Understanding Echinocandin Resistance in the Emerging Pathogen Candida auris

Area of Science:

• Mycology
• Infectious Diseases
• Antimicrobial Resistance

Background:

• * Candida auris is an emerging global fungal pathogen causing difficult-to-treat nosocomial infections.
• * Variable antifungal susceptibility and resistance development pose significant treatment challenges.
• * Echinocandins are a critical class of antifungal drugs used against Candida species.

Purpose of the Study:

• * To investigate the in vitro susceptibility of Candida auris to echinocandin antifungal drugs.
• * To determine the correlation between FKS1 gene mutations and echinocandin resistance.
• * To evaluate the impact of the Eagle effect on caspofungin susceptibility testing.

Main Methods:

• * In vitro antifungal susceptibility testing of 106 Candida auris clinical isolates against echinocandins.
• * FKS1 gene sequencing to identify mutations in hotspot regions.
• * In vivo efficacy assessment in a murine model of invasive candidiasis for select isolates.

Main Results:

• * Four isolates showed resistance to all tested echinocandins, possessing an S639F mutation in FKS1.
• * All other isolates were wild-type (WT) for FKS1 and susceptible to echinocandins, with micafungin being most potent.
• * An Eagle effect was observed for caspofungin in all FKS1 WT isolates, complicating in vitro testing.
• * In vivo studies confirmed caspofungin efficacy in therapeutic doses for non-mutated isolates, but not for those with S639F mutations.

Conclusions:

• * Echinocandin resistance in Candida auris is primarily associated with FKS1 mutations.
• * In vitro susceptibility testing for caspofungin in Candida auris warrants caution due to the Eagle effect.
• * FKS1 sequencing is a reliable method to predict echinocandin resistance in Candida auris.