heteroresistant

Heteroresistance is a phenomenon in which a clonal population of microorganisms contains a minority subpopulation with a higher level of resistance to an antimicrobial agent than the majority. The resistant subpopulation may constitute only a small fraction of the cells and can be missed by standard susceptibility testing, causing the overall population to appear susceptible despite the presence of resistant cells.

This phenomenon has been reported in several clinically important bacteria, including Staphylococcus aureus (notably the so-called heteroresistant vancomycin-intermediate S. aureus, or hVISA), Enterococcus species, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Mechanisms behind heteroresistance can involve spontaneous mutations in drug targets, gene amplification, changes in cell permeability, efflux pumps, or cell wall alterations. Subpopulations can be stable or transient, and under antibiotic pressure they may expand, potentially leading to treatment failure or relapse even when standard tests suggest susceptibility.

Clinical implications of heteroresistance include possible discrepancies between in vitro susceptibility results and in vivo therapeutic outcomes. It can complicate treatment planning, sometimes necessitating higher drug doses, alternative agents, or combination therapies. Detecting heteroresistance is challenging because routine MIC testing may not reveal the resistant minority. More sensitive methods, such as population analysis profiling (PAP) or similar techniques that assess growth across a range of drug concentrations, are used in research and some reference laboratories; these methods are not universally standardized in clinical practice.

Heteroresistance is an area of ongoing study in antimicrobial resistance. Understanding its presence in a pathogen can inform antimicrobial stewardship and contribute to more accurate interpretation of susceptibility testing and treatment planning.