Multicentre investigation of Wickerhamomyces anomalus fungemia in India: emerging resistance and mechanistic insights

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INTRODUCTION: Wickerhamomyces anomalus is an emerging pathogen in Indian hospitals, with limited data on antifungal resistance and its clinical impact. We aimed to explore its antifungal susceptibility, clinical outcomes, resistance mechanisms and molecular epidemiology. MATERIALS AND METHODS: Seventy clinical isolates of W. anomalus (2016-24) were collected from PGIMER, Chandigarh (n = 29), BHU, Varanasi (n = 33), and AIIMS, New Delhi (n = 8). Antifungal susceptibility testing (AFST) was done for amphotericin B, fluconazole, voriconazole, itraconazole, posaconazole, caspofungin, anidulafungin and micafungin. ERG11 sequencing, ERG11, MDR1 and CDR1 expression analysis (RT-qPCR), biofilm formation, ergosterol content and genetic relatedness [short tandem repeat (STR) typing] were performed. RESULTS: The AFST (n = 70) showed that 72% isolates were non-wild-type (NWT) for fluconazole, 17% cross-resistance with voriconazole, and 1.4% with micafungin. Among fungemia cases, 53.2% occurred in neonates. Respiratory distress syndrome was the most common associated comorbidity, 26/62 (41.9%), with mortality in 31/62 (50%). ERG11 sequencing revealed four non-synonymous mutations, N41K, R420K, P485L, and T486K(novel), in 28 (55%) NWT isolates. Gene expression analysis revealed upregulation of ERG11 (12.72-fold) and CDR1 (3.08-fold) in NWT isolates without ERG11 mutations. Biofilm formation was higher in NWT versus wild-type. STR genotyping revealed 22 genotypes and 5 clusters (≥3 isolates), suggesting clonal transmission. CONCLUSION: This multicentre study demonstrates the emergence of fluconazole-NWT W. anomalus in Indian hospitals, predominantly affecting neonates, with a high mortality. Resistance was associated with ERG11 mutations, efflux pump overexpression and biofilm formation. These findings highlight that the drug-resistant W. anomalus fungemia is an emerging concern.

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