Personalized phage therapy shows promise for difficult musculoskeletal infections

Musculoskeletal infections (MSIs), including fracture-related infections (FRIs) and periprosthetic joint infections (PJIs), remain difficult to treat due to biofilm formation and increasing antimicrobial resistance. Bacteriophage therapy (PT) has re-emerged as a promising adjunctive strategy, although prospective clinical evidence remains scarce. Here, we prospectively evaluated adjunctive local PT in 13 patients with refractory MSIs treated within the multidisciplinary PHAGEFORCE framework at University Hospitals Leuven (BE). Following surgery, personalized phage preparations were administered through a closed drain system for 8–10 days alongside systemic antibiotics. Clinical, microbiological, immunological, and genomic data were collected. Four patients with refractory MSIs lacking suitable phages served as a control cohort. Clinical remission was observed in nine of eleven evaluable phage-treated patients (82%), whereas all control patients experienced infection recurrence during follow-up. PT was well tolerated, with no serious adverse reactions or clinically meaningful toxicity. Local phage titers remained detectable throughout therapy despite interpatient variability. Serum-mediated phage neutralization was observed during and after PT, and longitudinal genomic monitoring revealed patient-specific phage dynamics, neither of which was clearly associated with clinical outcome. These findings demonstrate the feasibility and safety of standardized local PT and support further evaluation of this approach in controlled clinical trials.