1 / 39

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.

libitha
Download Presentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  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

More Related