Description

Invasive Fungal Infection (IFI) was identified as affecting up to 42% of liver transplant recipients in the past, with mortality rates ranging from 25-71%. This occurred prior to the period of antifungal prophylaxis. In high-risk LT recipients, current recommendations suggest for targeted fluconazole prophylaxis. This is partly based on the findings of a single-centre randomised, double-blind, placebo-controlled study, fluconazole (400 mg daily for 10 weeks) was linked to fewer IFIs (especially in patients with risk factors) and fewer deaths related to IFI. The majority of LT centres in North America claimed to use fluconazole as the main medication for targeted prophylaxis in high-risk LT recipients.

Despite the fact that the safety about not providing antifungal prophylaxis to low-risk liver transplant recipients has been established, nearly 30% of LT centres in North America reported providing universal prophylaxis. The 1-year incidence of IFI in LT recipients in the study is approximately 4% in the modern era of primarily targeted but also universal antifungal prophylaxis. This month's issue of despite the fact that only one established risk factor for IFI was required for eligibility, more than 80% of the patients in the study had at least two risk factors, placing them in the group for which targeted antifungal prophylaxis is currently recommended. There were no differences in safety, fungal invasion, rejection, fungal-free survival, or mortality between the anidulafungin (5.1%) and fluconazole (8.0%) groups after 90 days.

The fluconazole and anidu-lafungin are equally effective to avoiding IFI in LT recipients at high risk. However, the observed rate of IFI in the fluconazole group was lower than the expected rate (18%). The study was intended to perhaps identify a difference in IFIs between the two groups. Only two patients in the fluconazole arm of this study had invasive opportunistic infections, hence prevention of immune-compromised patients was not a concern. These results give facilities that still administer fluconazole prophylaxis confidence. The disagreement also implies that risk factors for invasive candidiasis and fungal infections are still changing and that IFI risk has been decreasing over time.

Even though just a small portion of the patients in this trial had previously received antifungal medication, almost 75% of the patients had a Model for End-stage Liver Disease (MELD) score of 30. Although recent studies have shown that MELD score 30 may be the most important risk factor for IFI, current recommendations do not list it as an indication for antifungal prophylaxis. The fact that a decreased incidence of breakthrough IFI was seen with anidulafungin prophylaxis in patients with either factor, as well as in patients who had major blood loss or needed renal replacement treatment, is extremely interesting. Future studies should further examine the potential benefit of echinocandin prophylaxis in patients with these risk factors. The length of antifungal prophylaxis varies significantly throughout facilities.

The median duration of prophylaxis in this study was 21 days, and the positive efficacy validates current guidelines that recommend prophylaxis for up to 4 weeks in patients with no on-going risk factors. Antifungal prophylaxis should be given for a shorter period of time in patients that do not have on-going risk factors for IFI. Because antifungal prophylaxis has been linked to a reduction in IFI-related mortality, one might hypothesise that preventing IFI would also result in improved overall survival in LT recipients. However, no single study or meta-analysis of antifungal prophylaxis in LT recipients has ever shown a link to improved patient mortality. One possible explanation for this paradox is that patient outcomes after IFI have improved as a result of increased clinical awareness, earlier recognition by transplant clinicians, and earlier administration of effective antifungal therapy. Remarkably, no deaths were linked to IFI in this study. However, the lack of a survival benefit should not diminish the value of antifungal prophylaxis in high-risk LT recipients because prevention of fungal infection is likely associated with favourable outcomes that have not been extensively studied, such as reduced hospitalisation and stay duration.