Echinocandins for antifungal prophylaxis in liver transplant recipients: Advance in the field or variation on a theme?

Abstract

Potential conflict of interest: Nothing to report. See Article on Page 427 It has been 20 years since the efficacy of fluconazole or amphotericin for reducing invasive fungal infections (IFIs) in liver transplant recipients was established.1 Identification of risk factors allowed centers to target antifungal prophylaxis to high‐risk liver transplant recipients (HR‐LTRs).2 Overall rates of IFIs have declined from up to 43% to as low as 4.7%.1 Despite these advances, no mortality benefit has yet been ascribed to antifungal prophylaxis in this population, making attempts at improving prophylactic strategies appear to be variations rather than progress in the field.5 Newer antifungal agents afford an opportunity to improve our strategies, but it remains unclear that these will lead to improved outcomes. Echinocandins are an attractive option for IFI prophylaxis. Although fluconazole retains activity against many of the common strains of Candida that complicate early posttransplant care, echinocandins and amphotericin have activity against increasingly prevalent nonalbicans Candida species, as well as Aspergillus species. Echinocandins have the advantage of ease of dosing compared to the azoles early after transplant, lack the metabolic interactions with calcineurin inhibitors, and lack the nephrotoxicity of amphotericin. Recently, 2 important randomized controlled trials (RCTs) have demonstrated the noninferiority of echinocandins compared to fluconazole (or standard of care) for IFI prophylaxis in HR‐LTRs.8 In the Liver Transplant European Study Into the Prevention of Fungal Infection (TENPIN) study, Saliba et al.9 compared open label micafungin to standard of care (mostly fluconazole or liposomal amphotericin) for 21 days in HR‐LTRs. Winston et al.8 compared anidulafungin to fluconazole for 21 days in a double‐blind RCT in HR‐LTRs. Both studies demonstrated insignificant differences in overall incidence of IFIs in each group. Likewise, graft rejection, fungal‐free survival, and overall mortality were similar. In this issue of Liver Transplantation, Fortún et al.10 corroborate these observations in a large, retrospective multicenter cohort study. The authors compared caspofungin to fluconazole prophylaxis in HR‐LTRs and demonstrated insignificant differences in global IFIs at 6 months. Caspofungin was, however, associated with a significant reduction in the rate of breakthrough IFIs while on prophylaxis, particularly in those patients on renal replacement therapy (RRT). By propensity matching, they report a significant reduction in invasive aspergillosis (IA) in patients receiving caspofungin. So although overall rates of IFIs were not affected by echinocandins, this study identifies patients at particular risk. On the basis of this and data from Winston et al.,8 a case can be made for using an echinocandin rather than fluconazole for those patients at particular risk for IA. Previous studies have suggested an increased risk for IA, rather than candidiasis alone, within the high‐risk categories used for targeted IFI prophylaxis. Patients with fulminant hepatic failure, RRT, and retransplantation are at particular risk for IA and may be considered for prophylaxis with an agent with activity against filamentous fungi (echinocandins, voriconazole, or amphotericin).11 Of interest is the finding that RRT was associated with more frequent breakthrough fungal infections, not from IA, but from fluconazole‐sensitive Candida species. What is implied is that RRT results in suboptimal fluconazole concentrations. Unintentional, suboptimal dosing of fluconazole in the intensive care unit setting has been reported in up to 33% of those on therapy.13 Fluconazole is removed at different rates for patients on intermittent and continuous forms of dialysis and requires detailed adjustments not required by the echinocandins. Ideal dosing of fluconazole for IFI prophylaxis has not been established. Fortún et al.10 described a range of doses (100‐400 mg), but whether these doses were appropriately adjusted according to renal function and mechanism of RRT is unclear. The authors report an increase in bilirubin (but decrease in transaminases) associated with caspofungin use, and this is of unclear importance. It did not appear to be related to specific hepatotoxicity. However, the impact on posttransplant care could be important. Elevations of bilirubin early after transplant may lead to additional testing (hepatic imaging and biopsies). Anidulafungin or micafungin, which are not implicated in hyperbilirubinemia, may be preferable in this setting. The current study raises additional questions. For example, the ideal duration of antifungal prophylaxis remains unclear. The authors report a median duration of prophylaxis of 22 and 24 days in each arm (without a reported range). This conforms with the treatment in the recent RCTs with many receiving shorter courses and many longer courses, abbreviated or lengthened at the discretion of the study investigators. Earlier studies have ranged from 7 days to 10 weeks of antifungal therapy. Similarly, the ideal time to assess the efficacy of prophylaxis is unclear. IFI outcomes were measured at 180 days by Fortún et al.,10 but prophylaxis occurred in the first 3‐4 weeks after transplant. Because most IFIs occur early after transplant, many studies have limited the follow‐up to 90‐100 days. This allows for the evaluation of breakthrough infection during prophylaxis and the subsequent emergence of IFI from ineffectively killed organisms. Late IFIs, beyond 90 days, appear to be associated with different risk factors than those predisposing to early IFIs. These include immunosuppressive therapies, cytomegalovirus infection, and recurrent hepatitis C cirrhosis, which is likely not impacted by early antifungal prophylaxis.14 What Fortún et al.10 have confirmed is that echinocandins are as effective as fluconazole for IFI prophylaxis in HR‐LTRs. Furthermore, they may be superior to fluconazole for patients with a specific risk for IA. They may have a role in patients on RRT due to the potential for inadvertently low dosing of fluconazole. These data add to the published body of data that indicate that those at risk for IFIs after liver transplantation are somewhat disparate. Some centers stratify risk, targeting those with the additional risk for IA differently than those at risk for Candida infection alone.15 Such an approach is advocated in published guidelines.16 Echinocandins may effectively bypass the need to think beyond the traditional risk factors by having activity against both Aspergillus and Candida without adding significant toxicity. Whether any of these seemingly more advanced approaches to IFI prophylaxis ultimately affects overall patient survival requires further study.