Trends in antifungal resistance and mechanistic insights into azole resistance in <i>Candidozyma auris</i> : A 13-Year Study of a comprehensive set of clinical isolates from India

BACKGROUND: The objective of the study was to elucidate antifungal resistance and associated azole resistance mechanisms in Candidozyma auris isolates across India over a period of 13 years (2009-2021). METHODS: A total of 596 C. auris isolates from 37 healthcare-centers were collected. Antifungal susceptibility was performed and ERG11 gene was sequenced for 45 representative isolates. The ERG11 and efflux pumps (MDR1 and CDR1) expression under fluconazole drug-pressure was assessed by qRT-PCR (n=20) along with cell wall ergosterol content estimation. Short tandem repeat (STR) genotyping was done on 235 isolates. RESULTS: The highest number of isolates (50.1%) were recovered from North India, followed by East (27.6%) and South India (13.6%). Majority of the isolates were recovered from private sector hospitals. A total of 80.0% and 27.9% of isolates were resistant to fluconazole and voriconazole, respectively. A notable increase in resistance to amphotericin B and caspofungin was observed, with 3.2% of isolates being multidrug-resistant (MDR). In ERG11, Y132F and K143R mutations were present in both fluconazole-susceptible and resistant isolates in addition to 50% of fluconazole-susceptible isolates showed elevated ERG11 expression and ergosterol content upon fluconazole treatment. Basal level cell wall ergosterol was higher in fluconazole-susceptible isolates. All isolates belonged to Clade I with STR genotyping. CONCLUSION: Our study demonstrates high levels of antifungal resistance in the largest collection of Indian C. auris clinical isolates reported till date. Besides mutations and gene expressions, other pathways conferring drug resistance such as stress response, must be studied to further understand the evolution of this pathogen.