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 respons...

Full description

Saved in:

Bibliographic Details
Published in:	Antimicrobial agents and chemotherapy Vol. 66; no. 1; p. e0165221
Main Authors:	Sharma, Dipti, Paul, Raees A, Rudramurthy, Shivaprakash M, Kashyap, Nisha, Bhattacharya, Sanjay, Soman, Rajeev, Shankarnarayan, Shamanth A, Chavan, Dipali, Singh, Shreya, Das, Parijit, Kaur, Harsimran, Ghosh, Anup K, Prasad, Rajendra, Sanyal, Kaustuv, Chakrabarti, Arunaloke
Format:	Journal Article
Language:	English
Published:	United States American Society for Microbiology 18-01-2022
Subjects:	Animals Antifungal Agents - pharmacology Candida auris - drug effects Candidiasis - drug therapy Disease Models, Animal Drug Resistance, Fungal - genetics Echinocandins - pharmacology Fungal Proteins - genetics Genotype Mechanisms of Resistance Mice Microbial Sensitivity Tests Mutation - genetics Mycology Candida auris FKS mutation FKS1 pharmacodynamics echinocandins murine model resistance chitin
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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 1 mutations and response to caspofungin in a murine model of disseminated candidiasis. In addition, the response to echinocandins was assessed in light of growth kinetics, chitin content; and transcript levels of chitin synthase and genes. We report 10 resistant C. auris isolates with four 1 mutations: F635Y ( = 2), F635L ( = 4), S639F ( = 3), and R1354S ( = 1). Of these, F635Y and R1354S exhibited the most profound resistance in mouse model of disseminated infection. S639F and F635L mutations conferred a moderate resistance, whereas wild-type isolates exhibiting borderline MIC were susceptible . 1 genotype was more accurate predictor of response than the MIC of the isolates. Isolates with high basal or inducible chitin content exhibited higher MIC in 1 mutant compared to wild type. 1 mutations play a major role in clinically relevant echinocandin resistance in C. auris with differential outcomes. This study could have implications for clinical practice and, therefore, warrants further studies.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 D.S. and R.A.P. contributed equally to this work and are co-first authors; author order was determined both alphabetically and in order of increasing seniority. The authors declare no conflict of interest.
ISSN:	0066-4804 1098-6596 1098-6596
DOI:	10.1128/AAC.01652-21