Bacteriophages targeting Acinetobacter baumannii in the era of antibiotic failure: a review

Acinetobacter baumannii has become a prominent healthcare-associated pathogen due to its exceptional environmental persistence, biofilm-forming capacity, and the global emergence of multidrug-resistant (MDR), extensively drug-resistant (XDR), and pan-drug-resistant lineages. The declining effectiveness of conventional antibiotics has renewed interest in bacteriophage-based strategies as alternative or adjunctive antimicrobial approaches. This review provides a comprehensive synthesis of recent advances in bacteriophages targeting A. baumannii, integrating microbiological, structural, immunological, and translational perspectives that shape therapeutic efficacy and resistance dynamics. We highlight the central role of bacterial surface structures, including capsular polysaccharides, outer membrane proteins, and lipooligosaccharides, which act simultaneously as virulence determinants, phage receptors, and modulators of antimicrobial susceptibility. Phage-mediated antibacterial activity is achieved through receptor-specific lysis, biofilm disruption, capsule and envelope remodeling, and indirect resensitization to antibiotics, frequently accompanied by fitness trade-offs in phage-resistant bacterial subpopulations. We further discuss how formulation strategies, phage-derived enzymes, engineered phages, and phage-antibiotic combinations influence treatment outcomes, with particular attention to delivery routes, dosing strategies, and host immune context. Importantly, we distinguish direct phage effects from secondary immunological consequences of bacterial clearance and critically evaluate evidence from in vitro studies, animal infection models, and emerging clinical reports. Finally, we examine regulatory and manufacturing challenges that currently limit broader clinical translation. This review positions bacteriophage-based interventions as a promising, evolution-aware complement to antibiotics for managing drug-resistant A. baumannii, while underscoring the requirements for their rational and durable clinical implementation.