Bacteriophage Monotherapy Achieves Clinical Suppression of Untreatable Multidrug-Resistant Periprosthetic Joint Infection

Introduction Periprosthetic joint infection (PJI) caused by multidrug-resistant (MDR) organisms is catastrophic when explantation is not feasible and antibiotics are exhausted. Biofilm-associated tolerance leaves clinicians without viable salvage options. Lytic bacteriophages offer intrinsic anti-biofilm activity and virulence attenuation, yet have been studied almost exclusively as antibiotic adjuncts. We evaluated personalized bacteriophage monotherapy as a standalone salvage strategy in a patient with non-operable MDR Pseudomonas aeruginosa PJI refractory to all conventional treatments. Clinical Course A patient with chronic knee and hip PJI refractory to multiple surgical revisions and antibiotic regimens was treated under FDA expanded access. Two lytic phages (PASA16 and Φ83), selected for high planktonic and biofilm activity against the MDR isolate, were administered intra-articularly and intravenously every 1–6 months without concurrent antibiotics. Monitoring included serial aspirations, ESR/CRP, hepatic function, and synovial phage titers. Investigations included in vitro biofilm and planktonic killing assays, neutralizing antibody profiling, Caenorhabditis elegans virulence modeling, motility assays, and whole-genome sequencing of 27 longitudinal isolates. Results By nine months, effusion, pain, and inflammatory markers resolved despite persistent culture positivity. At two years, the patient remained asymptomatic and fully ambulatory off all antibiotics, with only mild transient transaminitis. Both phages maintained >90% biofilm inhibition and eradication activity throughout, without genomic integration. Phage treatment attenuated C. elegans survival and bacterial motility, including in phage-resistant isolates, indicating virulence suppression as an independent mechanism. Minimal pathogen evolution was observed, and neutralizing antibodies did not diminish phage efficacy in vitro or clinically. Conclusion Intermittent bacteriophage monotherapy achieved durable clinical suppression of untreatable MDR P. aeruginosa PJI through biofilm disruption and virulence attenuation. Clinical control was maintained despite culture positivity and host antibody responses, dissociating microbiological eradication from clinical success. These findings support phage monotherapy as a salvage strategy in non-operable PJI and warrant prospective trials to define optimal selection criteria, dosing, and long-term outcomes.