DEFINING BACTERIOPHAGE DOSING AND PHARMACOKINETIC PARAMETERS FOR STAPHYLOCOCCUS EPIDERMIDIS PROSTHETIC JOINT INFECTION

Abstract

Prosthetic joint infections (PJI) remain a devastating complication after arthroplasty, occurring in up to 2% of the projected 1.2 million annual knee arthroplasty cases occurring in the US by 2030.1 Treatment of PJIs has an estimated direct cost of over $50,000 to treat a single case2 and an annual estimated US economic burden of almost 2 billion dollars.3 Treatment of PJI is also associated with the need for multiple operative procedures, while functional outcomes after treatment remain poor, with patients often remaining limited in their mobility.1, 4 In the case of chronic PJI management, bacterial biofilm formation on implanted hardware leads to intransigent infection that is resistant to antibiotic therapy or surgical debridement.5, 6 The standard-of-care in such cases involves either a one or two-stage explant and revision arthroplasty supplemented with long-term intravenous antibiotics, a highly morbid treatment course3 with a long-term infection remission rates of under 80%.4 Consequently, developing new treatment strategies to more effectively and safely eradicate knee PJIs represents a critical research imperative. Bacteriophages (phages) are one such potential novel strategy to address PJIs. Phages are viruses that target bacteria, and their administration therapeutically with the goal of infection remission, what is termed phage therapy, has garnered recent interest in PJI treatment.7 As a therapeutic modality, phages have little reported in vivo toxicity,8 are pervasive in normal bodily flora, and many have the key benefit of being able to penetrate and disrupt biofilms,5 thereby overcoming many of the limitations of conventional antibiotics, including limited biofilm penetrance and low local concentrations.9 Additionally, synergistic antibiosis has previously been reported across prior studies when antibiotics were co-administered with phages,10-13 further highlighting their therapeutic potential. Case reports of phage therapy for human PJIs show promising early results with infection remission in several case series at 1 year follow-up.8 A primary challenge to the clinical application of phage therapy remains a lack of understanding regarding optimal phage dosing and delivery strategies. Specifically, no consensus exists regarding optimal delivery method, dose of phage delivered, frequency of dosing, duration of therapy, or whether monophage or whether a combination of delivered phages (phage cocktail) is preferred.8 Preclinical and clinical studies most commonly report intravenous, intraarticular, or combined approaches for PJI treatment, with therapy durations ranging from a single dose to several weeks, but currently described phage therapy protocols remain highly variable without grounding in empiric evidence.8 Furthermore, studies of phage pharmacokinetics and pharmacodynamics remain limited in scope across clinical indications, impeding the development of evidence-based protocols to guide treatment.14 Consequently, the studies contained in this thesis seek to provide an initial evaluation of phage therapy dosing and pharmacokinetics, as relevant for its application in the setting of PJIs. The first study seeks to understand how dosing of bacteriophages influences bacterial growth in vitro using a biofilm forming strain of Staphylococcus epidermidis (Staph epi) and a known target lytic bacteriophage, vB_SepM_Alex, as the host-virus model pair. In the second study, using the same host-virus model pair, we sought to identify a set of basic pharmacokinetic parameters after intraarticular administration of vB_SepM_Alex in rats with an active Staph epi PJI. We chose to use a biofilm forming strain of Staph epi and a known target phage to allow us to contextualize our findings for Staph epi PJIs, one of the most clinically relevant bacteria for cases of chronic PJI. Our goal with the work presented in this thesis is to contribute to a foundational understanding of phage therapy in its application for PJIs. We hope the findings in this study can inform optimal phage delivery strategies for future in-human studies on PJIs and orthopedic biofilm eradication more broadly.