The utility of bacteriophage therapy in fracture-related infections: Preclinical research needed to create effective and reproducible treatment protocols

Abstract: Fracture-related infection (FRI) is a devastating complication of fracture surgery that can lead to wound breakdown, implant failure, septic nonunion, and even loss of limb. Despite costly interventions, failure to successfully treat infections can occur in up to 40% of cases. This stems from the inability of conventional antibiotics to eradicate bacteria in metabolically reduced phenotypes, occurring on orthopedic implants or on the bone itself. Consequently, novel therapeutics are needed to improve the outcomes of patients with FRI. One such novel therapeutic is bacteriophage therapy, which has 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 several gaps in knowledge to devise bacteriophage treatment protocols for FRI. First, the PIs will evaluate whether S. aureus FRI are clonal or polyclonal infections using whole genomic sequencing on S. aureus FRI clinical isolates. Additionally, the PIs will evaluate the location of biofilm formation in FRI by visualizing biofilm formation on explanted FRI implants. Finally, to determine an effective route of bacteriophage therapy administration and to ensure phage treatment is effective at the locations where 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 chronically infected rat femoral shaft fracture model. These will also be correlated with the production of neutralizing antibody production. Our working hypotheses are that (1) FRI are clonal infections, (2) biofilms on orthopedic hardware are located on bone-implant interface where they are not assessable with debridement surgery and (3) the most effective mode of administration will be intravenous administration, but this will come with a trade-off associated with a higher degree of neutralizing antibody production compared to other modes of administration. The expected outcome of this proposal is to gain an improved understanding of FRI and how best to use bacteriophages in FRI. Additionally, this work will improve our understanding of bacteriophage therapy to achieve our long-term goal to develop new, more effective treatment strategies for FRI as well as to better enhance the use of bacteriophages in other MSK infections.