1. Antifungal Prophylaxis in Solid Organ Transplant Recipients: Seeking Clarity Amidst Controversy Nina Singh, M.D.

2. Rationalizing antifungal prophylaxis and strategies n Diversity in the incidence of fungal infections n Risk of dissemination n Predilection towards specific pathogen n Time of onset

3. n Which solid organ transplant groups should receive prophylaxis? n Who are the high-risk patients? n Against which pathogens should prophylaxis be directed? n When should prophylaxis be administered and for how long?

4. Frequency of major fungal infections in organ transplant recipients Incidence of invasive fungalInfections due Infections due infections*to Aspergillusto Candida Renal1.4 - 14%0 - 10%2.0 - 100% Heart5 - 21%77 - 91%8 - 23% Liver7 - 42%9 - 34%35 -91% Lung and heart-lung15 - 35%25 - 50%43 - 72% Small-bowel40 - 59%0 - 3.6%80 - 100% Pancreas18 - 38%0 - 3%97 - 100%

5. Type ofIA,%DisseminatedMortality transplantrange (mean)aspergillosis, %rate, % Liver1-8 (2)50-6092 Lung3-14 (6)15-2074 Heart1-15 (5.2)20-3578 Kidney0.9 - 0 4 (.7)9-3677 Pancreas1.1 - 2.9 (1.3)NA100 Small bowel0 - 3.6% (2.2)NA100

6. Risk factors for invasive aspergillosis in liver transplant recipents n Poor allograft function n Renal failure, particularly requirement of dialysis Fisher et al., J Antimicrob Chemother, 99 Breigel et al., EJ Clin Micro Infect Dis, 95 Singh et al., Transplantation, 97

7. n Allograft dysfunction in 26/26 patients with IA; median serum bilirubin, 21.8 mg/dl n Fulminant hepatic failure (21% had IA) n Retransplantation (27% of the IA cases) Sampathkumar, Transplantation 99 Singh, Transplantation 97

8. n 54-92% of the patients, with IA have been on dialysis Fisher, 99; Singh, 97; Selby 97 n Renal failure and OKT3 use were independently significant risk factors Kusne, 92

9. n OKT3 use no longer a significant risk factor 1981-1990, 70% of IA patients received OKT3 1990-1996, 8% of IA patients received OKT3 n CMV not a risk factor Patel 98, Singh 97

10. Liposomal AmB for Prophylaxis No prophylaxis Prophylaxis (dialyzed cohort(Dialyzed before 1997) cohort since before 1997) cohort since 1997) 1997) Invasive fungal36% (8/22)0% (0/11) infections p =.03, prophylaxis independently protective (p =.017) Singh et al, Transplantation 01

11. n Retransplantation,dialysis, prophylaxis for SBP, CMV viremia, and return to surgery n Risk with <1 factor present 10.3% (0.R., 1.0) Risk with 1 factors present 25% (O.R., 2.9) Risk with 1 factors present 25% (O.R., 2.9) Risk with 2 factors present 61.1% (O.R., 136) Risk with 2 factors present 61.1% (O.R., 136) Risk with 3 factors present 87.5%(O.R., 60.7) Risk with 3 factors present 87.5%(O.R., 60.7) Risk with 4 factors present 100% Risk with 4 factors present 100% Chi-square for trend p =.001 Chi-square for trend p =.001 Hussain et al, ICAAC 01 Hussain et al, ICAAC 01

12. Thrombocytopenia and Infections after Liver Transplantation Nadir Nadir Nadir Nadir 30x10 3 /cmm 30x10 3 /cmm Early major infections43%17% p =.046 CMV infection14%10% p >.1 Bacterial infections38%21% p >.1 Fungal infections15% 0% p =.06 Chang, et al., Transplantation, 2000

13. Aspergillus Infections after Liver Transplantation n Median time to onset 15 - 17 days n 81 - 100% of the patients still in ICU Selby, 97; Fisher, 99

14. Extrapulmonary Spread of Aspergillus Liver transplant recipients92% (11/12) Hematologic patients30% (6/16) Non-liver transplant45% (9/20) recipients recipients p < 0.02 Boon, et al., J Clin Pathol, 90

15. Aspergillus Infections in Lung Transplant Recipients: Unique Characteristics n Transplanted organ is in direct communication with the environment n Bronchial anastomosis uniquely susceptible to infection with Aspergillus

16. Frequency of Aspergillus Colonization and Infection n Isolation of Aspergillus in29% (580/2,001), respiratory samplesrange 9-68% n Aspergillus airway23% (219/969) colonization n Isolated tracheobronchitis4% (35/615) Invasive aspergillosis6% (85/1,542) Invasive aspergillosis6% (85/1,542)

17. Aspergillus colonization portends a higher risk for subsequent infection n 17% (3/18) vs. 1.5% (2/133), p <.05 Cahill, Chest 97 n 29% (4/14) vs. 1.7% (1/57), p =.004 Husni, Clin Infect Dis 98 n Invasive disease almost exclusively due to Aspergillus fumigatus Cahill, Chest 97

18. Other Risk Factors n CMV Infection n Obliterative bronchitis n Rejection and augmented immunosuppression Paradowski, 97; Husni 98; Scott 91; Tazelaar 89

19. Median time to onset120 days Infections within 3 months49% Infections within 6 months68% Infections within 9 months79%

20. Aspergillus Infections in Other Solid Organ Transplant Recipients n Heart transplants, overall frequency 5.2% (102/1,948), range 1 to 15% n Rare in kidney and pancreas transplant recipients

21. Risk factors for Invasive Candidiasis Odds ratio (95% C.I.)P-value CMV infection3.0 (1.2 - 7.32).03 Prophylaxis for SBP11.0 (3.0 - 33.8).007 Retransplantation11.0 (3.2 - 36.4).0003 Posttransplant dialysis8.0 (3.1 - 20.0).0001 Hussain et al, ICAAC 01

22. Invasive Candidiasis in Liver Transplant Recipients in the Current Era n Over one-third of the infections due to non- albicans Candida spp. n Prior antifungal prophylaxis the only risk- factor for non-albicans Candida n Mortality 25 fold higher for cases than for controls (p =.0002); 58% for non-albicans, and 22.7% for albicans infections Husain et al, ICAAC 01

23. n Aspergillus in respiratory samples is virtually always indicative of invasive disease. n Prophylactic antifungal agent must rapidly be able to achieve systemic drug levels considered adequate for activity against Aspergillus.

24. Unconvincing Efficacy For n Itraconazole n Low-dose amphotericin B (.1 to.5 mg/kg/d)

25. Itraconazole Cyclodextrin for Prophylaxis in Liver Transplant Recipients Itraconazole SolutionPlacebo (n = 24)(n = 37) Invasive candidiasis4% (1/24)24% (9/37) p =.049 p =.049 Invasive aspergillosis0/240/37 Colby et al., ICAAC, 99

26. Nephrotoxicity of Amphotericin B in Solid Organ Transplant Recipients Increase in creatinine36% (15/42) to >2.5 mg/dL Dialysis required18% (10/55) Wingard et al, Clin Infect Dis,1999

27. CostLAmB > ABLC > ABCD > AmB ($698) ($231) ($194) ($6) Infusion ABCD > ABLC > LAmB relatedtoxicity

28. Ambisome (1 mg/kg/d for 7 days) Invasive fungal infections7% (4/58) Invasive aspergillosis3 Invasive candidiasis1 Lorf et al, Mycoses, 99

29. Recommendations for prophylaxis for aspergillosis in liver transplant recipients n ApproachTargeted n High-riskPoorly functioning allograft, populatione.g., PNF, fulminant populatione.g., PNF, fulminant hepatic failure, retransplant recipients, dialysis n Suggested Liposomal preparation of antifungal agentsAmB (3-5 mg/Kg/d) antifungal agentsAmB (3-5 mg/Kg/d) n Proposed duration4 weeks

30. n Less nephrotoxic n Equivalent or superior efficacy against invasive mycelial infections (Leenders, B J Hem 98, White, Clin Infect Dis 97, Linden, Transplantation 99) n Higher achievable tissue concentrations (17 to 78 times higher lung concentration) with ABLC (Williams, Transplantation 99) n Animal data supportive of decreased dissemination and increased survival (Leenders, J Antimicrob Chemother 96)

31. Aerosolized AmB for fungal infections in lung, heart-lung, and heart transplants Incidence ofIncidence of aspergillosis aspergillosis (3 months) (12 months) AmB (126)02% Control (101)11%12% p <.05 p <.005 p <.05 p <.005 Reichenspurner, Transplant Proceed 97

32. Recommendations for prophylaxis for lung transplant recipients n ApproachTargeted n High-riskPositive Aspergillus airway culture, populationparticularly in patients with rejection, populationparticularly in patients with rejection, obliterative bronchitis and CMV n AntifungalItraconazole, with or without agent aerosolized amphotericin B agent aerosolized amphotericin B n Suggested4 to 6 months (or until bronchial durationanastomosis has healed) durationanastomosis has healed)

33. Fluconazole in liver transplant recipients Fluconazole 400 mg/dx10 wksPlacebo (n = 108)(n = 104) Fungal infections9%43% Invasive fungal6%23% infections Invasive candidiasis5.5%19% Winston et al, Ann Intern Med 99

34. Recommendations for invasive candidiasis in transplant recipients n Type of organ LiverPancreas transplant transplant n ApproachTargetedTargeted n High-risk groupRetransplantationEnteric drainage, dialysis, retroperitoneal SBP prophylaxis graft placement, OR time > 8 hours OR time > 8 hours n Suggested duration4 weeks4 weeks

35. Principles of Prophylaxis n Antifungal strategies should be targeted towards high-risk patients and should not be universal n All modifiable risk factors should be corrected before considering prophylaxis n Must limit the duration of prophylaxis n Identify specific markers that predict infection

36. DialyzedAll other patientspatients (n=22) (n=126) (n=22) (n=126) Fungal 36% (8/22)7% (9/126)p =.0007 infections Invasive 14% (3/22)2% (2/126)p =.02 aspergillosis Singh et al, ICAAC 00

37. DialyzedAll other patientspatients (n=22) (n=126) (n=22) (n=126) Fungal 36% (8/22)7% (9/126)p =.0007 infections Invasive 14% (3/22)2% (2/126)p =.02 aspergillosis Singh et al, Transplantation 01

38. Dialyzed cohort Dialyzed cohortsince 1997 prior to 1997(antifungal (no prophylaxis) prophylaxis) (no prophylaxis) prophylaxis) Invasive 36% (8/22)0% (0/11)p =.03 fungalinfections Antifungal prophylaxis was independently protective from fungal infection (p=.017) (Singh et al, Transplantation 01)

39. Singh.ppt file: Prophylaxis 1/28/02