Impact of
FKS
1 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 FKS 1 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 FKS 1 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 . FKS 1 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 FKS 1 mutant compared to wild-type. Conclusions FKS 1 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.