Empirical antifungal therapy for patients with neutropenia and persistent fever: Systematic review and meta-analysis

Objectives: To assess the evidence for the current standard of practice of using empirical antifungal treatment in febrile neutropenic cancer patients. Methods: Systematic review and meta-analysis of randomised controlled trials comparing empirical or preemptive antifungal treatment with placebo, no intervention, or another antifungal. The primary outcomes were all-cause mortality and invasive fungal infections (IFI) (documented or probable). Relative risks (RR) with 95% confidence intervals (CI) were pooled. Results: Six trials assessed the efficacy of empirical treatment compared to no treatment and one compared empirical to preemptive therapy. Empirical treatment did not decrease mortality significantly (RR 0.82, 95% CI 0.50-1.34), but significantly decreased IFIs (RR 0.25, 0.12-0.54). Twenty-three trials assessed the efficiency of different antifungals. All-cause mortality was lower with azoles compared to amphotericin B (AB) (RR 0.81, 0.65-1.01); IFI rates were not different while adverse events were less frequent with azoles (RR 0.40; 0.34-0.66). Liposomal AB was associated with lower mortality and IFIs than other AB formulations (RR 1.57, 1.10-2.23 and 1.48, 0.98-2.25, respectively). Caspofungin was associated with fewer adverse events, but otherwise comparable to liposomal AB. All trials included patients with haematological malignancies. Major limitations included per-protocol analysis, non-blinded design and inconsistent definitions of IFIs. Conclusions: Empirical antifungal treatment is associated with a lower rate of IFIs but no significant difference in overall mortality. The assessment of IFIs in these trials may have been biased, offering only weak support to standard practice. Azoles, liposomal amphotericin B or caspofungin should be preferred. Pre-emptive antifungal therapy should be considered and further investigated.