Antifungal Drug Combinations in Invasive Fungal Infections

Invasive fungal infections constitute a major threat to immunocompromised patients worldwide, with Candida, Aspergillus and emerging pathogens such as Candida auris responsible for high morbidity and mortality. Monotherapy with azoles, echinocandins or polyenes often fails in the context of intrinsic or acquired resistance and limited drug penetration in sites such as the central nervous system. Combination regimens aim to exploit synergistic interactions between agents that target distinct fungal pathways—such as ergosterol biosynthesis and cell-wall glucan synthesis—to enhance fungicidal activity, broaden the spectrum of coverage and reduce the likelihood of resistance emergence. Advances in in vitro checkerboard assays, time–kill curves and pharmacokinetic/pharmacodynamic models have enabled systematic evaluation of drug pairs, while in vivo studies in mammalian and alternative models (for example Galleria mellonella or Caenorhabditis elegans) have begun to validate promising combinations. Clinically, such strategies may permit dose reduction of toxic drugs, improved clearance of deep-seated infections and tailored regimens for multidrug-resistant species.

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Antifungal Drug Combinations in Invasive Fungal Infections publication trend

The graph below shows the total number of articles in antifungal drug combinations in invasive fungal infections across all publications each year (not limited to Nature Index journals).

Technical terms

Azole: A class of antifungal agents that inhibit ergosterol synthesis by targeting lanosterol 14α-demethylase in fungal cell membranes, leading to impaired membrane integrity.

Echinocandin: A class of antifungal drugs that inhibit β-1,3-D-glucan synthase, disrupting fungal cell-wall synthesis and causing cell lysis.

Minimum inhibitory concentration (MIC): The lowest concentration of an antifungal agent that visibly inhibits fungal growth in vitro under standardised conditions.

Fractional inhibitory concentration index (FICI): A quantitative measure of drug interaction in combination testing, calculated by summing the MIC ratios of each agent in combination relative to its MIC alone; values ≤0.5 indicate synergy.

Synergy: A pharmacodynamic interaction in which the combined antifungal effect of two agents exceeds the sum of their individual effects, often resulting in enhanced efficacy or reduced resistance risk.

References

1. In vitro and in vivo evaluation of antifungal combinations against azole-resistant Aspergillus fumigatus isolates. Frontiers in Cellular and Infection Microbiology (2023).
2. Combining Fluconazole with Benzo[a]phenoxazine Derivatives as a Promising Strategy Against Fluconazole-Resistant Candida Species. Molecules (2024).
3. Heightened Efficacy of Anidulafungin When Used in Combination with Manogepix or 5-Flucytosine against Candida auris In Vitro. Antimicrobial Agents and Chemotherapy (2023).
4. Techniques for the Assessment of In Vitro and In Vivo Antifungal Combinations. Journal of Fungi (2021).