Bacteriophage therapy for multidrug-resistant bacterial infections: recent advances, clinical evidence, and translational challenges

The increasing prevalence of multidrug-resistant (MDR) bacterial infections has substantially limited the effectiveness of existing antibiotics and highlights the need for alternative therapeutic strategies. Bacteriophage therapy has re-emerged as a potential option, largely due to its ability to selectively target bacterial pathogens, replicate at sites of infection, and disrupt biofilms. This review examines the key mechanisms underlying phage-mediated bacterial killing, including receptor-specific infection, lytic replication, and the action of phage-derived enzymes such as endolysins and depolymerases. Current clinical evidence, largely derived from compassionate-use cases and small case series rather than well-controlled randomized trials, suggests that phage therapy can be beneficial in selected patients with infections caused by organisms such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Staphylococcus aureus, particularly when conventional treatments have failed. The potential advantages of combining phages with antibiotics are also discussed, although the extent and consistency of this synergy remain uncertain. Despite growing interest, the clinical development of phage therapy remains limited by several factors, including narrow host specificity, the emergence of phage resistance, host immune responses that lead to rapid phage clearance and the formation of neutralizing antibodies, heterogeneity in study designs, and the absence of standardized production and regulatory frameworks. Importantly, robust randomized controlled trials are still scarce, making it difficult to draw firm conclusions about efficacy. While recent advances in genomics and phage engineering are likely to support future progress, a clear gap remains between experimental promise and routine, standardized clinical application.