Phage-Antibiotic Combination Therapy for Antibiotic-Resistant Bacteria; Synergistic Mechanisms and Clinical Applications: A Systematic Review

Background: Antimicrobial resistance (AMR) is a major global health challenge requiring innovative therapeutic strategies. Phage–antibiotic combination therapy has emerged as a potential approach for treating multidrug-resistant (MDR) bacterial infections. This systematic review summarizes reported synergistic effects and clinical outcomes of this combined strategy. Methods: This review was conducted according to PRISMA guidelines. PubMed, Scopus, Web of Science, and the Cochrane Library were searched for studies published between January 2000 and December 2024 assessing combined bacteriophage and antibiotic therapy against MDR bacteria. Eligible studies focused on therapeutic synergy, bacterial resensitization, and clinical outcomes, with results synthesized narratively. Results: A total of 25 studies were included, comprising 10 in vitro studies, 7 in vivo animal studies, and 8 clinical investigations. Phage–antibiotic combinations demonstrated synergistic effects in more than 70% of cases, resulting in enhanced bacterial eradication, improved biofilm disruption, and reduced resistance development compared with monotherapy. The mean Fractional Inhibitory Concentration Index (FIC-I) for synergistic combinations in in vitro studies was 0.29±0.11. Animal studies reported protection or survival rates ranging from 64% to 100%. Clinical reports, including case studies and one phase 2 trial, documented successful treatment of refractory MDR infections without major safety concerns, although adverse events were inconsistently reported. Conclusion: Phage–antibiotic combination therapy appears to be a promising approach for managing MDR bacterial infections. Despite encouraging evidence of enhanced efficacy, challenges such as phage resistance, host immune responses, and variability in interactions remain. Larger, well-designed clinical trials and individualized testing are necessary to confirm clinical efficacy and optimize therapeutic application.