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Anti-Infective Prophylaxis in the Solid-Organ Transplant Population

Anti-Infective Prophylaxis in the Solid-Organ Transplant Population. W. Scott Waggoner, PharmD Solid-Organ Transplant Pharmacist Children’s Hospital of Wisconsin. Children’s Hospital of Wisconsin. 296 bed hospital Largest pediatric solid-organ transplant center in Wisconsin

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Anti-Infective Prophylaxis in the Solid-Organ Transplant Population

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  1. Anti-Infective Prophylaxis in the Solid-Organ Transplant Population W. Scott Waggoner, PharmD Solid-Organ Transplant Pharmacist Children’s Hospital of Wisconsin

  2. Children’s Hospital of Wisconsin • 296 bed hospital • Largest pediatric solid-organ transplant center in Wisconsin • 2012 Solid-Organ Transplant Statistics • 18 Heart • 1 Heart-Liver • 6 Kidney • 1 Liver

  3. Objectives • Identify prophylactic anti-infective agents in the solid-organ transplant population. • Pneumocystis • Fungus • Virus • Describe consensus guidelines for anti-infective prophylaxis in the solid-organ transplant population. • Not become the next treatment for insomnia

  4. Fungal: Pneumocystis jiroveci • 5-15% Incidence prior to routine prophylaxis • 10-40% lung & heart-lung recipients • 2-10% liver & kidney • Mortality as high as 60% • Signs & Symptoms • Fever • Dyspnea • Cough • Chest pain • Abnormal chest radiograph • Hypoxemia

  5. Fungal: Pneumocystis jiroveci cont. • Risk factors for Pneumocystis pneumonia • Immunosuppression • CMV disease • Allograft rejection • Neutropenia • Low CD4+ counts - HIV • Graft versus host disease

  6. Pneumocystis prophylaxis • Trimethoprim-Sulfamethoxazole (TMP/SMX) • 5mgTMP/kg/day on 3 days a week (max 160mg TMP) • Stendahl et al. – 88% of pediatric heart centers surveyed • Pentamidine 300mg inhaled every 30 days • Children < 4 yoa: 150mg inhaled every 30 days • Dapsone 2mg/kg once daily (max. 100mg) or 4mg/kg weekly (max 200mg) • Hemolytic anemia (G6PD def.), aplastic anemia, nephrotic syndrome, albuminuria, cholestatic jaundice syndrome, elevated liver transaminases, toxic hepatitis • Atovaquone 30mg/kg once daily (max. 1500mg)

  7. Pneumocystis prophylaxis cont. • Duration varies greatly by organ transplanted and transplant center • None-lifetime • Lung and Small-Bowel • Lifetime • Children’s Hospital of Wisconsin • Heart – 6 months • Kidney – lifetime • Liver – 12 months

  8. Pneumocystis prophylaxis cont. • Kidney – recent data points that lifelong prophylaxis not necessary • Anand et al. – 4/1352 (0.3%) PCP infections over 7 years • 2 patients < 12 months post-kidney transplant • Both had CMV infection 2 & 4 months prior to PCP • 3 patients received 1 month of PCP prophylaxis • Inhaled pentamidine • 2 TMP-SMX • 1 patient received 1 year of TMP-SMX prophylaxis

  9. Pneumocystis prophylaxis survey! • First-line agent other than TMP/SMX? • Second line agent • Dapsone • Atovaquone • Inhaled Pentamidine • IV Pentamidine • Duration of prophylaxis • <3months • 3-6 months • 6-12 months • >12 months

  10. Fungal Infection • Incidence varies greatly by organ 5-42% overall • Liver 7-42% • Heart 5-21% • Lung 15-35% • Pancreas 18-38% • Candida and Aspergillus spp. are most common • Blastomycosis, Histoplasmosis, Coccidiodomycosisless common • Mortality rates for invasive infection • Candida spp. 70% • Aspergillusspp. 100%

  11. Pappas PG, Silveira FP, et al. Candida in solid organ transplant recipients. American Journal of Transplantation 2009; 9 (Suppl 4): S173-S179.

  12. Singh N, Husain S, et al. Invasive Aspergillosis in solid organ transplant recipients. American Journal of Transplantation 2009; 9 (Suppl 4): S180-S191.

  13. Anti-fungal prophylaxis • Always watch for Drug-Drug Interactions! • Fluconazole 6mg/kg once daily (max. 400mg) • Nystatin 1-5mL swish & swallow TID-QID • Stendahl et al. – 94% of pediatric heart centers surveyed • Select Populations • Voriconazole 6-8mg/kg IV/PO Q12h (max. 400mg) • Follow Kinetics – some need Q8h dosing • Amphotericin B lipid formulations 1-5mg/kg IV Q24h • Amphotericin B aerosolized – limited data in lung transplant • Micafungin 4-12mg/kg IV q24h • Caspofungin 70mg/m² x 1, then 50mg/m² IV Q24h

  14. Anti-fungal prophylaxis survey! • Nothing • Fluconazole • Nystatin • Amphotericin B • Echinocandin • Other

  15. Cytomegalovirus (CMV) • Herpes-virus family • 60-90% of adults are seropositive • Less in children • CMV infection • Evidence of CMV replication • CMV disease • CMV infection with attributable symptoms

  16. Incidence of CMV McDevitt LM. Etiology and impact of cytomegalovirus disease on solid organ transplant recipients. Am J Health-Sys Pharm 2006; 63(Suppl 5): S3-S9.

  17. CMV Disease Risk Factors • Donor CMV-seropositivity and recipient CMV-seronegativity (D+/R-) • Certain types of organ transplants • Liver • Lung • Pancreas • Use of highly immunosuppressive drug therapies • High degree of HLA mismatch • Young patient age

  18. CMV Prevention • Prophylaxis • All patients or at-risk patients receive medication • Stendahl et al. – 91% of pediatric heart centers surveyed use routine prophylaxis • Preemptive therapy • Regular, frequent CMV monitoring • Initiate treatment therapy at certain viral replication threshold • Little evidence in some populations • Combination of both

  19. CMV Prophylaxis • Valganciclovir – 15-18mg/kg orally daily (max. 900mg) • Adverse effects: anemia, neutropenia, GI effects • Manufacturer’s dosing (mg) = 7 x body surface area x creatinineclearance (CrClSchwartz) • 25kg, 128cm, CrCl 120ml/min: Dose = 800mg/day • Some evidence of 450mg orally daily • Lower drug cost, less neutropenia • Not recommended in “International Consensus Guidelines on Management of CMV in Solid-Organ Transplant Patients” – sponsored by Roche

  20. CMV Prophylaxis cont. • Ganciclovir– 5mg/kg IV every 24h • Adjust in renal dysfunction • Valacyclovir – limited data available • 15-30mg/kg/dose 3 times daily (max. dose 2000mg) • Resistant CMV – no data for best practice • Foscarnet has most evidence • Cidofovir has little evidence

  21. Duration of CMV Prophylaxis • D+/R- patients • Should be between 3-6 months (longer for high risk groups) • Humar et al. (IMPACT) trial • 200 vs. 100 days of prophylaxis in kidney transplants • 21.3% vs 38.7% incidence of CMV disease at 2 years • No difference in acute rejection or graft survival • D+/R+ & D-/R+ patients: at least 3 months • D-/R- patients: consider acyclovir or valacyclovir

  22. CMV Survey! • CMV prevention • Prophylaxis • Pre-emptive • Duration of prophylaxis? • < 3months • 3-6 months • 6-12 months • > 12 months • Low or “Mini-” dosing • Regular dosing

  23. Conclusion • Many prophylaxis options available • Choice must be made on risk factors and patient population • Little data and few guidelines available

  24. Questions?

  25. References • Fishman, JA. Infection in solid-organ transplant recipients. NEJM2007; 357: 2601-14. • Anand S, Samaniego M, et al. Pneumocystis jiroveci pneumonia is rare in renal tranplant recipients receiving only one month of prophylaxis. Transpl Infect Dis 2011; 13: 570-4. • Goto N & Oka S. Pneumocystis jirovecipneumonia in kidney transplantation. Transpl Infect Dis2011; 13: 551-8. • de Boer MGJ, Kroon FP, et al. Risk factors for Pneumocystis jirovecipneumonia in kidney transplant recipients and appraisal of strategies for selective use of chemoprophylaxis. Transpl Infect Dis2011; 13: 559-69. • Wang EHZ, Partovi N, et al. Pneumocystis pneumonia in solid organ transplant recipients: not yet an infection of the past. Transpl Infect Dis 2012; 14: 519-25. • Martin SI, Fishman JA, et al. Pneumocystis pneumonia in solid organ transplant recipients. American Journal of Transplantation 2009; 9 (Suppl 4): S227-S233. • Playford EG, Webster AC, et al. Antifungal agents for preventing fungal infections in solid-organ transplant recipients. The Cochrane Database of Systematic Reviews 2004, Issue 3. • Singh N, Husain S, et al. Invasive Aspergillosis in solid organ transplant recipients. American Journal of Transplantation2009; 9 (Suppl 4): S180-S191. • Pappas PG, Silveira FP, et al. Candida in solid organ transplant recipients. American Journal of Transplantation 2009; 9 (Suppl 4): S173-S179. • Proia L, Miller R, et al. Endemic fungal infections in solid organ trasplant recipients. American Journal of Transplantation 2009; 9 (Suppl 4): S199-S207.

  26. References • Kotton CN, Kumar D, et al. International consensus guidelines on the management of Cytomegalovirus in solid organ transplantation. Transplantation 2010; 89: 779-95. • Luan FL, Kommareddi M, et al. Impact of Cytomegalovirus Disease in D+/R- kidney transplant patients receiving 6 months low-dose valganciclovir prophylaxis. American Journal of Transplantation 2011; 11: 1936-42. • Humar A, Lebranchu Y, et al. The efficacy and safety of 200 days valganciclovir Cytomegalovirus prophylaxis in high-risk kidney transplant recipients. American Journal of Transplantation 2010; 10: 1228-37. • Kalil AC, Sun J, et al. IMPACT trial results should not change current standard of 100 days for cytomegalovirus prophylaxis. American Journal of Transplantation 2011; 11(1): 18-21. • Snydman DR. Putting the IMPACT study into perspective: should CMV prophylaxis be extended 6 months for high risk transplants? American Journal of Transplantation 2011; 11: 6-7. • McDevitt LM. Etiology and impact of cytomegalovirus disease on solid organ transplant recipients. Am J Health-Sys Pharm 2006; 63(Suppl 5): S3-S9. • Subramanian AK. Antimicrobial prophylaxis regimens following transplantation. CurrOpin Infect Dis 2011; 24: 344-9. • Snydman DR, Limaye AP, et al. Update and review: state of the art management of Cytomegalovirus infection and disease following thoracic organ transplantation. Transplantation Proceedings 2011; 43: S1-S17. • Demmler-Harrison GJ. Cytomegalovirus infection and disease in newborns, infants, children and adolescents.  In: UpToDate, Edwards, MS (Ed), UpToDate, Waltham, MA, 2012. • Lexi-Comp OnlineTM , Pediatric & Neonatal Lexi-Drugs OnlineTM , Hudson, Ohio: Lexi-Comp, Inc.; October 5, 2012. • Stendahl G, Bobay K, et al. Organizational structure and processes in pediatric heart transplantation: A survey of practices. Pediatric Transplantation 2012; 16(3):257-64.

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