Phage therapy has emerged as a promising treatment for infections caused by difficult-to-treat resistant (DTR) bacteria.1 Prosthetic joint infection (PJI) represents an optimal scenario in which phage therapy could be used because of the difficulty in eradicating the biofilm forms caused by these microorganisms and for the presence of DTR bacteria.2 However, the effectiveness of phage therapy in these scenarios remains unclear due to a lack of well-designed randomized controlled trials.3
Case reportWe present the case of a 32-year-old woman with an Edwing sarcoma of the left tibia diagnosed when she was 15-y. She initially underwent multiple resection surgeries and chemotherapy in 2007. She then presented with sequelae of chronic pain and functional impotence of the limb. For this reason, the patient requested a transtibial amputation, which was performed in 2021. The procedure involved amputation and the placement of a prosthesis to provide a bionic implant (Fig. 1a).
The patient remained stable with an active practice life for the next two years. In 2023 she presented with pain, tenderness and fistula of the left knee: debridement with antibiotic and implant retention (DAIR) was performed. Surgical cultures were positive for Enterobacter cloacae and Staphylococcus epidermidis. Because of a previous trimethoprim–sulfamethoxazole allergy, we tried ciprofloxacin and dalbavancin, but she had an allergic reaction after the first dose of dalbavancin, and the treatment was changed to ciprofloxacin and fosfomycin for 6 months.
Six months after the end of the treatment, she presented with a re-infection of the prosthesis requiring another DAIR in April 2024. Specimens were positive for methicillin-resistant Staphylococcus aureus. Resistance to quinolones and rifampin was also present and the patient then received clindamycin and fosfomycin. Due to the difficulty in achieving a successful outcome with this treatment, the administration of phage therapy was requested as a compassionate use. Phage susceptibility testing in semi-solid and liquid culture was previously performed and two phages were selected for the treatment. Phage amplification, production and vials preparation following an in-house method at the Environmental and Biomedical Virology (Universitat de València-CSIC) for the two phages resulted in therapeutic doses containing 2×109 plaque forming units (PFU)/dose for Mallokai and 108PFU/dose for IPLA-RODI 1. Quality testing of the final vials confirmed the identity of the produced phages, the absence of high amounts of bacterial DNA, low level of endotoxin, and the sterility of the preparations. Both phages were previously used as compassionate use.4,5
A second debridement was scheduled for September 2024, with the previously requested phages administered once during surgery (Fig. 1b). The patient then received antibiotic treatment with clindamycin and fosfomycin for a further three months, which was finally stopped in December 2024. At the 6-month follow-up, the patient showed no signs of recurrence. She has undergone another bionic implant and is leading an active life.
DiscussionWe presented a successful case of phage therapy in a patient with a PJI who had few therapeutic alternatives.
PJI is a complex infection in which the bacteria involved form organized biofilms on the prosthetic material.6 Biofilm removal is therefore critical to eradicating the infection without recurrence. Current guidelines recommend surgical replacement of the prosthesis, either in one or two surgical revisions.7 However, the surgical approach is sometimes technically difficult, and implants are often left in place. In this scenario, DAIR represents the best available option, with a success rate of over 70.8 After DAIR, experts recommend suppressive antibiotic therapy, often for life, which carries a risk of adverse events.9
PJI treated with the DAIR method represents an optimal scenario for phage therapy for the following reasons: first, the prosthetic material is not removed. Second, the successful cure rate is lower than replacement techniques. Third, phages have demonstrated antibiofilm activity.3,10 And fourth, because of this chronic nature and for the need of the surgical approach, it led a time for acquiring the precise phages for the bacteria involved.
Despite reports of successful outcomes in patients treated with phage therapy the efficacy of adding phage therapy to the standard treatment remains unclear, with a reported success rate of over 85%. However, as in our case, most of the evidence is derived from experience with single cases or case series.4 We need randomized clinical trials to demonstrate the superiority of phage administration over current approaches. In addition, legislation must provide a framework for the safe, rapid and effective delivery of treatments, and facilitate access to this therapy beyond its use in compassionate cases.
FundingThis study was carried out as part of our routine work.
Conflict of interestThe authors reported no conflict of interest.
We want to thank Benjamin K. Chan and Pilar García for providing phages, and Mireia Bernabéu-Gimeno and Marco Pardo-Freire for the preparation of the therapeutic phage vials.
