Adjunctive Local Bacteriophage Therapy for Refractory Musculoskeletal Infections: A Prospective Case Series

Musculoskeletal infections (MSI), including periprosthetic joint infections (PJI) and fracture-related infections (FRI), continue to challenge standard treatment strategies due to biofilm formation and rising antimicrobial resistance (AMR) (1). Bacteriophage therapy (PT) has re-emerged as an adjunctive approach, although prospective clinical data remain scarce and heterogeneous (1). To address this gap, the PHAGEFORCE study evaluates the safety and clinical outcome of adjunctive local PT within a standardized multidisciplinary framework (2). Methods Patient eligibility was assessed by a multidisciplinary team. Thirteen patients with last-resort MSIs were enrolled prospectively and received adjunctive PT. All patients underwent surgical debridement followed by local administration of personalized PT via a closed drainage system, three times daily for 7-10 days, in combination with systemic antibiotics. Clinical, microbiological, immunological and genomic data were collected longitudinally, with a minimum follow-up period of one year. Phage titers and serum-mediated neutralization were assessed using standardized assays. Results Infection eradication was achieved in 82% of evaluable patients (n=11), with two patients lost to follow-up. No serious adverse events attributable to PT were observed. Vital signs remained clinically stable, and laboratory parameters showed no evidence of treatment-related toxicity, with changes mainly reflecting inflammatory activity. Phage titers showed variability over time, with transient, non sustained fluctuations. Serum-mediated phage neutralization varied substantially between patients. Genomic analyses demonstrated patient-specific bacterial and phage dynamics, with largely stable antimicrobial resistance profiles. Neither serum-mediated neutralization nor genomic variation showed a consistent association with clinical outcome. Conclusions Adjunctive local bacteriophage therapy appears safe and feasible in patients with refractory MSIs, achieving promising success rates within a standardized, multidisciplinary framework. The observed variability in phage kinetics and immune neutralization was not associated with clinical outcome in our study. Future research should further investigate the clinical relevance of these factors in larger, controlled cohorts. Overall, these findings highlight the need for standardized yet adaptable treatment protocols for clinical implementation of PT.