Impact of FKS1 genotype on echinocandin in-vitro susceptibility in Candida auris and in-vivo response in a murine model of infection.

Objectives: Echinocandins are frontline antifungal agents in the management of invasive infections due to multi-drug 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. Methods: A total of 199 C. auris isolates originating from thirty centres 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. Results: 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. Conclusions 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.