Beyond antifungal susceptibility: molecular mechanisms, detection, and clinical implications of fungal heteroresistance.

Fungal heteroresistance has emerged as an important yet underrecognized phenomenon that may contribute to antifungal treatment failure in invasive fungal infections. It is characterized by the presence of resistant subpopulations capable of surviving high concentrations of antifungal agents within an otherwise phenotypically susceptible fungal population. Because these subpopulations frequently escape detection by conventional antifungal susceptibility testing, fungal heteroresistance poses substantial diagnostic challenges and its clinical significance is likely underestimated. Although heteroresistance has been more extensively investigated in bacteria, its definition, underlying molecular mechanisms, diagnostic criteria, and clinical implications in fungi remain incompletely understood. Moreover, the lack of standardized diagnostic approaches and the overlap of fungal heteroresistance with other adaptive responses further complicate its recognition and clinical interpretation, particularly in clinically important fungal pathogens such as Candida spp., Cryptococcus spp., and Aspergillus spp. This review critically appraises the current evidence on fungal heteroresistance, focusing on its definition, molecular mechanisms, diagnostic challenges, and clinical implications. By integrating current knowledge across clinically important fungal pathogens, this review critically synthesizes the available evidence and discusses the potential implications of fungal heteroresistance for antifungal susceptibility testing and therapeutic decision-making.