1. Candida Fungemia Risks and Therapy Hail M. Al-Abdely, M.D. Associate Consultant King Faisal Specialist Hospital

2. Questions need Answers 1.How significant is Candidemia? 2.Who gets Candidemia? 3.Are there better ways to diagnose invasive Candidiasis than Candidemia? 4.What are the best therapeutic strategies for Candidemia? Continue...

3. Questions need Answers 5.What are the chemotherapeutic agents that can be used to treat candidemia? Is one better than the other? 6.When to give prophylaxis against Candida? And with what? 7.What is in the horizon?

4. Pathogenic Candida Species C. albicans C. tropicalis C. parapsilosis C. glabrata C. krusei C. Lusitaniae C. stellatoidea C. kyfer C. rugosa C. dubliensis C. guilliermondii C. lipolytica C. zeylanoides

7. Candida glabrata

8. How significant is Candidemia? How prevalent? How serious?

9. How prevalent is Candidemia? Hospital pathogen Primarily opportunist.

10. Nosocomial Blood Stream Infections, National Nosocomial Infection Surveilance System (NNIS) 1985-1988 Rank 1988PathogenPercentRank 1984 1 Coag-neg Staph 25.5 1 2 S. aureus 15.0 2 3 Enterococci 7.9 6 4 Candida sp. 7.7 8 5 E. coli 6.8 3 6 Enterobacter 5.2 7 7 P. aeruginosa 5.0 5 8 Klebsiella spp. 4.4 4 Horan T, et al. Antimicrob Newsletter 5:56, 1988

11. National Nosocomial Infection Surveilance System (NNIS) 1980-1990 Fungal Infection Rate 19801990 Small non-teaching Hospitals 0.9 2.4 Large non-teaching Hospitals 1.2 2.5 Small teaching Hospitals 2.1 3.5 Large teaching Hospitals 2.4 6.6 Beck-Sague CM, et al. J Infect Dis 167:1247, 1993 Total Number of Nosocomial Fungal Infections30,477 Blood stream infections 5.4 9.9

12. Candida species that cause Candidemia Candida sp. % C. albicansNon-albicans 1972-1977 1 54.3 45.7 1980-1990 2 66.9 33.1 1990-1992 3 60.0 40.0 1993-1994 3 47.0 53.0 1. Klein JI, et al. Am J Med 67:51, 1979 2. Beck-Sague CM, et al. J Infect Dis 167:1247, 1993 3. Nguyen MH, et al. Am J Med 100:617, 1996

13. Candidemia in Tertiary Care Centers in the US 1990-1994 Prospective observational Study of pts with positive blood cultures for Candida sp. In 4 tertiary care centers. Non-albicans Candidemia increased significantly in each center P=0.01. And during 1993-94 it surpassed C. albicans Candidemia 40% to 53%. 13% of Candidemias occurred in patients already on antifungals C. parapsilosis and C. krusei- prior fluconazole C. glabrata – prior Ampho B. Isolates causing break through Candidemia exhibited higher MIC to fluconazole (>8 mcg/ml) – 72% vs. 12% Nguyen MH, et al. Am J Med 100:617, 1996

15. Location of Patients with Candidemia at KFSH&RC 1994-1998

16. C. albicans vs. Non-albicans Isolates at KFSH&RC

17. Mortality and Excess Hospital Stay due to Candidemia VariablePoint Estimate % Crude mortality Cases (n=88)57 Controls (n=88)19 Attributable mortality38 Median length of hospital Stay ( 34 surviving pairs) Cases70 days Controls40 days Attributable excess stay30 days Wey SB, et al. Arch Intern Med 148:2642, 1988

18. Pathogens in 2064 ICU-acquired Infection in EPIC Study PathogenIncidence % Enterobacteriaceae34.4 S. aureus30.1 P. aeruginosa28.7 Coag neg staph19.1 Fungi17.1

19. Outcome of Patients with Candidemia Wenzel RP. Clin Infect Dis 20:1531, 1995

20. Who gets Candidemia? Risk Factors for Candidemia Neutropenia Multiple Blood transfusions Prolonged Central venous catheters Candida colonization Diabetes Broad spectrum antibiotics Length of ICU stay Corticosteroids Immunosuppressives Hemodialysis Parenteral alimentation Mechanical ventilation Prematurity

21. Candida colonization Development of Candidemia in cancer Patients Candidemia % Ref 1Ref 2 Multiple site colonization 22 32 Single site colonization 5 1 No colonization 0 0.5 1. Martino P. Am J Med Sci 306:225, 1993 2. Martino P. Cancer 64:2030, 1989

22. Candida colonization

23. Therapy for Candidemia 1.The pathogen Drug selection Optimize dose Adjunctive therapy (e.g surgery) 2.The host Modify risk factors Immunomodulation. ?cytokine therapy

24. Targets for Antifungal Agents

25. Antifungal Agents Polyenes Amphotericin B (deoxycholate) - 1958 Liposomal amphotericin B (AmBisome) - 1997 Amphotericin Lipid Complex (ABLC) - 1996 Amphotericin Colloidal Dispersion (ABCD) - 1996 Azoles Miconazole (intravenous) - 1979 Ketoconazole (P.O) - 1981 Fluconazole (P.O, intravenous) - 1990 Itraconazole (capsule, solution, intravenous) - 1992 Others Griseofulvin - 1959 5-Flucytosine - 1972 Terbinafine - 1996 Currently available

26. PolyenesSordarins Liposomal Nystatin GM 193663 Amphotericin B Cochleate GM 222712 KY62 GM 237354 Partricins (IB643) AzolesChintinases VoriconazolePradimicins SCH56592Nikkomycins BMS-207147 Nikkomycin z UR-9825 EchinocandinsPeptides M-0991 Defensin LY303366 Pretregrin Antifungal Agents In the Pipeline

27. Cell wall Envelope of C. albicans Fimbrial Layer Mannoprotein B-Glucan B-Glucan, Chitin Mannoprotein Plasma membrane Pradimicin Echanocandins Nikkomycin, Chinases Amphotericin

28. Pharmacokinetics of AMB Lipid Formulations DrugLipidMeanMeanMean CmaxVdAUC AMBNA2.948.6 L-AMBLiposome    ABCDDisklike    ABLCRibbon-like  Similar 

29. Amphotericin B versus ABLC for Invasive Candidiasis (Prospective randomized multi-center Study) Response % ParameterABLC(5mg)Ampho B(0.6mg) P value Overall response81/124 (65)43/70 (61) 0.64 Infection type Candidemia67/105 (64)32/58 (55) 0.32 Single organ13/18 (72)11/12 (92) 0.36 Pathogen 0.53 C. albicans45/66 (68)21/33 (64) Non-albicans32/50 (64)22/30 (57) Anaissie EJ, et al. 35 th ICAAC, 1995

30. Amphotericin B versus ABLC for Invasive Candidiasis (Prospective randomized multi-center Study) Response % ParameterABLC(5mg)Ampho B(0.6mg) P value Doubling Cr41/145 (28) 36/76 (47) 0.007 Median time82 days 19 days 0.028 Infusion-related toxicity67/153 (44) 34/78 (44) 1.00 Anaissie EJ, et al. 35 th ICAAC, 1995

31. Therapeutic Strategies for Invasive Candidiasis? Insensitive diagnostic tools for invasive Candidiasis. Sensitivity ~ 50%. Mortality of invasive Candidiasis ~ 70% 1.Targeted prophylaxis 2.Early presumptive therapy Available less toxic Antifungals

32. Prophylaxis against Candida Indicated Bone marrow transplant patients. Goodman, NEJM 326:845, 1992 Invasive candidiasis by 50%. ? Indicated Leukemia Multiple risk factors for invasive Candidiasis - > 14 days of Antibiotics -CVL -Hyperalimentation -Complicated intra-abdominal surgery -Colonization from multiple sites

33. Early Presumptive Therapy Definition Initiation of systemic antifungal therapy in patients with sepsis that are at high risk of invasive Candidiasis and no identifiable source or explanation for sepsis.

34. A Randomized Double-Blind Safety Study of AmBisome and ABLC in Febrile Neutropenic Patients ABLCL-AmB (5mg)L-AmB (5mg)P value n=78 n=81 n=85 Chills 79.5 23.5 18.8< 0.001 Fever 57.7 19.8 23.5< 0.001 Hypoxia 11.5 1.2 0.00< 0.01 Others 41.0 25.9 18.8< 0.05 Doubling 42.3 14.8 14.1< 0.001 S Cr. No difference in efficacy between all the 3 arms Wingard JR, 9 th FFI, March 1999

35. International Conference of a Consensus on the Management of Candidiasis Careful selection of 22 experts on treatment of Candidiasis Participants are from USA, Europe and Japan Met in a conference room at UCLA Voting was anonymous by an electronic device Data was generated by a computer system Question on different management issues relating to Candidiasis Edwards JE, Clin infect Dis 25:43, 1997

36. Should all Candidemic patients be treated with antifungals?

37. WHAT ANTIFUNGAL AGENTS SHOULD BE USED FOR CANDIDEMIA IN NON-NEUTROPENIC STABLE PATIENT?

38. WHAT ANTIFUNGAL AGENTS SHOULD BE USED FOR CANDIDEMIA IN NON-NEUTROPENIC UNSTABLE PATIENT? Patient’s condition No prior Fluconazole Rx Fluconazole5/20 Fluc+AMB5/20 AMB8/20 Lipid AMB2/20 Itraconazole0/20

39. Predictors of Poor Outcome in Candidemia