Heteroresistens

Heteroresistens, also called heteroresistance, is a phenomenon in microbial populations in which a clonal population contains a subpopulation with higher resistance to an antimicrobial agent than the majority. Standard susceptibility testing may therefore classify the overall population as susceptible even though a minority can withstand drug concentrations that inhibit the main population.

Origins and mechanisms are diverse. The resistant subpopulation can arise from gene amplification, chromosomal mutations in only a subset of cells, or regulatory changes that upregulate resistance determinants. Plasmid loss or unstable plasmid copy number can also contribute, as can efflux pump upregulation or other adaptive responses. Importantly, the resistant subpopulation may be unstable and disappear when drug pressure is removed, or it may expand under continued exposure to the antimicrobial.

Detection and challenges are notable. Conventional susceptibility tests may miss heteroresistance, because they reflect the dominant population. Specialized methods such as population analysis profiling, extended incubation testing, or focused screening for subpopulations under selective pressure are used to identify heteroresistance. Genomic or single-cell approaches can reveal minority variants, but routine clinical adoption varies and prevalence is pathogen- and drug-dependent.

Clinical implications are significant. Heteroresistance can contribute to treatment failure, relapse, and the need for alternative or combination therapies even when isolates are labeled susceptible. It underscores the importance of considering subpopulations in treatment planning for certain infections, and it motivates ongoing research to improve detection and management. Well-documented examples include vancomycin heteroresistance in Staphylococcus aureus (hVISA) and similar phenomena in other organisms.