Impact of FKS1 Genotype on Echinocandin In Vitro Susceptibility in Candida auris and In Vivo Response in a Murine Model of Infection.

Echinocandins are frontline antifungal agents in the management of invasive infections due to multidrug resistant Candida auris. The study aimed to evaluate echinocandin resistance in C. auris isolates of multicentric origin, identify the resistance mechanism, and analyze the pharmacodynamic response to caspofungin in a neutropenic mouse model of infection. A total of 199 C. auris isolates originating from 30 centers across India were tested for susceptibility to echinocandins. Isolates with reduced susceptibility were evaluated for FKS1 mutations and in vivo response to caspofungin in a murine model of disseminated candidiasis. In addition, the response to echinocandins was assessed in light of in vitro growth kinetics, chitin content; and transcript levels of chitin synthase and FKS1 genes. We report 10 resistant C. auris isolates with four FKS1 mutations: F635Y (n = 2), F635L (n = 4), S639F (n = 3), and R1354S (n = 1). Of these, F635Y and R1354S exhibited the most profound resistance in mouse model of disseminated infection. S639F and F635L mutations conferred a moderate in vivo resistance, whereas wild-type isolates exhibiting borderline MIC were susceptible in vivo. FKS1 genotype was more accurate predictor of in vivo response than the MIC of the isolates. Isolates with high basal or inducible chitin content exhibited higher in vitro MIC in FKS1 mutant compared to wild type. FKS1 mutations play a major role in clinically relevant echinocandin resistance in C. auris with differential in vivo outcomes. This study could have implications for clinical practice and, therefore, warrants further studies.