The gastrointestinal tract is a major source of echinocandin drug resistance in a murine model of Candida glabrata colonization and systemic dissemination [PublishAheadOfPrint]

Candida species are a part of the human microbiome and can cause systemic infection upon immune suppression. C. glabrata infections are increasing and have greater rates of antifungal resistance compared to other species. Here, we present a C. glabrata gastrointestinal (GI) colonization model to explore whether colonized yeast exposed to caspofungin, an echinocandin antifungal, develop characteristic resistance mutations, and upon immunosuppression, breakthrough causing systemic infection. Daily therapeutic dosing (5 mg/kg) of caspofungin resulted in no reduction in fecal burdens, organ breakthrough rates similar to control groups, and resistance rates (0-10%) similar to those reported clinically. Treatment with 20 mg/kg caspofungin initially reduced burdens, but a rebound following 5-9 days of treatment was accompanied by high levels of resistance (FKS1/2 mutants). Although breakthrough rates decreased in this group, the same FKS mutants were recovered from organs. In an attempt to negate drug tolerance critical for resistance development, we co-treated mice with daily caspofungin and the chitin synthase inhibitor nikkomycin Z. The largest reduction (3-log) in GI burdens was obtained within 3-5 days of 20 mg/kg caspofungin plus nikkomycin treatment. Yet, echinocandin resistance, characterized by a novel Fks1-L630R substitution, was identified following 5-7 days of treatment. Therapeutic caspofungin plus nikkomycin treatment left GI burdens unchanged, but significantly reduced organ breakthrough rates (20%; p<0.05). Single dose pharmacokinetics demonstrated low levels of drug penetration into the GI lumen post caspofungin treatment. Overall, we show that C. glabrata echinocandin resistance can arise within the GI tract and that resistant mutants can readily disseminate upon immunosuppression.

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