ABATRACT:
Osteomyelitis due to orthopaedic device-related infections (ODRIs), is a major complication in orthopaedic
medicine, resulting in approximately 200,000 cases in the US per year (~3% of the estimated 6 million elective
orthopaedic surgeries), and is predicted to rise as the US population ages. Current treatment requires 4 to 6
weeks of IV antibiotic administration and multiple surgeries to remove the infected implants and surrounding
tissue and restore the device, resulting in a large economic burden and significant patient morbidity. ODRIs are
extremely recalcitrant to antibiotic treatment as these are biofilm infections, in which the bacterial pathogens
are attached to surfaces surrounded by a self-produced matrix. A hallmark of biofilms is their resistance to
antibiotics and the host immune system. Furthermore, antibiotics administered orally or parenterally
(intravenously or through intramuscular injection) have poor bone penetration. Another treatment complication
is the rise in ODRIs due to antibiotic- and multidrug-resistant (MDR) bacteria. Local delivery of antibiotics by
their incorporation into polymethylmethacrylate (PMMA) beads has improved treatment. We developed and
tested a local antibiotic delivery system of biodegradable poly(lactic-co-glycolic acid) (PLGA) microspheres that
retain the advantages of PMMA antibiotic delivery, but do not require removal. An emerging strategy to treat
MDR infections is to directly target and lyse the bacterial pathogen using IV administration of bacteriophage
(viruses that kill bacteria) or `phage'. Phage self-replicate at the site of infection, do not share resistance
mechanisms with antibiotics, and may even restore bacterial susceptibility to antibiotics. As IV phage
administration has drawbacks including the loss of phage during delivery and long-term exposure to the
immune system, we propose here an innovative nanotechnology strategy using our biodegradable delivery
system to locally administer lytic phage to treat ODRIs.
We have recently demonstrated that phage K, which effectively lyses many strains of Staphylococcus aureus,
the most common cause of ODRIs, can be incorporated into PLGA microspheres. Further, eluted phage are
able to kill S. aureus within in vitro biofilms on orthopaedic materials. Our long-term goal is to develop effective
local delivery of lytic phage to treat MDR ODRIs. We plan the following short-term goals: 1) optimize the phage
incorporation into PLGA microspheres, 2) generate lytic phage cocktails to treat S. aureus ODRI that eliminate
bacterial phage resistance, 3) test of the optimized phage-containing microspheres in in-vitro cell culture and
an in-vivo rat model of ODRI. It is anticipated that the investigations proposed in this application will pave the
way for clinical trials using local delivery of lytic phage to treat ODRI infections thereby improving patient
outcomes.
