocandins -Caspofungin acetate - micafungin
Atlas of fungal Infections, Richard Diamond Ed. 1999Introduction to Medical Mycology. Merck and Co. 2001
Amphotericin B (Fungizone™) • Binds ergosterols in fungal cell membrane forming pores
in the membrane & interferes with permeability and transport functions.
• Broad spectrum antifungal
• Lipid formulations facilitate drug insertion within the fungal cytoplasmic membrane while reducing uptake in human cells, so limiting toxicity.
Lipid Amphotericin B Formulations
Ribbon-like particlesRibbon-like particlesCarrier lipids: DMPC, Carrier lipids: DMPC, DMPGDMPG (1:1)(1:1)Particle size Particle size (µm): 1.6-: 1.6-11 11
Abelcet Abelcet ®® ABLC ABLC Amphotec Amphotec ®® ABCD ABCD Ambisome Ambisome ®® L-AMB L-AMB
Disk-like particlesDisk-like particlesCarrier lipids: Cholesteryl Carrier lipids: Cholesteryl sulfate sulfateParticle size Particle size (µm): 0.12-: 0.12-0.14 0.14
UnilaminarUnilaminar liposomeliposomeCarrier lipids: HSPC, Carrier lipids: HSPC, DSPG, cholesterolDSPG, cholesterol(1:9)(1:9)Particle size Particle size (µm) : 0.08 : 0.08
DMPC-Dimyristoyl phospitidylcholineDMPG- Dimyristoyl phospitidylcglycerol
HSPC-Hydrogenated soy phosphatidylcholineDSPG-Distearoyl phosphitidylcholine
Lipid AMB Formulations-Summary
• Efficacy– Lipid formulation > AMB-deoxy
• Nephrotoxicity– L-AMB < ABLC < ABCD << AMB-deoxy
• Infusion related toxicity– L-AMB < ABLC < ABCD < AMB-deoxy
• Product cost (AWP)– L-AMB > ABLC > ABCD > AMB-deoxy
Amphotericin B - Nephrotoxicity
• Renovascular and tubular mechanisms– Vascular-(decrease in renal blood flow) leading to drop
in GFR, azotemia– Tubular-distal tubular ischemia, wasting of potassium,
sodium, and magnesium
• Sodium loading-> blunt the vasoconstriction and tubular-glomerular feedback– Administration of 500 ml of NaCl before and after
amphotericin B infusion
Azole Antifungals for Systemic Infections
• Itraconazole (Sporanox)• Fluconazole (Diflucan)• Voriconazole (Vfend)
Triazoles (3N)
“2nd generationtriazole”
Fluconazole Ketoconazole
Azoles - Mechanism
• Azoles bind to (fungal P450 enzymes) lanosterol 14-demethylase inhibiting the production of ergosterol– Some cross-reactivity is seen with
mammalian cytochrome p450 enzymes
• Drug Interactions• Impairment of steroidneogenesis
(ketoconazole, itraconazole)
Fluconazole
• Well tolerated• IV/PO formulations• Favorable
pharmacokinetics• Good activity against
C. albicans and Cryptococcus
• Fungistatic• Resistance is
increasing• Narrow spectrum• (Drug interactions)• Not in biofilm
Advantages Disadvantages
Key Biopharmaceutical Characteristics of the Triazole Antifungals
Fluconazole Voriconazole
Spectrum vs. Candida and Aspergillus
C. albicans, C. tropicalis +/-
No Aspergillus
Broad, includes most Candida spp., Aspergillus, Fusarium sp. Not Zygomycoses
Oral formulation
(% bioavailibility)
Tablet (>90%) Tablet (>90%)
Intravenous formulation
Available, no solubilizer Available, cyclodextrin
R.E. Lewis 2002. Exp Opin Pharmacother 3:1039-57.
Voriconazole –Dose & Side Effects
• Dose 6mg/kg 1st day 6mg/kg bid then 4mg/kg bid
• Visual disturbances (~ 30%)– Decreased vision, photophobia, altered color
perception and ocular discomfort– IV > oral– No evidence of structural damage to retina
The Fungal Cell Wall
mannoproteins
1,6glucans
1,3
chitin
ergosterol
1,3 glucansynthase
Cellmembrane
Atlas of fungal Infections, Richard Diamond Ed. 1999Introduction to Medical Mycology. Merck and Co. 2001
Echinocandins inhibition of ß-(1,3)glucan synthaseosmotic fragility
Echinocandins - spectrum
Highly activeCandida albicans, Candida glabrata,Candida tropicalis, Candida krusei
Low MIC ,with fungicidal activity and good in-vivo
Very activeCandida parapsilosisCandida gulliermondiiAspergillus fumigatusAspergillus flavus
Low MIC, but without fungicidal activity in most instances.
Echinocandins Caspofungin Micafungin Anidulafungin
Absorption Not orally absorbed. IV only
Metabolism spontaneous degradation, hydrolysis and N-acetylation
Chemical degradated Not hepatically
metabolized
Elimination Limited urinary excretion. Not dialyzable
Half-life 9-23 hours 11-21 hours 26.5 hours
Dose 70 mg IV on day1, then 50 mg IVdaily thereafter
100 mg IVonce daily
200 mg IV on day 1,then 100 mg IVdaily thereafter
Dose Adjustment
Child-Pugh B70 mg IV on day 1, then 35 mg IV daily
thereafter
None None
Review
• Different types of Invasive fungi
• Changing epidemiology
• Risk factors
• Clinical picture
• Diagnosis
• Treatment &prophylaxis
• Updated guidelines
Candidemia• If species is unknown, either fluconazole (800mg loading dose, 400 mg
daily) or an echinocandin is appropriate initial therapy for most adult patients (AI)
• An echinocandin is favored if
– Moderately severe to severe illness.
– Recent azole use for treatment or prophylaxis (AIII), or
– Isolate is known to be C. glabrata or C. krusei (BIII)
• Fluconazole for patients who are
– less critically ill and
– who have no recent azole exposure (AIII).
• Remove or exchange intravenous catheters
• Treat for two weeks after clearance of bloodstream
IDSA Guidelines 2010.
Treatment optionsof blood candidal infections in adults
Treatment options of invasive fungal infections in adults 2010
Candidemia: catheter removal
• Removal of central venous line – is a consensus recommendation for the
non-hematological patients II A- in hematology patients the quality of
evidence is lower IIIB- removal is always recommended when
C parapsilosis is isolated II A
IDSA Guidelines 2010.
Duration of antifungal therapy in candidemia : recommendations
Non-neutropenic adults: at least 14 days after the last +ve
blood culture and resolution of signs and symptoms : III B
Neutropenic patients: at least 14 days after the last +ve
blood culture and resolution of signs and symptoms and
resolved neutropenia: III C
IDSA Guidilines 2010.
Invasive pulmonary aspergillosis :1st line
Agent Grade Comments
Voriconazole I A 2 x 6 mg/kg D1 then 4 mg/kg BID
Ambisome I B 3 – 5 mg/kg
Caspofungin I C
Amphotericin B I D
IDSA Guidelines 2010.
Treatment optionsof aspergillus infections
Treatment options of invasive fungal infections in adults 2010
Aspergillosis
• Surgery (CIII) in case of
– Lesion near to a large vessel
– Hemoptysis from a single lesion (embolization is an alternative)
– Localized extrapulmonary lesion including central nervous system lesion
– Fungal sinusitis
Empirical antifungal treatment in ICU
Clinical Prediction Rule Clinical Prediction Rule (CPR)(CPR)• All of
– [(day 1–3 of ICU stay): mechanical ventilation,
– broad spectrum antibiotics
– And central venous catheter CVC
• And ONE of– TPN (total parentral neutrition) (d1-3)
– Dialysis (d1-3)
– Major surgery (d-7-0),
– Pancreatitis (d-7-0),
– Steroids (d-7-3),
– Other immunosuppressive agents (d-7-0)].
sensitivity of 90%, a specificity of 48%
Ostrosky-Zeichner L, et al. 2007. Eur J Clin Microbiol Infect Dis, 26:271–6.Ostrosky-Zeichner L, et al. Mycoses. 2011 Jan;54
The Candida ScoreThe Candida Score• Parenteral nutrition ................................................. (+1)
• Prior surgery ............................................................ (+1)
• Multifocal Candida colonization *........................... (+1)
• Severe sepsis ........................................................... (+2)
The authors concluded that a “Candida score” of 2.5 could accurately select patients who would benefit from early antifungal treatment
Empirical antifungal treatment in ICU
Leon C, et al. 2006. Crit Care Med, 34:730–7.Leon C, et al. 2009 Crit Care Med 37:1624–1633.
• Lipid formulation of AmB (II 2)– 3-5 mg/kg/day
• Or an Echinocandin (II 3)
• Duration 3-4 weeks or until resolution of risk factors
Prophylaxis of high-risk patients after Liver
transplantation (Recommendations of the AST Infectious disease Community of
Practice)
Singh N et al, Am J Transplant 2009, 9, S180-S191 .
Prophylaxis for high-risk patients after Lung transplantation (recommendations of the AST Infectious disease Community of
Practice) • Inhaled lipid formulations of amphotericin B
– Nebulized L-AmB• 25 mg three times per week x 2 months
• In high-risk patients
– Voriconazole* : 400 mg/day x 4 months
Singh N et al, Am J Transplant 2009, 9, S180-S191 .
• Voriconazole– 200mg BID for 50-150 days
Prophylaxis for high-risk patients after
Heart transplantation (Recommendations of the AST Infectious disease Community of
Practice)
Singh N et al, Am J Transplant 2009, 9, S180-S191 .
Antifungal prophylaxis in haematology patients
3rd European Conference on Infections in Leukaemia (ECIL-3)
CLINICAL MICROBIOLOGY AND INFECTION April 2012