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

Antifungal Prophylaxis in Solid Organ Transplant Recipients: Seeking Clarity Amidst Controversy Nina Singh, M.D. Rationalizing antifungal prophylaxis and strategies. Diversity in the incidence of fungal infections Risk of dissemination Predilection towards specific pathogen Time of onset.

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

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

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

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

  4. Frequency of major fungal infections in organ transplant recipients Incidence of invasive fungal Infections due Infections due infections* to Aspergillus to Candida Renal 1.4 - 14% 0 - 10% 2.0 - 100% Heart 5 - 21% 77 - 91% 8 - 23% Liver 7 - 42% 9 - 34% 35 -91% Lung and heart-lung 15 - 35% 25 - 50% 43 - 72% Small-bowel 40 - 59% 0 - 3.6% 80 - 100% Pancreas 18 - 38% 0 - 3% 97 - 100%

  5. Type of IA ,% Disseminated Mortality transplant range (mean) aspergillosis, % rate, % Liver 1-8 (2) 50-60 92 Lung 3-14 (6) 15-20 74 Heart 1-15 (5.2) 20-35 78 Kidney 0.9 - 0 4 (.7) 9-36 77 Pancreas 1.1 - 2.9 (1.3) NA 100 Small bowel 0 - 3.6% (2.2) NA 100

  6. Risk factors for invasive aspergillosis in liver transplant recipents • Poor allograft function • 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. Allograft dysfunction in 26/26 patients with IA; median serum bilirubin, 21.8 mg/dl • Fulminant hepatic failure (21% had IA) • Retransplantation (27% of the IA cases) Sampathkumar, Transplantation 99 Singh, Transplantation 97

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

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

  10. Liposomal AmB for Prophylaxis No prophylaxis Prophylaxis (dialyzed cohort (Dialyzed before 1997) cohort since 1997) Invasive fungal 36% (8/22) 0% (0/11) infections p = .03, prophylaxis independently protective (p = .017) Singh et al, Transplantation 01

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

  12. Thrombocytopenia and Infections after Liver Transplantation Nadir Nadir < 30x103/cmm >30x103/cmm Early major infections 43% 17% p =.046 CMV infection 14% 10% p > .1 Bacterial infections 38% 21% p > .1 Fungal infections 15% 0% p = .06 Chang, et al., Transplantation, 2000

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

  14. Extrapulmonary Spread of Aspergillus Liver transplant recipients 92% (11/12) Hematologic patients 30% (6/16) Non-liver transplant 45% (9/20) recipients p < 0.02 Boon, et al., J Clin Pathol, 90

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

  16. Frequency of Aspergillus Colonization and Infection • Isolation of Aspergillus in 29% (580/2,001), respiratory samples range 9-68% • Aspergillus airway 23% (219/969) colonization • Isolated tracheobronchitis 4% (35/615) • Invasive aspergillosis 6% (85/1,542)

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

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

  19. Median time to onset 120 days Infections within 3 months 49% Infections within 6 months 68% Infections within 9 months 79%

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

  21. Risk factors for Invasive Candidiasis Odds ratio (95% C.I.) P-value CMV infection 3.0 (1.2 - 7.32) .03 Prophylaxis for SBP 11.0 (3.0 - 33.8) .007 Retransplantation 11.0 (3.2 - 36.4) .0003 Posttransplant dialysis 8.0 (3.1 - 20.0) .0001 Hussain et al, ICAAC 01

  22. Invasive Candidiasis in Liver Transplant Recipients in the Current Era • Over one-third of the infections due to non-albicansCandida spp. • Prior antifungal prophylaxis the only risk-factor for non-albicansCandida • 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. Aspergillus in respiratory samples is virtually always indicative of invasive disease. • Prophylactic antifungal agent must rapidly be able to achieve systemic drug levels considered adequate for activity against Aspergillus.

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

  25. Itraconazole Cyclodextrin for Prophylaxis in Liver Transplant Recipients Itraconazole Solution Placebo (n = 24) (n = 37) Invasive candidiasis 4% (1/24) 24% (9/37) p = .049 Invasive aspergillosis 0/24 0/37 Colby et al., ICAAC, 99

  26. Nephrotoxicity of Amphotericin B in Solid Organ Transplant Recipients Increase in creatinine 36% (15/42) to >2.5 mg/dL Dialysis required 18% (10/55) Wingard et al, Clin Infect Dis ,1999

  27. Cost LAmB > ABLC > ABCD > AmB ($698) ($231) ($194) ($6) Infusion ABCD > ABLC > LAmB related toxicity

  28. Ambisome (1 mg/kg/d for 7 days) Invasive fungal infections 7% (4/58) Invasive aspergillosis 3 Invasive candidiasis 1 Lorf et al, Mycoses, 99

  29. Recommendations for prophylaxis for aspergillosis in liver transplant recipients • Approach Targeted • High-risk Poorly functioning allograft, population e.g., PNF, fulminant hepatic failure, retransplant recipients, dialysis • Suggested Liposomal preparation of antifungal agents AmB (3-5 mg/Kg/d) • Proposed duration 4 weeks

  30. Less nephrotoxic • Equivalent or superior efficacy against invasive mycelial infections (Leenders, B J Hem 98, White, Clin Infect Dis 97, Linden, Transplantation 99) • Higher achievable tissue concentrations (17 to 78 times higher lung concentration) with ABLC (Williams, Transplantation 99) • 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 of Incidence of aspergillosis aspergillosis (3 months) (12 months) AmB (126) 0 2% Control (101) 11% 12% p < .05 p < .005 Reichenspurner, Transplant Proceed 97

  32. Recommendations for prophylaxis for lung transplant recipients • Approach Targeted • High-risk Positive Aspergillus airway culture, population particularly in patients with rejection, obliterative bronchitis and CMV • Antifungal Itraconazole, with or without agent aerosolized amphotericin B • Suggested 4 to 6 months (or until bronchial duration anastomosis has healed)

  33. Fluconazole in liver transplant recipients Fluconazole 400 mg/dx10 wks Placebo (n = 108) (n = 104) Fungal infections 9% 43% Invasive fungal 6% 23% infections Invasive candidiasis 5.5% 19% Winston et al, Ann Intern Med 99

  34. Recommendations for invasive candidiasis in transplant recipients • Type of organ Liver Pancreas transplant • Approach Targeted Targeted • High-risk group Retransplantation Enteric drainage, dialysis, retroperitoneal SBP prophylaxis graft placement, OR time > 8 hours • Suggested duration 4 weeks 4 weeks

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

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

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

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