The global burden of invasive fungal disease (IFD) is substantial and escalating. Combination antifungal therapy (CAF) may improve patient outcomes by reducing development of resistance, improving drug penetration and rate of fungal clearance, and allowing for lower, less toxic antifungal drug doses; yet, increased cost, antagonism, drug-drug interactions, and toxicity are concerns. Clinical practice guidelines recommend antifungal monotherapy, rather than CAF, for most IFDs due to a lack of comparative randomized clinical trials. An examination of the existing body of CAF research should frame new hypotheses and determine priorities for future CAF clinical trials. We performed a systematic review of CAF clinical studies for invasive candidiasis, cryptococcosis, invasive aspergillosis, and mucormycosis. Additionally, we summarize findings from animal models of CAF and assess laboratory methods available to evaluate CAF efficacy. Future CAF trials should be prioritized according to animal models showing improved survival and observational clinical data supporting efficacy and safety.

The authors have declared no competing interest.

This study did not receive any funding.

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Yes

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All data produced in the present study are available upon reasonable request to the authors.