Redefining Antimicrobial Resistance in Acinetobacter baumannii: A Mechanistic Framework Linking Intracellular Antibiotic Activity to Treatment Failure.

Acinetobacter baumannii (A. baumannii) is a major cause of multidrug-resistant infections, yet resistance is often interpreted from a gene-centered perspective that does not explain inconsistent treatment outcomes. This narrative review redefines resistance as a treatment-associated phenotype arising from interactions among molecular resistance mechanisms, bacterial physiology, and the infection environment. Unlike previous reviews that examine determinants in isolation, this work integrates efflux, permeability, enzymatic activity, and target modification with phenotypic states such as structured growth, metabolic adaptation, and stress response within a unified framework. Within this framework, bacterial elimination depends on whether antibiotics maintain sufficient target engagement under infection conditions. Antibiotic performance varies with local environment, population diversity, and cellular activity, which explains the gap between laboratory susceptibility results and clinical response. Antimicrobial failure therefore results from the combined effects of impaired drug exposure, adaptive bacterial physiology, and resistance mechanisms within the infection environment. Based on this framework, therapeutic strategies are reconsidered with emphasis on enhancing drug access, modulating cellular behavior, and disrupting population structures that sustain persistence. The review also highlights key gaps, including limited representation of infection environments in experimental models, insufficient resolution of population diversity, and weak integration between pharmacokinetics and bacterial physiology. This framework supports a mechanistic interpretation of resistance and therapeutic response in A. baumannii.