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Immunotherapy synergizes with debridement and antibiotic therapy in a murine 1‐stage exchange model of MRSA implant‐associated osteomyelitis
Author(s) -
Yokogawa Noriaki,
Ishikawa Masahiro,
Nishitani Kohei,
Beck Christopher A.,
Tsuchiya Hiroyuki,
Mesfin Addisu,
Kates Stephen L.,
Daiss John L.,
Xie Chao,
Schwarz Edward M.
Publication year - 2018
Publication title -
journal of orthopaedic research®
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.041
H-Index - 155
eISSN - 1554-527X
pISSN - 0736-0266
DOI - 10.1002/jor.23801
Subject(s) - medicine , vancomycin , osteomyelitis , combination therapy , osteolysis , implant , antibiotics , immunotherapy , staphylococcus aureus , surgery , methicillin resistant staphylococcus aureus , debridement (dental) , microbiology and biotechnology , biology , cancer , bacteria , genetics
Methicillin‐resistant Staphylococcus aureus (MRSA) reinfection following revision surgery remains a major orthopaedic problem. Toward the development of immunotherapy with anti‐glucosaminidase monoclonal antibodies (anti‐Gmd), we aimed to: (i) develop a murine 1‐stage exchange model of bioluminescent MRSA (USA300LAC::lux) contaminated femoral implants; and (ii) utilize this model to demonstrate the synergistic effects of combination vancomycin and anti‐Gmd therapy on reinfection and bone healing. Following an infection surgery, the original plate and two screws were removed on day 7, and exchanged with sterile implants. Mice were randomized to five groups: (i) no infection control; (ii) infected placebo; (iii) anti‐Gmd; (iv) vancomycin; and (v) combination therapy. Bioluminescent imaging (BLI) was performed on days 0, 1, 3, 5, 7, 8, 10, 12, and 14. Mice were euthanized on day 14 (day 7 post‐revision), and efficacy was assessed via colony forming units (CFU) on explanted hardware, micro‐CT, and histology. As monotherapies, anti‐Gmd inhibited Staphylococcus abscess communities, and vancomycin reduced CFU on the implants. However, only combination therapy prevented increased BLI post‐revision surgery, with a significant 6.5‐fold reduction on day 10 ( p < 0.05 vs. placebo), and achieved sterile implant levels by day 12. Synergistic effects were also apparent from reduced osteolysis and increased new bone formation around the screws only observed following combination therapy. Taken together, we find that: (i) this murine femoral plate 1‐stage revision model can efficiently evaluate therapies to prevent reinfection; and (ii) immunotherapy plays a distinct role from antibiotics to reduce reinfection following revision surgery, such that synergy to achieve osseointegration is possible. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1590–1598, 2018.