Preclinical Research to Determine Prosthetic Joint Infection Pathophysiology Needed to Direct Clinical Bacteriophage Therapy

Abstract: Prosthetic joint infections (PJI) are a devastating complication of arthroplasty surgery that can lead to tremendous morbidity and mortality that rivals that of some cancers. The reason PJI are so arduous to treat is secondary to high antibiotic tolerance of biofilm. Consequently, novel therapeutics are needed to improve the outcomes of patients with PJI. One such novel therapeutic is bacteriophage therapy, which have innate anti-biofilm capabilities. However, many aspects of bacteriophage therapy are not well understood leading to poorly reproducible protocols. The objective of this proposal is to address the several gaps in knowledge that are currently present to help devise bacteriophage treatment protocols for PJI. First, the PIs will evaluate whether S. aureus PJI are clonal or polyclonal infections using whole genomic sequencing on S. aureus PJI clinical isolates. Additionally, the PIs will evaluate the location of biofilm formation in PJI by visualizing biofilm formation on explanted PJI prosthetics. Finally, to determine an effective route of bacteriophage therapy administration and to ensure phage treatment is effective at the locations that biofilm forms on implants in vivo, the PIs will evaluate the efficacy of bacteriophage therapy in reducing biofilm burden using different routes of bacteriophage administration in a murine PJI model. These will also be correlated with the production of neutralizing antibody production. Our working hypotheses are that (1) S. aureus PJI are clonal infections, (2) biofilms on infected prosthetics will be located on both the prosthetic-synovial interface as well as are located on bone-implant interface where it is not assessable with debridement surgery and (3) the most effective mode of administration will be intraarticular and repeated intravenous administrations, but this will come with a trade-off associated with higher degree of neutralizing antibody production compared to other modes of administration. The expected outcome of this proposal is to gain improved understanding of PJI and how best to use bacteriophages in PJI. As well, this work will improve our understanding of bacteriophage therapy to achieve our long-term goal to develop new, more effective treatment strategies for PJI as well as to better enhance the use of bacteriophages in other MSK infections.