AWARD NUMBER: W81XWH-10-1-0872 TITLE: “Inhibition of Orthopaedic Implant Infections by Immunomodulatory Effects of Host Defense Peptides” PRINCIPAL INVESTIGATOR:

Background Innate defense regulator peptide-1018 (IDR1018) is a 12-amino acid, synthetic, immunomodulatory host defense peptide that can reduce soft tissue infections and is less likely to induce bacterial resistance than conventional antibiotics. However, IDRs have not been tested on orthopaedic infections and the immunomodulatory effects of IDR-1018 have only been characterized in response to lipopolysacharide, which is exclusively produced by Gram-negative bacteria. Questions/purposes We sought (1) to more fully characterize the immunomodulatory effects of IDR-1018, especially in response to Staphylococcus aureus; and (2) to determine whether IDR-1018 decreases S aureus infection of orthopaedic implants in mice and thereby protects the implants from failure to osseointegrate. Methods In vitro effects of IDR-1018 on S aureus were assessed by determining minimum inhibitory concentrations in bacterial broth without and with supplementation of physiologic ion levels. In vitro effects of IDR-1018 on macrophages were determined by measuring production of monocyte chemoattractant protein-1 (MCP-1) and proinflammatory cytokines by enzyme-linked immunosorbent assay. In vivo effects of IDR-1018 were determined in a murine model of S aureus implant infection by quantitating bacterial burden, macrophage recruitment, MCP-1, proinflammatory cytokines, and osseointegration in nine mice per group on Day 1 postimplantation and 20 mice per group on Day 15 postimplantation. Results IDR-1018 demonstrated antimicrobial activity by directly killing S aureus even in the presence of physiologic ion levels, increasing recruitment of macrophages to the site of infections by 40% (p = 0.036) and accelerating S aureus clearance in vivo (p = 0.008) with a 2.6-fold decrease in bacterial bioburden on Day 7 postimplantation. One or more of the authors has received research funding from the Department of Defense Peer Reviewed Orthopaedic Research Program Idea Development Award (EMG), the Harry E. Figgie III MD Professorship (EMG), the Mochida Memorial Foundation for Medical and Pharmaceutical Research (HC), the Cleveland Department of Veterans Affairs (RAB), the Veterans Affairs Merit Review Program award number 1I01BX001974 (RAB), the Geriatric Research Education and Clinical Center VISN 10 (RAB), the National Institute of Allergy and Infectious Diseases of the National Institutes of Health awards R01AI063517 and R01AI10056 (RAB), and the Antibiotic Resistance Leadership Group under National Institutes of Health award UM1AI104681 (RAB). The content is solely the responsibility of the authors and does not represent the official views of the Department of Defense, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the National Institutes of Health, or the Department of Veterans Affairs. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research editors and board members are on file with the publication and can be viewed on request. Clinical Orthopaedics and Related Research neither advocates nor endorses the use of any treatment, drug, or device. Readers are encouraged to always seek additional information, including FDAapproval status, of any drug or device prior to clinical use. Each author certifies that his or her institution approved the animal protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research. H. Choe, A. S. Narayanan, D. A. Gandhi, R. E. Marcus, E. M. Greenfield (&) Department of Orthopaedics, Case Western Reserve University, Biomedical Research Building, Room 331, 2109, Adelbert Road, Cleveland, OH 44106, USA e-mail: [email protected]; [email protected] A. Weinberg Department of Biological Sciences, Case Western Reserve University, Cleveland, OH, USA 123 Clin Orthop Relat Res DOI 10.1007/s11999-015-4301-2 Clinical Orthopaedics and Related Research® A Publication of The Association of Bone and Joint Surgeons®