Population genomics reveals a long-term increase in azole resistance associated with the emerging cluster AZR among <i>Candida tropicalis</i> causing invasive infections

A notable increase in azole resistance among Candida tropicalis has been observed worldwide, particularly in the Asia-Pacific region, associated with the expansion of an emerging resistant population named cluster AZR. Here, we present up-to-date epidemiological, antifungal susceptibility and population genomic data from the China Hospital Invasive Fungal Surveillance Net (CHIF-NET) study. A total of 911 C. tropicalis isolates causing invasive candidiasis were collected in 2022-2023, representing 16.1% of all Candida isolates and ranking as the third most common species. High resistance rates to fluconazole (42.3%) were observed, with 87.5% showing cross-resistance to voriconazole. Candidemia isolates showed significantly higher azole resistance than non-candidemia isolates (46.1% vs 39.2%, p = 0.036). Fluconazole resistance rate was higher in medical departments (55.0%) but lower in ICUs (33.7%). Longitudinal analysis demonstrated an overall upward trend in fluconazole resistance from 5.7% since 2009. Although a transient decline was observed during 2020-2021, resistance rebounded thereafter and reached a historical peak of 43.1% in 2022. Population genomic analysis of 604 isolates identified cluster AZR as the predominant fluconazole-resistant population (58.6%), and its expansion was associated with the temporal increase in azole resistance. Of note, all cluster AZR isolates harboured the ERG11 A395 T key resistant mutation, and 98.2% had increased ERG11 copy number. Besides, genomic analysis identified strain replacement and dual-clade mixed infection in cluster AZR-associated clinical cases. In conclusion, the high prevalence of azole resistance in C. tropicalis and the expansion of cluster AZR represent a significant clinical challenge and underscore the need for effective interventions.