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

2. 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, Coccidiodomycosis less common Mortality rates for invasive infection – Candida spp. 70% – Aspergillus spp. 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 OrganCMV Infection (%)CMV Disease (%) Kidney8-328 Liver22-2929 Heart9-3525 Lung or Heart-Lung39-4139 Pancreas or Kidney-Pancreas50 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 creatinine clearance (CrCl Schwartz) 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 1.Fishman, JA. Infection in solid-organ transplant recipients. NEJM 2007; 357: 2601-14. 2.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. 3.Goto N & Oka S. Pneumocystis jiroveci pneumonia in kidney transplantation. Transpl Infect Dis 2011; 13: 551-8. 4.de Boer MGJ, Kroon FP, et al. Risk factors for Pneumocystis jiroveci pneumonia in kidney transplant recipients and appraisal of strategies for selective use of chemoprophylaxis. Transpl Infect Dis 2011; 13: 559-69. 5.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. 6.Martin SI, Fishman JA, et al. Pneumocystis pneumonia in solid organ transplant recipients. American Journal of Transplantation 2009; 9 (Suppl 4): S227-S233. 7.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. 8.Singh N, Husain S, et al. Invasive Aspergillosis in solid organ transplant recipients. American Journal of Transplantation 2009; 9 (Suppl 4): S180-S191. 9.Pappas PG, Silveira FP, et al. Candida in solid organ transplant recipients. American Journal of Transplantation 2009; 9 (Suppl 4): S173-S179. 10.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 11.Kotton CN, Kumar D, et al. International consensus guidelines on the management of Cytomegalovirus in solid organ transplantation. Transplantation 2010; 89: 779-95. 12.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. 13.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. 14.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. 15.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. 16.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.Subramanian AK. Antimicrobial prophylaxis regimens following transplantation. Curr Opin Infect Dis 2011; 24: 344-9. 18.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. 19.Demmler-Harrison GJ. Cytomegalovirus infection and disease in newborns, infants, children and adolescents. In: UpToDate, Edwards, MS (Ed), UpToDate, Waltham, MA, 2012. 20.Lexi-Comp Online TM, Pediatric & Neonatal Lexi-Drugs Online TM, Hudson, Ohio: Lexi-Comp, Inc.; October 5, 2012. 21.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.