Advances in antibiotic heteroresistance in Acinetobacter baumannii.

Acinetobacter baumannii is a major nosocomial pathogen, and its increasing multidrug-resistant and pandrug-resistant profiles pose a serious challenge to anti-infective therapy. In recent years, heteroresistance to multiple antibiotics in A. baumannii has attracted growing attention. Heteroresistance refers to the presence of low-frequency resistant subpopulations within an isolate that is classified as susceptible by conventional susceptibility testing. These resistant subpopulations can survive under antibiotic selective pressure and subsequently expand, potentially leading to treatment failure. Owing to the lack of standardized and unified detection methods, heteroresistance is often overlooked in clinical practice. Current evidence indicates that heteroresistance in A. baumannii arises through diverse molecular mechanisms, including genetic mutations, gene amplification, efflux pump overexpression, and membrane structural modifications. The mechanisms underlying heteroresistance vary among different classes of antibiotics, and even for a single antibiotic, multiple resistance pathways may coexist. Given this mechanistic complexity, monotherapy is often insufficient to eradicate all heteroresistant subpopulations and may instead promote the enrichment of resistant cells under selective pressure. Combination therapy has therefore been proposed as a promising strategy to suppress heteroresistance, although its efficacy, safety, and clinical applicability require further validation. With the rapid development of emerging technologies, such as single-cell analysis, microfluidic platforms, and high-throughput sequencing, promise for enabling precise and rapid detection of heteroresistance. This review systematically summarizes the definition, detection methods, molecular mechanisms, and therapeutic strategies related to heteroresistance in A. baumannii, with the aim of providing a reference for rational antimicrobial use and the development of novel antibacterial strategies.