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.
