title: Early local delivery of vancomycin suppresses ectopic bone formation in a rat model of trauma-induced heterotopic ossification.
abstract: Heterotopic ossification (HO) is a debilitating sequela of high-energy injuries. It frequently requires surgical excision once symptomatic and there is no practical prophylaxis for combat-injured patients. In this study, we examined the effect of local vancomycin powder on HO formation in a small animal model of blast-related, post-traumatic HO. Male Sprague-Dawley rats were subjected to a polytraumatic extremity injury and amputation with or without methicillin-resistant Staphylococcus aureus infection. Animals were randomized to receive a single local application of vancomycin (20 mg/kg) at the time of injury (POD-0, n = 34) or on postoperative day-3 (POD-3, n = 11). Quantitative volumetric measurement of ectopic bone was calculated at 12-weeks post-injury by micro-CT. Bone marrow and muscle tissues were also collected to determine the bacterial burden. Blood for serum cytokine analysis was collected at baseline and post-injury. Vancomycin treatment on POD-0 suppressed HO formation by 86% and prevented bone marrow and soft tissue infections. We concurrently observed a marked reduction histologically in nonviable tissue, chronic inflammatory cell infiltrates, bone infection, fibrous tissue, and areas of bone necrosis within this same cohort. Delayed treatment was significantly less efficacious. Neither treatment had a marked effect on the production of pro-inflammatory cytokines. Our study demonstrates that local vancomycin treatment at the time of injury significantly reduces HO formation in both the presence and absence of infection, with decreased efficacy if not given early. These findings further support the concept that the therapeutic window for prophylaxis is narrow, highlighting the need to develop early treatment strategies for clinical management. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2397-2406, 2017.
authors.affiliation: Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland.|Orthopaedics, USU-Walter Reed Department of Surgery, Walter Reed National Military Medical Center, Bethesda, Maryland.
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Seavey
authors.affiliation: Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland.|Orthopaedics, USU-Walter Reed Department of Surgery, Walter Reed National Military Medical Center, Bethesda, Maryland.
authors.forename: Benjamin M
authors.identifier: 0000-0003-0105-8258
authors.initials: BM
authors.lastname: Wheatley
authors.affiliation: Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland.|Orthopaedics, USU-Walter Reed Department of Surgery, Walter Reed National Military Medical Center, Bethesda, Maryland.
authors.forename: Gabriel J
authors.initials: GJ
authors.lastname: Pavey
authors.affiliation: Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland.
authors.forename: Allison M
authors.initials: AM
authors.lastname: Tomasino
authors.affiliation: Department of Pathology, Naval Medical Research Center, Silver Spring, Maryland.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Hanson
authors.affiliation: Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Sanders
authors.affiliation: Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland.
authors.forename: Devaveena
authors.initials: D
authors.lastname: Dey
authors.affiliation: Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland.
authors.forename: Kaitlyn L
authors.initials: KL
authors.lastname: Moss
authors.affiliation: Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland.|Orthopaedics, USU-Walter Reed Department of Surgery, Walter Reed National Military Medical Center, Bethesda, Maryland.
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Potter
authors.affiliation: Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland.|Orthopaedics, USU-Walter Reed Department of Surgery, Walter Reed National Military Medical Center, Bethesda, Maryland.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Forsberg
authors.affiliation: Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland.
authors.forename: Ammar T
authors.initials: AT
authors.lastname: Qureshi
authors.affiliation: Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, Maryland.|Orthopaedics, USU-Walter Reed Department of Surgery, Walter Reed National Military Medical Center, Bethesda, Maryland.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Davis
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D058491:Bacterial Load; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D004353:Drug Evaluation, Preclinical; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects; D055624:Methicillin-Resistant Staphylococcus aureus; D009999:Ossification, Heterotopic / Q000097:blood / Q000000981:diagnostic imaging / Q000209:etiology / Q000517:prevention & control*; D017207:Rats, Sprague-Dawley; D018461:Soft Tissue Infections / Q000209:etiology / Q000517:prevention & control; D013203:Staphylococcal Infections / Q000517:prevention & control; D018746:Systemic Inflammatory Response Syndrome / Q000097:blood / Q000209:etiology / Q000517:prevention & control; D014640:Vancomycin / Q000008:administration & dosage*; D014947:Wounds and Injuries / Q000150:complications*; D055114:X-Ray Microtomography
chemical_list: D000900:Anti-Bacterial Agents; D016207:Cytokines; D014640:Vancomycin
keywords: blast injuries; heterotopic ossification; trauma; vancomycin; wound infection