1. Invasive Candida Infections in the ICU B. Guery Lille Infectious Diseases Summit: Fungal Series

2. Invasive Candida infections in the ICU Epidemiology and pathophysiology Diagnosis The molecules Key studies Available guidelines

3. Nosocomial infections Vincent et al, JAMA 1995

4. Incidence (/1000) Beck JID 1993 Candida infections Invasive Candidiasis10 Documented colonisations200 ? Unknown colonisations 800? Candidemia 1

5. Increasing rate of candidiasis in the US Martin et al, NEJM 2003;348:1546 +300% +600%

6. 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

7. Epidemiology of candidemia

8. Evolution of the distribution Marchetti, Clin Infect Dis 2004.

9. 300 patients with proven invasive candida infection

10. 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-H 2, high Apache score…

12. Physiopathology 12 may 16 may 21 may 25 may Blood culture 27 may endogenous >> exogenous Pittet Am J Med 1991 / Ann Surg 1994 / Nucci & Anaissie CID 2001

13. Invasive Candida infections in the ICU Epidemiology and pathophysiology Diagnosis The molecules Key studies Available guidelines

14. Colonisation/Infection 1,0 0,8 0,6 0,4 0,2 0,0 0204060140 Length of colonisation (d) Colonisation Index Infected Colonized Prospective cohort study in the ICU 5,3 distincts sites /patient Colonisation Index : Prospectively defined Measured 3 times/we nb distincts colonized sites nb distincts sampled sites (Pittet et al, Ann Surg 94 ; 220 : 751-8)

15. Se Sp PPVNPV >2 colonized sites 10022 44 100 ≥3 colonized sites 4572 50 68 Index >0,510069 66 100

16. Prediction rules IMV: Invasive mechanical ventilation CPB: cardiopulmonary bypass duration

17. Prediction rules Se: 81% Sp: 74%

18. Prediction rules The CS - total parenteral nutrition 1 - surgery 1, - multifocal Candida colonization 1 - severe sepsis 2

19. 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.

20. 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

21. Invasive Candida infections in the ICU Epidemiology and pathophysiology Diagnosis The molecules Key studies Available guidelines

22. Mecanisms of action

23. Amphotericin B Lipid complexes AMBLiposomal AMB AMB deoxycholate

24. Fluconazole Good oral absorption CNS diffusion Half life 25-30 h Side effects Nausea, vomiting Rash Liver toxicity (lower compared to other azoles)

25. 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

26. Echinocandins Only intravenously Fungicidal 3 molecules Caspofugin Anidulafungin Micafungin Different metabolisms

27. AnidulafunginCaspofungin Micafungin Glarea lozoyensisAspergillus 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 H H H O H CH 3 O O H2NH2N OH NH HO H2NH2N NH HNHN OH HN OH NHNH HO H3CH3C CH 3 O O O N O O HN N O O O O O N O H3CH3C S O O HO OH HO OH HNHN NH H3CH3C H2NH2N HO OH NH OH CH 3 O O N H3CH3C O N O O O O O HO OH HNHN NH OH HO OH NH HN CH 3 OH NH H3CH3C H3CH3C Side chains are key determinants of lipophilicity, solubility, antifungal activity, and toxicity

28. Pharmacology: Metabolism, Elimination, Bioavailability, and Protein Binding CaspofunginMicafunginAnidulafungin MetabolismHepatic metabolism by hydrolysis and N-acetylation Spontaneous nonhepatic chemical degeneration Hepatic metabolism by arylsulfatase and catechol-O- methyltransferase Nonhepatic chemical degradation Elimination/excretionUrine 41% Feces 34% Urine + feces 82.5% Feces 71% Urine <1% Feces ≈30% Protein Binding 97%>99% Oral Bioavailability<5% DialyzableNo Adapted from Micafungin US Prescribing Information; Anidulafungin US Prescribing Information; Dodds Ashley ES et al. Clin Infect Dis. 2006;43:S28–S39.

29. Pfaller et al, JCM 2008 No evidence of emerging resistance

31. Invasive Candida infections in the ICU Epidemiology and pathophysiology Diagnosis The molecules Key studies Available guidelines

32. Caspofungin Mora-Duarte J et al. N Engl J Med 2002 * ° * p=0.03 ° p=0.05 224 patients Non inferiority

33. Primary analysis (ITTm*) Success at 12 weeks Kullberg BJ et al, Lancet 2005 Sucess rate

34. Voriconazole Voriconazole (n = 248) AmB  fluconazole (n = 122) p End of treatment 70 % (173) 74 % (90)0,42 ; NS 2 weeks after EOT 52 % (130) 53 % (64)0,99 ; NS 6 weeks after EOT 44 % (110) 46 % (56)0,78 ; NS Kullberg BJ et al, Lancet 2005 Secondary Analysis (ITTm*) on inferiority

35. Voriconazole Amphotericin B/Fluconazole Caspofungin 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 Probability of Positive Culture 025201510543216987111413121619181721242322 0.0 0.2 1.0 0.8 0.6 0.4 Time to First Negative Blood Culture

36. Investigator-Assessed Responses Improved at EOT Success at 2 Weeks Success at 6 Weeks Success at 12 Weeks Voriconazole Amphotericin B  Fluconazole Cancidas NA

37. Reboli et al, NEJM 2007 Etude de non infériorité

39. Invasive Candida infections in the ICU Epidemiology and pathophysiology Diagnosis The molecules Key studies Available guidelines

44. Nonneutropenic patients Moderately to severe illness/Recent azole exposure YesEchinocandinCaspofunginAnidulafunginmicafunginNoFluconazole Transition to fluconazole Isolates likely to be susceptible and stable Glabrata: echinocandin preferred Parapsilosis: fluconazole preferred Catheter removal Duration: 2 wk post clearance

45. Neutropenic patients Less critically ill/No recent azole exposure NoEchinocandinCaspofunginAnidulafunginMicafunginLFAmBYesMold CoverageYesVoriconazoleNoFluconazole Glabrata: echinocandin preferred Parapsilosis: fluconazole preferred Catheter removal Duration: 2 wk post clearance

46. Conclusion Epidemiology and pathophysiology Increased rate of non albicans Diagnosis Remains difficult The molecules Echinocandins have a proeminent place Available guidelines Association?