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
• 2012 Solid-Organ
Transplant Statistics
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–
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18 Heart
1 Heart-Liver
6 Kidney
1 Liver
Objectives
• Identify prophylactic anti-infective agents in
the solid-organ transplant population.
– Pneumocystis
– Fungus
– Virus
• Describe consensus guidelines for antiinfective prophylaxis in the solid-organ
transplant population.
• Not become the next treatment for insomnia
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
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Fever
Dyspnea
Cough
Chest pain
Abnormal chest radiograph
Hypoxemia
Fungal: Pneumocystis jiroveci cont.
• Risk factors for Pneumocystis pneumonia
– Immunosuppression
– CMV disease
– Allograft rejection
– Neutropenia
– Low CD4+ counts - HIV
– Graft versus host disease
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)
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
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
Pneumocystis prophylaxis survey!
• First-line agent other than TMP/SMX?
• Second line agent
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–
–
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Dapsone
Atovaquone
Inhaled Pentamidine
IV Pentamidine
• Duration of prophylaxis
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< 3months
3-6 months
6-12 months
> 12 months
Fungal Infection
• Incidence varies greatly by organ 5-42% overall
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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%
Pappas PG, Silveira FP, et al. Candida in solid organ transplant recipients. American Journal of Transplantation 2009; 9 (Suppl 4): S173S179.
Singh N, Husain S, et al. Invasive Aspergillosis in solid organ transplant recipients. American Journal of Transplantation 2009; 9
(Suppl 4): S180-S191.
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
Anti-fungal prophylaxis survey!
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•
•
•
Nothing
Fluconazole
Nystatin
Amphotericin B
Echinocandin
Other
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
Incidence of CMV
Organ
CMV Infection (%)
CMV Disease (%)
Kidney
8-32
8
Liver
22-29
29
Heart
9-35
25
Lung or Heart-Lung
39-41
39
50
50
Pancreas or Kidney-Pancreas
McDevitt LM. Etiology and impact of cytomegalovirus disease on solid organ transplant recipients. Am J Health-Sys Pharm 2006;
63(Suppl 5): S3-S9.
CMV Disease Risk Factors
• Donor CMV-seropositivity and recipient CMVseronegativity (D+/R-)
• Certain types of organ transplants
– Liver
– Lung
– Pancreas
• Use of highly immunosuppressive drug therapies
• High degree of HLA mismatch
• Young patient age
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
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
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
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
CMV Survey!
• CMV prevention
– Prophylaxis
– Pre-emptive
• Duration of prophylaxis?
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< 3months
3-6 months
6-12 months
> 12 months
• Low or “Mini-” dosing
• Regular dosing
Conclusion
• Many prophylaxis options available
• Choice must be made on risk factors and
patient population
• Little data and few guidelines available
Questions?
References
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Fishman, JA. Infection in solid-organ transplant recipients. NEJM 2007; 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 jiroveci pneumonia in kidney transplantation. Transpl Infect Dis
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de Boer MGJ, Kroon FP, et al. Risk factors for Pneumocystis jiroveci pneumonia in kidney
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Infect Dis 2011; 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 Transplantation 2009; 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.
References
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Luan FL, Kommareddi M, et al. Impact of Cytomegalovirus Disease in D+/R- kidney transplant patients receiving
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Humar A, Lebranchu Y, et al. The efficacy and safety of 200 days valganciclovir Cytomegalovirus prophylaxis in
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