CSA-90 demonstrates reduced cytotoxicity and improved in vivo stability compared with endogenous peptides and has also shown proosteogenic potential, a desirable attribute in the management of open fractures. Its steroid-like structure is able to disrupt cell membranes and therefore confers a broad range of activity against Gram-positive and Gram-negative bacteria, including vancomycin and methicillin-resistant strains. With increasing resistance to conventional antibiotics, there is a pressing need to identify and develop novel antimicrobial therapies, particularly for orthopaedic applications.ĬSA-90 is a small synthetic peptidomimetic compound based on endogenous cationic antibacterial peptides such as LL-37. The incidence of community-acquired antibiotic-resistant strains such as methicillin-resistant S aureus (MRSA) and methicillin-resistant S epidermidis (MRSE) is increasing, particularly in the United States, with rates of up to 25% reported. Although S epidermidis is considered a less virulent pathogen than S aureus, there is evidence to suggest that S epidermidis strains may be acquiring more invasive properties and are just as effective at forming biofilms, particularly on orthopaedic implants. Staphylococcus aureus is frequently isolated in open fracture infections along with other coagulase-negative Staphylococci including Staphylococcus epidermidis. Although there is some controversy regarding the exact treatment window for exploration, débridement, and fixation, it generally is accepted that for most fractures, this should occur within 6 to 24 hours and systemic antibiotic prophylaxis usually is delivered for 72 hours or until definitive wound closure. Even when wounds are not visibly contaminated, it is accepted that open fractures have a substantially increased risk of becoming infected compared with equivalent closed fractures. Infection of open fractures remains a significant cause of morbidity and mortality to patients worldwide. Modified Kirby-Bauer disc diffusion assays were used to quantify antimicrobial activity in vitro using four different delivery methods, including bone cement.

Micro-CT quantification of bone volume and descriptive histologic analysis were performed for all in vivo studies.

For the ectopic bone formation assay, 0 to 10 µg BMP-2 and 0 to 500 µg CSA-90 were delivered on a collagen sponge into bilateral quadriceps muscle pouches of 8-week-old rats (n = 10 per group). The primary outcome of both fracture studies was fracture infection, incorporating survival, radiographic union, and deep tissue swab cultures. An independent, blinded veterinarian reviewed twice-weekly radiographs, and rats showing osteolysis and/or declining overall health were culled at his instruction. All animals were reviewed daily for signs of local infection and/or sepsis. In the delayed treatment study, débridement and treatment with 500 µg CSA-90 were performed at Day 1 and Day 5 after injury and bacterial insult ( S aureus). In the open fracture studies, 12-week-old male Wistar rats underwent open midshaft femoral fractures stabilized with a 1.1-mm Kirschner wire and 10 µg BMP-2 ± 500 µg CSA-90 was applied to the fracture site using a collagen sponge along with 1 x 10 4 colony-forming units of bacteria ( S aureus/MRSA/MRSE n = 10 per group). All in vivo studies were approved by the local animal ethics committee.

Tegan daugherty