First Use of Phage Therapy in Canada for the Treatment of a Life-Threatening, Multidrug-Resistant Staphylococcus epidermidis Periprosthetic Joint Infection

Abstract

We describe the first use of phage therapy in Canada for the treatment of a life-threatening periprosthetic joint infection (PJI), with successful outcome. PJI is a devastating complication of joint replacement surgery, with high morbidity and mortality. Our patient presented with early sepsis from a chronic recalcitrant multidrug-resistant (MDR) Staphylococcus epidermidis hip PJI which had repeatedly failed standard therapy. She had previously undergone 10 operations of the right hip, and only three weeks after completing a prolonged course of daptomycin following her most recent hip revision, she developed a draining sinus tract. Given the high burden of disease, inability to achieve surgical source control, and lack of antibiotic treatment options for long-term suppressive therapy, bacteriophage (phage) therapy was pursued. The patient underwent irrigation and debridement with complex flap reconstruction: intraoperative tissue cultures again yielded MDR S. epidermidis. We developed a novel phage therapy protocol for this patient, with twice daily, intra-articular and intravenous (7 × 10⁹ PFU/dose) phage delivery over a planned 14-day course. Complete healing of the wound with cessation of drainage occurred within one month after treatment. A marked improvement in right hip pain and mobility occurred within three months after treatment. Twelve months following phage treatment, there is normalization of serum inflammatory markers with diminished pain, increased mobility, and no recurrent surgery. Our patient continues to improve and is currently living independently at home, with sustained clinical control of infection.

1. Introduction

A female patient in her 70s presented to our periprosthetic joint infection (PJI) clinic with a one-week history of subjective fever and a draining abscess overlying the right hip (Figure 1). Relevant co-morbidities included chronic kidney disease (stage 1), hypertension, and dyslipidemia. Her past medical history was significant for drug reaction with eosinophilia and systemic symptoms (DRESS), and thus β-lactam and glycopeptide antibiotic classes were avoided. Her orthopedic surgery history was extensive, including 10 operations of the right hip, with development of a recalcitrant multidrug resistant (MDR) Staphylococcus epidermidis right hip PJI (antibiotic susceptibilities shown in

Table 1. Staphylococcus epidermidis isolate extended antibiotic susceptibility profile.

Antibiotic	S. epidermidis Minimum Inhibitory Concentration (MIC) or Zone of Inhibition	Interpretation
Oxacillin	2 mg/L	Resistant
Clindamycin	>4 mg/L	Resistant
Ciprofloxacin	7 mm	Resistant
Rifampin	≤0.25 mg/L	Susceptible
Tetracycline	6 mm	Resistant
Trimethoprim/Sulfamethoxazole	4 mg/L	Resistant
Vancomycin	1 mg/L	Susceptible
Daptomycin	≤0.5 mg/L	Susceptible
Linezolid	≤2 mg/L	Susceptible
Ceftaroline	0.38 mg/L	Unknown *
Ceftobiprole	0.75 mg/L	Unknown *
Fosfomycin	16 mg/L	Unknown *

* Note that no Clinical and Laboratory Standards Institute (CLSI) minimum inhibitory concentration (MIC) breakpoints currently exist.

). Her index surgery (right anterior superior iliac spine osteotomy and open reduction and internal fixation of the right acetabulum) occurred several years prior to presentation due to a mechanical fall, with conversion to a right total hip arthroplasty shortly thereafter. She suffered multiple right hip dislocations, with S. epidermidis PJI being diagnosed approximately three years after the index surgery. She had failed treatment with multiple surgeries and prolonged courses of antibiotics, including, just prior to presentation, a 12-week course of daptomycin with concurrent revision of the right total hip arthroplasty and acetabular reconstruction. While on daptomycin, she developed peripheral neuropathy and myalgias.

Only three weeks after completion of daptomycin, she developed increasing fatigue, right hip pain, subjective fever, rigors, and a draining sinus tract overlying the right hip posterior incision site. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were 85 mg/L and 67 mm/h, respectively. Creatinine kinase was within normal limits. The patient was afebrile but appeared unwell and lethargic. Copious purulent fluid was draining from the right hip sinus tract. A pelvic X-ray and computed tomography (CT) of the right hip are shown in Figure 2 and Figure 3, respectively. She was promptly readmitted. A goals of care discussion was held: given that surgical source control with complete implant removal (i.e., a right hemipelvectomy) could not be safely achieved, and viable antibiotic treatment options for long-term suppressive therapy were not available, bacteriophage (phage) therapy was pursued. The patient underwent irrigation and debridement with complex flap reconstruction and was restarted on daptomycin with the addition of oral ciprofloxacin empirically, given her history of DRESS, pending microbiology. All four intraoperative tissue cultures yielded MDR S. epidermidis. Antimicrobial therapy was transitioned to daptomycin and oral rifampin once microbiology was confirmed. She re-developed myalgias and peripheral neuropathy on daptomycin, even at reduced dosing.

2. Methods and Results

In collaboration with Cytophage Technologies, Ltd. (Winnipeg, MB, Canada), we developed a novel phage therapy protocol for this patient. Regulatory, research ethics board, and institutional approvals from Health Canada and the Ottawa Hospital Research Institute (OHRI) were obtained (OHRI Protocol#: 20240008-01H). Preclinical in vitro testing against the S. epidermidis isolate led to the identification and characterization of the therapeutic potential of a single, lytic phage. The phage was not cultivated using the clinical isolate (GenBank Accession Number: CP197380), as whole-genome sequencing identified two intact prophages which could contaminate final phage preparations. Rather, the phage was propagated within an avirulent Staphylococcus succinus host. Resultant phage lysates were concentrated and purified. The therapeutic quality of the monophage preparation was profiled using rigorous testing by Cytophage and a third party, thus ensuring final product potency (7 × 10⁹ PFU/mL), purity, fidelity, and safety. These tests included United States Pharmacopeia (USP) standards, including sterility certification, endotoxin level of 3.66 EU/mL, and physical chemistry (clarity: 9.8 NTU; osmolality: 301 mOsm/kg; pH: 7.35; and particulate matter: 1408 particles/mL (≥10 μm) and 99 particles/mL (≥25 μm)), and final product identity measures (electron microscopy, PCR, and sequencing), verifying product fidelity, in adherence to compassionate-use recommendations [1].

Phage Therapy Protocol and Treatment Course: The patient was admitted, underwent ultrasound-guided percutaneous drainage catheter insertion into a right hip fluid collection, and was administered phage therapy, twice daily, both intra-articularly and intravenously (7 × 10⁹ PFU/dose). She received concomitant daptomycin 400 mg (6 mg/kg) daily and oral rifampin 300 mg twice daily. The catheter became malpositioned on day seven of treatment which was then removed to prevent the introduction of additional microorganisms into the joint space (intra-articular phage administration was discontinued). Intravenous phage therapy was continued for an additional seven days, completing the planned 14-day treatment course. After phage administration, the patient developed initial and immediate mild hypotension, followed by hypertension, low-grade fever, chest pain, rigors, and wheezing, lasting approximately 30 min from treatment on days one to five. These reactions were more marked following intra-articular phage delivery which followed intravenous administration, peaking after the second dose on day one, then subsiding with each subsequent dose, with resolution by day five. Liver enzymes (aspartate aminotransferase [AST], alanine transaminase [ALT], alkaline phosphatase [ALP], and gamma-glutamyl transpeptidase [GGT]) increased and peaked in the first week of treatment (baseline and peak values: AST 30 to 99 U/L; ALT 29 to 108 U/L; ALP 124 to 223 U/L; GGT 61 to 105 U/L). Liver enzymes began to fall at week two of treatment and returned to baseline by one month after treatment. Baseline inflammatory biomarkers, ESR and CRP, were 51 mm/h and 28 mg/L, respectively. CRP peaked on day 3 of treatment (93 mg/L) and decreased to 43 mg/L at one-month follow-up. ESR remained overall unchanged throughout treatment.

The patient was monitored in the PJI clinic. Complete healing of the wound with cessation of drainage occurred within one month after treatment. A marked improvement in right hip pain and mobility occurred within three months after treatment. Daptomycin was transitioned to oral linezolid three months after treatment and rifampin was discontinued after seven months. An overall decrease in serum CRP and ESR occurred with normalization 12 months after treatment.

Table 2. Overall trend of inflammatory markers during and after phage treatment.

	Baseline	Week 1 of Treatment	Week 2 of Treatment	Month 6 Follow-Up	Month 12 Follow-Up
CRP (mg/L)	28	64	34	23	2.4
ESR (mm/h)	51	55	46	43	5

shows an overall trend in inflammatory markers. There is sustained improvement in right hip pain and mobility, and the patient has moved from family-assisted living to independent living in her own home. Given how high risk this patient is for relapse of infection (with significant associated mortality and morbidity), a decision was made to continue linezolid, with close monitoring for toxicity. Should this occur, three-times weekly linezolid will be considered, with eventual cessation of therapy, assuming ongoing clinical improvement and/or stability. A repeat hip aspirate will be considered then.

3. Discussion

PJI is a catastrophic disease which complicates 1–2% of primary joint replacements [2]. In Canada, PJI is one of the leading causes of revision operations in hip and knee replacements and poses a large burden of disease [3]. Early recognition, accurate microbiologic diagnosis, and prompt surgical and medical treatment of PJI are critical to preventing recalcitrant infection, which is not only incurable, but associated with significant morbidity and mortality [4]. Frequently, chronic PJI requires long-term antibiotic therapy and multiple surgical interventions. In severe cases, resection arthroplasty or amputation may be needed. There is an unmet need for novel therapeutic approaches.

Phage therapy is underexplored for PJI. Phages are viruses which are ubiquitous in nature and specifically infect bacteria. In specific cases, phage is an attractive adjunctive therapeutic option for targeted antimicrobial therapy, and for combating antimicrobial drug resistance. Overall, promising outcomes with phage therapy as a treatment for PJI have been summarized in recent reviews [5,6]. In all cases, phage therapy was delivered to patients that repeatedly failed standard treatment options. Phage treatment protocols were variable with respect to preparations (monophage or cocktails), dosing (single or sequential; concentration), frequency and duration, method of delivery (e.g., intra-articular, topical, and/or intravenous), concurrent surgical intervention, co-administration of antibiotic(s), and follow-up. In a systematic review by Yang et al., 16 clinical studies were screened (one prospective controlled clinical trial and 15 case reports), in total including 42 patients with hip and/or knee PJI who received phage therapy. Following phage therapy, two cases demonstrated relapse of infection, while others demonstrated improved outcomes [5]. In a systematic review by Suh et al., the outcomes of 33 bone and joint infection cases treated with phage therapy since 2010 were highlighted. Of these cases, 87% achieved favourable outcomes (microbiologic or clinical success), with only rare mild adverse events [6]. Overall, despite having non-standardized protocols, phage therapy appears to be a potential adjunctive modality to treat orthopedic infections, including PJI.

Phage therapy is generally considered safe, although rare and minor adverse events have been reported such as local reactions at the treatment site (erythema, pain), transient pruritis, shortness of breath and wheezing, fevers and chills, flushing, and hypotension [7,8,9]. Our patient demonstrated an interesting tempo of reactions during phage treatment which have not, to our knowledge, been reported, including initial and transient hypotension, followed by hypertension, low-grade fever, chest pain, rigors, and wheezing during early treatment These were worse following initial intra-articular phage delivery (which followed intravenous injections) and resolved by day five of treatment. Little is known about the immunobiology of these reactions, although data may point towards the release of endotoxins (in cases of Gram-negative bacterial infection) or other bacterial components (e.g., DNA, lipoteichoic acid, membrane-embedded proteins, and secreted exotoxins) as stimulators of inflammatory cytokine responses [10].

In the current study, we developed a novel phage treatment protocol consisting of twice-daily intra-articular and intravenous monophage administration over a planned 14 days, in conjunction with surgical debridement and flap reconstruction, for the treatment of a recalcitrant MDR S. epidermidis PJI which had repeatedly failed standard surgical and medical therapy. At 10-month follow-up, the patient demonstrated complete clinical recovery without recurrence or adverse events. Our clinical course and outcome align well with the limited available literature in this area and further support the safety and efficacy of tailored phage therapy in highly refractory, MDR cases. However, despite these encouraging findings, this literature is limited by small sample sizes, non-standardized phage protocols, and a predominance of uncontrolled studies and case reports. There is a clear need for standardization in phage therapy protocols, including monophage versus cocktail phage preparations, optimal dosing, delivery route, and duration. Moreover, regulatory and logistical challenges in phage production and clinical approval remain significant barriers to widespread use in Canada, in particular.

Future research should prioritize well-designed, prospective randomized controlled trials to evaluate the efficacy of phage therapy in PJI and other orthopedic infections. Such studies should aim to define standardized patient selection criteria for phage therapy, establish pharmacokinetic and pharmacodynamic profiles for different delivery routes, and assess the optimal integration of phage therapy into existing surgical and antibiotic treatment pathways. Additionally, the development of large-scale, curated phage libraries and rapid phage susceptibility testing platforms will be crucial for facilitating timely and personalized clinical applications. Together, these efforts will help clarify the therapeutic role of phage in orthopedic infection management and move the field from anecdotal success toward evidence-based standard of care. Our research team is actively collaborating with industry partners and government agencies to develop standardized national guidelines for the clinical use of phage therapy in Canada. In parallel, we are working to improve public education by providing patients with accurate information about phage therapy and clear pathways to connect with clinician-scientists and treatment programs. Addressing misinformation remains a key priority, as it poses a significant barrier to the responsible advancement and acceptance of this promising therapeutic approach.

4. Conclusions

We report the first use of phage therapy in Canada for the treatment of a life-threatening hip PJI, with successful outcome of wound healing, diminished pain, increased mobility, and normalization of inflammatory biomarkers, without recurrent surgery. Our patient continues to improve and is currently living independently at home, with sustained clinical control of infection. Several barriers to the widespread use of phage therapy exist, including regulatory hurdles and a lack of standardization and high-quality evidence to better understand which PJI patients would benefit most from this therapy. Despite these challenges, phage therapy appears to be a promising potential adjunct for recalcitrant PJI where standard medical and surgical management has repeatedly failed.