Antifungal stewardship in solid-organ transplantation: What is needed?

BACKGROUND: Antifungal stewardship (AFS) lags behind antimicrobial stewardship (AMS) in terms of implementation, evidence base, and workforce experience. Solid-organ transplantation (SOT) carries a significant risk of invasive fungal infection, with high associated mortality, and is therefore associated with significant opportunities to optimize antifungal use. METHODS: A literature search for the terms "antifungal stewardship" and "solid-organ transplant" revealed a small evidence base to support AFS programs in this patient group. RESULTS: There is significant overlap in the methodology used in AMS and AFS programs, with notable differences in diagnostics, which are discussed in detail. The primary AFS interventions tested in SOT recipients are implementation of clinical guidelines and care bundles, digital enablers of AFS, and post-prescription review/audit and feedback. CONCLUSION: There is an urgent need for further research to support effective AFS strategies in this highly susceptible population.

Fungal infection in cardiothoracic transplant recipients: outcome without systemic amphotericin therapy.

Transplant recipients require immunosuppression to prevent allograft rejection, placing them at risk of opportunistic infections including fungal infection. Difficulties in managing fungal infections include: establishing diagnosis, poor treatment response, drug interactions and toxicity. We report our single centre experience of treating fungal infections using systemic non-Amphotericin current generation antifungals. Patients receiving inpatient antifungal therapy from September 2005 to December 2010 were identified from pharmacy records. Fungal infections were retrospectively classified according to European Organization for Research and Treatment of Cancer (EORTC) criteria. Treatment outcomes were classified in a manner similar to those used in clinical trials. Two hundred and forty-nine recipients received antifungal treatment, 204 lungs and 45 hearts. One hundred and one patients received Voriconazole, 82 Caspofungin and 65 received both agents. One patient was unsuccessfully treated with additional Amphotericin. Treatment duration varied from 1.5 to 12 weeks. One hundred and sixty-five patients had a complete response, 24 had a partial response and in 60 patients treatment was unsuccessful. The response to systemic non-Amphotericin based antifungal therapy was high. We propose that diagnostic criteria without positive identification of a fungus allow treatment to be started early with few clinically relevant side effects.

Chronic kidney disease after heart transplantation.

BACKGROUND: Chronic kidney disease (CKD) is a complication of heart transplantation related to calcineurin inhibitor nephrotoxicity. However, it is unclear whether early ciclosporin (CsA) exposure influences CKD in the long term. METHODS: We analysed risk factors for CKD in 352 patients who underwent orthotopic heart transplantation (1995-2005). In 2000, we reduced our target CsA levels in the first year after transplantation. RESULTS: Actuarial patient survival was 79% at 1 year and 62% at 10 years. Estimated median glomerular filtration rate (eGFR) by the four-variable Modification of Diet in Renal Disease formula was 64 ml/min/1.73 m2 before transplantation, inter-quartile range (IQR) 54-78. After transplantation, the eGFR was 48 (IQR 37-61) at Year 1, and 41(35-57) at Year 10. The cumulative probability of eGFR <45 ml/min/1.73 m2 was 45% at Year 1, 71% at Year 5 and 83% at Year 10. A multivariable logistic regression model was constructed for the development of eGFR <45 ml/min/1.73 m2 by 3 years. The risk factors were post-operative renal replacement therapy for acute renal failure (ARF), P < 0.001; pretransplant diabetes, P = 0.005; increasing recipient age, P < 0.001; female recipient, P = 0.029; female donor, P = 0.04, but not CsA regimen. The cumulative probability of developing stage 5 CKD (eGFR <15) was 3% at Year 5 and 12% at Year 10. Although lower ciclosporin initial levels were associated with less renal dysfunction at Year 1 (P = 0.008), there was no significant effect by Year 3 (P = 0.7). CONCLUSION: The incidence of CKD increased with time and was not influenced by the CsA regimen. Some risk factors are not modifiable but measures to reduce the incidence of post-operative ARF may help to reduce CKD.

Mycophenolate mofetil may allow cyclosporine and steroid sparing in de novo heart transplant patients.

BACKGROUND: Mycophenolate mofetil (MMF) provides superior prophylaxis against acute rejection when compared with azathioprine (AZA) in heart and renal transplantation. However, it remains unclear whether this results in improved survival or reduced morbidity after heart transplantation. METHOD: In a sequential study, 240 cardiac transplant patients were treated with either MMF (n=119) or AZA (n=121) both in combination with cyclosporine and corticosteroids after rabbit antithymocyte globulin induction. RESULTS: By protocol lower cyclosporine levels were targeted in the MMF group during the first year (e.g. 203+/-52 ng/mL MMF vs. 236+/-59 ng/mL AZA, P=0.0006 at 6 months). Patient survival at 1 year (82% MMF vs. 79% AZA, P=0.55) and at 3 years was similar in both groups. The cumulative probability of receiving antirejection treatment within 1 year was lower in the MMF group, as was biopsy-proven acute rejection with International Society of Heart and Lung Transplantation grade > or =3A (24% vs. 35%, P=0.03). The MMF group also had fewer episodes requiring cytolytic therapy (6% vs. 13%, P=0.04) and more patients had steroids withdrawn by 1 year (66% vs. 32%, P<0.001). Renal function was better in the MMF group with lower creatinine levels at 1 year (133+/-45 vs. 155+/-46 micromol/L, P=0.0004). Calculated creatinine clearance (Cockcroft and Gault formula) at 1 year was also better (MMF 74+/-32 mL/min vs. AZA 62+/-24 mL/min, P=0.004). CONCLUSION: Our results suggest that immunosuppression with MMF rather than AZA may allow lower cyclosporine levels, better renal function, and increased steroid weaning at 1 year while also achieving better control of acute rejection.