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.
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. 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.
Clinical relevance: 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.