Understanding echinocandin resistance in the emerging pathogen Candida auris [PublishAheadOfPrint]

Candida auris has emerged simultaneously on five continents as a fungal pathogen causing nosocomial outbreaks. One of the challenges in the treatment of C. auris infections is variable antifungal susceptibility profiles among clinical isolates and the development of resistance to single or multiple classes of available antifungal drugs. Here, in vitro susceptibility to echinocandin antifungal drugs and FKS1 sequencing was performed on 106 C. auris clinical isolates. Four isolates were identified as resistant to all tested echinocandins (MIC ≥ 4 mg/l) and harbored a S639F mutation in FKS1 HS1. All remaining isolates were FKS wildtype (WT) and echinocandin-susceptible with micafungin being the most potent echinocandin (MIC₅₀= 0.125 mg/l). Antifungal susceptibility testing with caspofungin was challenging due to the fact that all FKS1 WT isolates exhibited an 'Eagle effect' (also known as paradoxical growth effect), of varying intensity. To assess whether the 'Eagle effect' resulted in pharmacodynamics resistance, 8 representative isolates were evaluated for in vivo drug response in a murine model of invasive candidiasis. All isolates were susceptible to caspofungin at a human therapeutic dose, except for those harboring the S639F mutation. The data suggest that only isolates carrying mutations in FKS1 are echinocandin-resistant and that routine in vitro susceptibility testing of C. auris isolates with caspofungin by broth microdilution method should be cautiously viewed or avoided.

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