title: Immunomodulatory Peptide IDR-1018 Decreases Implant Infection and Preserves Osseointegration.
abstract: BACKGROUND
  Innate defense regulator peptide-1018 (IDR-1018) 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.
  
  
  OBJECTIVE
  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. In vitro immunomodulatory activity of IDR-1018 included inducing production of MCP-1 in the absence of other inflammatory stimuli and to potently blunt excess production of proinflammatory cytokines and MCP-1 induced by lipopolysaccharide. Higher concentrations of IDR-1018 were required to blunt production of proinflammatory cytokines and MCP-1 in the presence S aureus. The largest in vivo immunomodulatory effect of IDR-1018 was to reduce tumor necrosis factor-α levels induced by S aureus by 60% (p = 0.006). Most importantly, IDR-1018 reduced S aureus-induced failures of osseointegration by threefold (p = 0.022) and increased osseointegration as measured by ultimate force (5.4-fold, p = 0.033) and average stiffness (4.3-fold, p = 0.049).
  
  
  CONCLUSIONS
  IDR-1018 is potentially useful to reduce orthopaedic infections by directly killing bacteria and by recruiting macrophages to the infection site.
  
  
  CONCLUSIONS
  These findings make IDR-1018 an attractive candidate to explore in larger animal models to ascertain whether its effects in our in vitro and mouse experiments can be replicated in more clinically relevant settings.
authors.affiliation: Department of Orthopaedics, Case Western Reserve University, Biomedical Research Building, Room 331, 2109, Adelbert Road, Cleveland, OH, 44106, USA.
authors.forename: Hyonmin
authors.initials: H
authors.lastname: Choe
authors.forename: Arvind S
authors.initials: AS
authors.lastname: Narayanan
authors.forename: Deep A
authors.initials: DA
authors.lastname: Gandhi
authors.forename: Aaron
authors.initials: A
authors.lastname: Weinberg
authors.forename: Randall E
authors.initials: RE
authors.lastname: Marcus
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Lee
authors.forename: Robert A
authors.initials: RA
authors.lastname: Bonomo
authors.forename: Edward M
authors.initials: EM
authors.lastname: Greenfield
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D007155:Immunologic Factors / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D016348:Osseointegration / Q000187:drug effects*; D016459:Prosthesis-Related Infections / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D013203:Staphylococcal Infections / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development / Q000276:immunology; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D007155:Immunologic Factors; D018836:Inflammation Mediators; C555052:innate defense regulating peptide 1018