Bacteriophage therapy for antimicrobial-resistant, biofilm‑associated diabetic foot infection: delivery routes, phage antibiotic synergy, and practical wound‑care integration.

Diabetic foot infections (DFIs) are a significant public health problem, associated with a delayed healing process and high rates of recurrence, which culminates in amputation. Two main factors, antimicrobial resistance (AMR) and biofilm formation, are responsible for the persistence and therapeutic failure of DFIs, resulting in extended healing time, infection recurrence, and an increased risk of amputation. In addition, the emergence of multidrug-resistant (MDR) pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa has made traditional antibiotic treatment less effective, necessitating alternative or adjunctive therapy. Phage therapy is an alternative approach to treat biofilm-associated and antimicrobial-resistant DFIs. Bacteriophages, viruses that infect bacteria, are highly specific to their bacterial hosts, can disrupt biofilms, and increase the activity of antimicrobial drugs used alone or in combination. This review focuses on the therapeutic potential of phage-based interventions for AMR and biofilm-related DFIs, highlighting delivery methods, phage-antibiotic synergy (PAS), incorporation into wound care regimens, and novel translational potential. Further interest in phage-based therapeutics has grown with recent advances in engineered phages, phage-derived enzymes, and precision diagnostics. Clinical and preclinical data indicate that phage therapy may be a promising strategy to improve bacterial control in specific DFI applications. Experimental studies have shown activity against MDR pathogens and biofilm-associated infections, and early clinical reports show potential for therapeutic benefit. The evidence base is currently small and is skewed towards in vitro studies, animal models, case reports, and small clinical trials. However, significant clinical evidenceis still needed before they can be widely adopted. There are several important barriers, such as the absence of large-scale randomized controlled trials, standardized treatment protocols, manufacturing consistency, and harmonized regulatory frameworks. Rigorous clinical evaluation, enhanced diagnostics (e.g., metagenomics profiling), delivery optimization, and regulatory coordination will be the key factors for further progress. Together, these advances could facilitate the integration of phage therapy into a multidisciplinary approach to DFI treatment and improve outcomes for patients with complex biofilm-related and AMR infections.