Beyond susceptibility results: understanding the clinical and diagnostic burden of bacterial heteroresistance

Heteroresistance has emerged as a clinically significant form of antimicrobial resistance that challenges microbiology laboratories, infectious disease management, and public health systems. It is defined by the presence of resistant subpopulations within an otherwise phenotypically susceptible bacterial population, capable of surviving high antibiotic concentrations. As conventional antimicrobial susceptibility testing methods frequently fail to detect these minor subpopulations, heteroresistance is associated with diagnostic uncertainty, treatment failure, recurrent infections, and the selection and expansion of resistant strains. Accumulating evidence across diverse bacterial species, particularly among Gram-negative pathogens, has highlighted the growing clinical relevance of this phenomenon. Despite this, its recognition and management remain hindered by the lack of standardized diagnostic methodologies, incomplete elucidation of underlying molecular mechanisms, and limited incorporation into clinical guidelines. This review provides a comprehensive overview of heteroresistance, emphasizing its definition, diagnostic challenges, and clinical implications, while aiming to increase awareness of its clinical significance. Furthermore, it addresses key knowledge gaps and outlines perspectives aimed at improving detection strategies and informing more effective therapeutic decision-making.