Phage to ESKAPE: Personalizing Therapy for MDR Infections—A Comprehensive Clinical Review

The proliferation of multidrug-resistant (MDR) ESKAPE pathogens—Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.—constitutes a critical global health crisis, rendering conventional antibiotics increasingly ineffective. This comprehensive review evaluates the re-emerging potential of bacteriophage therapy as a personalized treatment for infections caused by these organisms. Phages, being viruses that specifically infect and lyse bacteria, offer significant advantages, including high specificity that spares host microbiota, self-replication at the infection site, and potent activity against biofilms. This paper synthesizes current preclinical and clinical evidence, including compassionate-use cases, for phage therapy against each of the ESKAPE pathogens. While case reports and small studies demonstrate considerable success, particularly in salvage therapy for otherwise untreatable infections, significant challenges remain. These include the narrow host range of phages, the potential for bacterial resistance, unpredictable pharmacokinetic and pharmacodynamic parameters, and a complex, non-harmonized regulatory landscape. The review highlights that phage–antibiotic synergy and the use of phage cocktails are promising strategies to overcome some of these limitations. Future progress in phage therapy will depend on standardized manufacturing, robust clinical trials to establish dosing and efficacy, and the development of adaptive regulatory pathways. Phage therapy is positioned not as a replacement for antibiotics but as a vital adjunctive tool in the armamentarium against MDR infections, heralding a move towards a more personalized approach to infectious disease management.