A pan-azole and pan-echinocandin resistant Wickerhamomyces anomalus isolate causing bloodstream infection: ERG11Y140F, K151R with copy number variation and FKS1F665S mutation.

Fungal infections pose a growing global threat, particularly due to the emergence of multidrug-resistant pathogens. This study reports the first globally documented case of a Wickerhamomyces anomalus isolate (XN272) displaying dual high-level resistance to all tested azoles and echinocandins. Genomic analysis of the strain, which was isolated from a bloodstream infection in a 64-year-old male post-pancreatic surgery, identified two key resistance mechanisms: the azole target gene ERG11 harbored missense mutations (Y140H, K151R) and tandem copy number variations, while the echinocandin target gene FKS1 carried an F665S mutation. Transcriptomic profiling under antifungal exposure suggested an additional resistance mechanism, the upregulation of membrane-associated genes and efflux transporters (e.g., FLU1). Strain XN272 exhibited robust biofilm-forming capacity, a trait linked to reduced drug susceptibility. Despite its resistant phenotype, virulence assessments in immunosuppressed mice showed comparable tissue colonization and clearance rates to strain ATCC 8168. The discovery of pan-azole and pan-echinocandin resistance in W. anomalus highlights the expanding landscape of antifungal resistance and its clinical management challenges.