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We investigated whether local rifampin\u2010loaded hydrogel can combat infection and improve healing in a murine model of methicillin\u2010resistant <jats:italic>Staphylococcus aureus<\/jats:italic> (MRSA) osteomyelitis. A transverse fracture was made at the tibia midshaft of C57BL\/6J mice aged 10\u201312 weeks and stabilized with an intramedullary pin. A total of 1\u2009\u00d7\u200910<jats:sup>6<\/jats:sup> colony\u2010forming units (CFU) of MRSA was inoculated. A collagen\u2010based hydrogel containing low\u2010dose (60\u2009\u03bcg) and high\u2010dose (300\u2009\u03bcg) rifampin was applied before closure. Postoperative treatment response was assessed through bacterial CFU counts from tissue and hardware, tibial radiographs and microcomputed tomography (\u03bcCT), immunohistochemistry, and histological analyses. All untreated\u00a0MRSA\u2010infected fractures progressed to nonunion by 28 days with profuse MRSA colonization. Infected fractures demonstrated decreased soft callus formation on safranin O stain compared to controls. Areas of dense interleukin\u20101\u03b2 stain were associated with poor callus formation. High\u2010dose rifampin hydrogels reduced the average MRSA load in tissue (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001) and implants (<jats:italic>p<\/jats:italic>\u2009=\u20090.041). Low\u2010dose rifampin hydrogels reduced tissue bacterial load by 50% (<jats:italic>p<\/jats:italic>\u2009=\u20090.021). Among sterile models, 88% achieved union compared to 0% of those infected. Mean radiographic union scale in tibia scores improved from 6 to 8.7 with high\u2010dose rifampin hydrogel (<jats:italic>p<\/jats:italic>\u2009=\u20090.024) and to 10 with combination local\/systemic rifampin therapy (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001). \u03bcCT demonstrated reactive bone formation in MRSA infection. Histology demonstrated restored fracture healing with bacterial elimination. Rifampin\u2010loaded hydrogels suppressed osteomyelitis, prevented implant colonization, and improved healing. Systemic rifampin was more effective at eliminating infection and improving fracture healing. Further investigation into rifampin\u2010loaded hydrogels is required to correlate these findings with clinical efficacy.<\/jats:p>","DOI":"10.1002\/jor.24965","type":"journal-article","created":{"date-parts":[[2020,12,18]],"date-time":"2020-12-18T18:13:44Z","timestamp":1608315224000},"page":"402-414","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Locally delivered adjuvant biofilm\u2010penetrating antibiotics rescue impaired endochondral fracture healing caused by MRSA infection"],"prefix":"10.1002","volume":"39","author":[{"given":"Sean V.","family":"Cahill","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery Washington University in St. Louis St. Louis Missouri USA"},{"name":"Department of Orthopaedics and Rehabilitation Yale School of Medicine New Haven Connecticut 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