Heightened Efficacy of Anidulafungin When Used in Combination with Manogepix or 5-Flucytosine against Candida auris

Candida auris is an emerging, multidrug-resistant fungal pathogen that causes refractory colonization and life-threatening, invasive nosocomial infections. The high proportion of C. auris isolates that display antifungal resistance severely limits treatment options. Combination therapies provide a possible strategy by which to enhance antifungal efficacy and prevent the emergence of further resistance. Therefore, we examined drug combinations using antifungals that are already in clinical use or are undergoing clinical trials. Using checkerboard assays, we screened combinations of 5-flucytosine and manogepix (the active form of the novel antifungal drug fosmanogepix) with anidulafungin, amphotericin B, or voriconazole against drug resistant and susceptible C. auris isolates from clades I and III. Fractional inhibitory concentration indices (FICI values) of 0.28 to 0.75 and 0.36 to 1.02 were observed for combinations of anidulafungin with manogepix or 5-flucytosine, respectively, indicating synergistic activity. The high potency of these anidulafungin combinations was confirmed using live-cell microfluidics-assisted imaging of the fungal growth. In summary, combinations of anidulafungin with manogepix or 5-flucytosine show great potential against both resistant and susceptible C. auris isolates.

Déclaration de conflit d'intérêts

The authors declare a conflict of interest. E.B. and D.D.T. were funded by Gilead Sciences. D.D.T. received consultancy fee from OwlStone Medical in the last 5 years. T.B. has received research funding from Gilead Sciences, MSD and Pfizer; speaker fees from Gilead Sciences and Pfizer and Advisory Board fees from Gilead Sciences and Mundipharma. M.H. reports grants and research funding from Astellas, Gilead, MSD, Pfizer, Euroimmun, F2G, Pulmocide, IMMY, Mundipharma and Scynexis, outside the submitted work. T.S.H. has received speaker fees from Gilead and Pfizer, an investigator award to institution from Gilead, and has served as advisor to F2G.