Local Delivery of the Cationic Steroid Antibiotic CSA-90 Enables Osseous Union in a Rat Open Fracture Model of Staphylococcus aureus Infection

BACKGROUND:Treatment of infected open fractures remains a major clinical challenge. In this study, we investigated the novel broad-spectrum antibiotic CSA-90 (cationic steroid antibiotic-90) as an antimicrobial agent. METHODS:CSA-90 was screened in an osteoblast cell culture model for effects on differentiation and mineralization. Local delivery of CSA-90 was then tested alone and in combination with recombinant human bone morphogenetic protein-2 (rhBMP-2) in a mouse ectopic bone formation model (n = 40 mice) and in a rat open fracture model inoculated with pathogenic Staphylococcus aureus (n = 84 rats). RESULTS:CSA-90 enhanced matrix mineralization in cultured osteoblasts and increased rhBMP-2-induced bone formation in vivo. All animals in which an open fracture had been inoculated with Staphylococcus aureus and not treated with local CSA-90, including those treated with rhBMP-2, had to be culled prior to the experimental end point (six weeks) because of localized osteolysis and deterioration of overall health, whereas CSA-90 prevented establishment of infection in all open fractures in which it was used (p ≤ 0.012). Increased union rates were seen for the fractures treated with rhBMP-2 or with the combination of rhBMP-2 and CSA-90 compared with that observed for the fractures treated with CSA-90 alone (p = 0.04). CONCLUSIONS:CSA-90 can promote osteogenesis and be used for prevention of Staphylococcus aureus infection in preclinical models. CLINICAL RELEVANCE:Local delivery of CSA-90 represents a novel strategy for prevention of infection and may have specific benefits in the context of orthopaedic injuries.