Transcript Infections Fongiques - Infectio

Invasive Candida Infections in the
ICU
Infectious Diseases Summit: Fungal Series
B. Guery
Lille
Invasive Candida infections in the
ICU
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Epidemiology and pathophysiology
Diagnosis
The molecules
Key studies
Available guidelines
Nosocomial infections
P. aeruginosa
Candida spp
S. aureus
Others
24%
30%
29%
17%
Vincent et al, JAMA 1995
Candida infections
Incidence (/1000)
Candidemia
1
Invasive Candidiasis
10
Documented colonisations
Unknown colonisations
200 ?
800?
Beck JID 1993
Increasing rate of candidiasis in
the US
+600%
+300%
+300%
Martin et al, NEJM 2003;348:1546
Viridans streptococci
E. coli
S. aureus
Coag neg staph
P. aeruginosa
Enterobacter spp
Candida spp
22,5 days
Klebsiella spp
Enterocci
Serratia spp
0
5
10
15
20
25
Edmond et al, Clin Inf Dis 1999
Epidemiology of
candidemia
Tortorano
Trick
Diekem a
Richet
Pfaller
Marche tti
(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
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Colonisation
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Antibiotics
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Major risk factor (Wey, Arch Intern Med 1989)
Wide spectrum, increase with time (Pittet, Ann Surg 1994)
Neutropenia
Venous access:
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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
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
Blood culture
Pittet Am J Med 1991 / Ann Surg 1994 / Nucci & Anaissie CID 2001
endogenous >> exogenous
Invasive Candida infections in the
ICU
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Epidemiology and pathophysiology
Diagnosis
The molecules
Key studies
Available guidelines
Colonisation/Infection
Colonisation Index
Infected
Colonized • Prospective cohort study in the ICU
• 5,3 distincts sites /patient
1,0
• Colonisation Index :
Prospectively defined
Measured 3 times/we
0,8
0,6
nb distincts colonized sites
nb distincts sampled sites
0,4
0,2
0,0
0
20
40
60
140
Length of colonisation (d)
(Pittet et al, Ann Surg 94 ; 220 : 751-8)
Se
Sp
PPV
NPV
>2 colonized sites
100
22
44
100
≥3 colonized sites
45
72
50
68
Index >0,5
100
69
66
100
(Pittet et al, Ann Surg 94 ; 220 : 751-8)
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
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Positive blood culture or isolation from a
normaly sterile site (except urine)
Surrogate markers
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1,3 bD glucan
Mannans
Germ tube antibody
Hyphal wall protein 1
PCR
Invasive Candida infections in the
ICU
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Epidemiology and pathophysiology
Diagnosis
The molecules
Key studies
Available guidelines
Mecanisms
of action
Amphotericin B
AMB deoxycholate
Liposomal AMB
Lipid complexes AMB
Fluconazole
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Good oral absorption
CNS diffusion
Half life 25-30 h
Side effects
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Nausea, vomiting
Rash
Liver toxicity (lower compared to other azoles)
Voriconazole
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Oral and IV
Large distribution volume
Half life 6h (200mg)
CSF concentration ≈ 50% serum
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Side effects:
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Photopsia, abdominal pain, rash, nausea, diarrhea,
Liver toxicity
Johnson et al, Clin Infect Dis 2003
Echinocandins
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Only intravenously
Fungicidal
3 molecules
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Caspofugin
Anidulafungin
Micafungin
Different metabolisms
Echinocandins
Caspofungin
Micafungin
Anidulafungin
Glarea lozoyensis
Coleophoma empetri
Aspergillus nidulans
H2 N
HO O
NH OH
HOO
H3C
H2 N
HO OH
HOO
O
NH
NH
NH
N
O
N
O
OH
HN
H2N N H O H
O
OH
OHN
H3 C
H
CH3
HO NH O
H
O
CH3
N
CH
CH
3
3
H
O
HO NH
HO
HH H
N
O
OH
O
OH
N
OH
S
O
OH
O O
OH O
O
HO
HO
H3 C
O
NH
H3 C
N
O
HO OH
N
NH
O
O HN OH
HO NH O
CH3
O
N
H
HO
N
OH
OH O
O
O
H3 C
HO
H3 C
• Side chains are key determinants of lipophilicity, solubility,
antifungal activity, and toxicity
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.
Pharmacology: Metabolism,
Elimination, Bioavailability, and
Protein Binding
Caspofungin
Micafungin
Anidulafungin
Hepatic metabolism
by hydrolysis and
N-acetylation
Hepatic metabolism
by arylsulfatase and
catechol-Omethyltransferase
Nonhepatic chemical
degradation
Urine 41%
Feces 34%
Urine + feces 82.5%
Feces 71%
Urine <1%
Feces ≈30%
Protein Binding
97%
>99%
>99%
Oral Bioavailability
<5%
<5%
<5%
No
No
No
Metabolism
Spontaneous nonhepatic
chemical degeneration
Elimination/excretion
Dialyzable
Adapted from Micafungin US Prescribing Information; Anidulafungin US Prescribing Information; Dodds Ashley ES et al. Clin Infect Dis.
2006;43:S28–S39.
No evidence of emerging resistance
Pfaller et al, JCM 2008
Invasive Candida infections in the
ICU
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Epidemiology and pathophysiology
Diagnosis
The molecules
Key studies
Available guidelines
Caspofungin
*
°
224 patients
Non inferiority
* p=0.03
° p=0.05
Mora-Duarte J et al. N Engl J Med 2002
Sucess rate
Primary analysis (ITTm*)
Success at 12 weeks
Kullberg BJ et al, Lancet
2005
on inferiority
Voriconazole
End of treatment
2 weeks after
EOT
6 weeks after
EOT
Voriconazole
(n = 248)
AmB 
fluconazole
(n = 122)
p
70 % (173)
74 % (90)
0,42 ; NS
52 % (130)
53 % (64)
0,99 ; NS
44 % (110)
46 % (56)
0,78 ; NS
Secondary Analysis (ITTm*)
Kullberg BJ et al, Lancet 2005
Time to First Negative
Blood Culture
Probability of Positive Culture
1.0
0.8
Voriconazole
Amphotericin B/Fluconazole
0.6
Caspofungin
0.4
0.2
0.0
0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Note: Data on file. Pfizer. Adapted from Kullberg BJ, et al. N Engl J Med. In press
Sources: Candidemia 1 (Rex, 1994); Candidemia 2 (Rex, 2003); Caspofungin (Mora-Duarte, 2002); Itraconazole
(Tuil,
2003; ISICEM); Global Candidemia Study
Investigator-Assessed
Responses
Voriconazole
Amphotericin B  Fluconazole
Cancidas
72% 72% 73%
50% 51% 51%
42%
45% 43%
42% 42%
NA
Improved at
EOT
Success at
2 Weeks
Success at
6 Weeks
Success at
12 Weeks
Etude de non infériorité
Reboli et al, NEJM 2007
Invasive Candida infections in the
ICU
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Epidemiology and pathophysiology
Diagnosis
The molecules
Key studies
Available guidelines
Nonneutropenic patients
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Moderately to
severe
illness/Recent
azole exposure
Transition to
fluconazole
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Yes
No
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Echinocandin
Fluconazole
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Caspofungin
Anidulafungin
micafungin
Isolates likely to be
susceptible and stable
Glabrata: echinocandin
preferred
Parapsilosis: fluconazole
preferred
Catheter removal
Duration: 2 wk post
clearance
Neutropenic patients
Less critically
ill/No recent
azole exposure
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No
Yes
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Caspofungin
Echinocandin
LFAmB
Anidulafungin
Micafungin
Mold Coverage
Yes
No
Voriconazole
Fluconazole
Glabrata: echinocandin
preferred
Parapsilosis: fluconazole
preferred
Catheter removal
Duration: 2 wk post
clearance
Conclusion
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Epidemiology and pathophysiology
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Diagnosis
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Remains difficult
The molecules
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Increased rate of non albicans
Echinocandins have a proeminent place
Available guidelines
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Association?