title: Local delivery of the cationic steroid antibiotic CSA-90 enables osseous union in a rat open fracture model of Staphylococcus aureus infection.
abstract: 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.
  
  
  CONCLUSIONS
  Local delivery of CSA-90 represents a novel strategy for prevention of infection and may have specific benefits in the context of orthopaedic injuries.
authors.affiliation: Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia. E-mail address for A. Schindeler: aaron.schindeler@sydney.edu.au. E-mail address for N.Y.C. Yu: n.yu@unsw.edu.au. E-mail address for T.L. Cheng: tegan.cheng@sydney.edu.au. E-mail address for K. Sullivan: kates3@live.com. E-mail address for K. Mikulec: kathy.mikulec@health.nsw.gov.au. E-mail address for L. Peacock: lauren.peacock@health.nsw.gov.au. E-mail address for D.G. Little: david.little@health.nsw.gov.au.
authors.forename: Aaron
authors.initials: A
authors.lastname: Schindeler
authors.affiliation: Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia. E-mail address for A. Schindeler: aaron.schindeler@sydney.edu.au. E-mail address for N.Y.C. Yu: n.yu@unsw.edu.au. E-mail address for T.L. Cheng: tegan.cheng@sydney.edu.au. E-mail address for K. Sullivan: kates3@live.com. E-mail address for K. Mikulec: kathy.mikulec@health.nsw.gov.au. E-mail address for L. Peacock: lauren.peacock@health.nsw.gov.au. E-mail address for D.G. Little: david.little@health.nsw.gov.au.
authors.forename: Nicole Y C
authors.initials: NY
authors.lastname: Yu
authors.affiliation: Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia. E-mail address for A. Schindeler: aaron.schindeler@sydney.edu.au. E-mail address for N.Y.C. Yu: n.yu@unsw.edu.au. E-mail address for T.L. Cheng: tegan.cheng@sydney.edu.au. E-mail address for K. Sullivan: kates3@live.com. E-mail address for K. Mikulec: kathy.mikulec@health.nsw.gov.au. E-mail address for L. Peacock: lauren.peacock@health.nsw.gov.au. E-mail address for D.G. Little: david.little@health.nsw.gov.au.
authors.forename: Tegan L
authors.initials: TL
authors.lastname: Cheng
authors.affiliation: Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia. E-mail address for A. Schindeler: aaron.schindeler@sydney.edu.au. E-mail address for N.Y.C. Yu: n.yu@unsw.edu.au. E-mail address for T.L. Cheng: tegan.cheng@sydney.edu.au. E-mail address for K. Sullivan: kates3@live.com. E-mail address for K. Mikulec: kathy.mikulec@health.nsw.gov.au. E-mail address for L. Peacock: lauren.peacock@health.nsw.gov.au. E-mail address for D.G. Little: david.little@health.nsw.gov.au.
authors.forename: Kate
authors.initials: K
authors.lastname: Sullivan
authors.affiliation: Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia. E-mail address for A. Schindeler: aaron.schindeler@sydney.edu.au. E-mail address for N.Y.C. Yu: n.yu@unsw.edu.au. E-mail address for T.L. Cheng: tegan.cheng@sydney.edu.au. E-mail address for K. Sullivan: kates3@live.com. E-mail address for K. Mikulec: kathy.mikulec@health.nsw.gov.au. E-mail address for L. Peacock: lauren.peacock@health.nsw.gov.au. E-mail address for D.G. Little: david.little@health.nsw.gov.au.
authors.forename: Kathy
authors.initials: K
authors.lastname: Mikulec
authors.affiliation: Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia. E-mail address for A. Schindeler: aaron.schindeler@sydney.edu.au. E-mail address for N.Y.C. Yu: n.yu@unsw.edu.au. E-mail address for T.L. Cheng: tegan.cheng@sydney.edu.au. E-mail address for K. Sullivan: kates3@live.com. E-mail address for K. Mikulec: kathy.mikulec@health.nsw.gov.au. E-mail address for L. Peacock: lauren.peacock@health.nsw.gov.au. E-mail address for D.G. Little: david.little@health.nsw.gov.au.
authors.forename: Lauren
authors.initials: L
authors.lastname: Peacock
authors.affiliation: Department of Animal Care, Westmead Hospital, Westmead, NSW 2145, Australia. E-mail address: ross.matthews@health.nsw.gov.au.
authors.forename: Ross
authors.initials: R
authors.lastname: Matthews
authors.affiliation: Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia. E-mail address for A. Schindeler: aaron.schindeler@sydney.edu.au. E-mail address for N.Y.C. Yu: n.yu@unsw.edu.au. E-mail address for T.L. Cheng: tegan.cheng@sydney.edu.au. E-mail address for K. Sullivan: kates3@live.com. E-mail address for K. Mikulec: kathy.mikulec@health.nsw.gov.au. E-mail address for L. Peacock: lauren.peacock@health.nsw.gov.au. E-mail address for D.G. Little: david.little@health.nsw.gov.au.
authors.forename: David G
authors.initials: DG
authors.lastname: Little
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D023181:Antimicrobial Cationic Peptides / Q000008:administration & dosage*; D019485:Bone Morphogenetic Proteins / Q000008:administration & dosage; D002113:Calcification, Physiologic / Q000187:drug effects; D002478:Cells, Cultured; D002828:Choristoma / Q000188:drug therapy / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005264:Femoral Fractures / Q000150:complications* / Q000000981:diagnostic imaging; D017102:Fracture Healing / Q000187:drug effects*; D005597:Fractures, Open / Q000150:complications* / Q000000981:diagnostic imaging; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010000:Osteitis / Q000188:drug therapy* / Q000382:microbiology; D010006:Osteoblasts / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects; D011278:Pregnanes / Q000008:administration & dosage*; D011437:Propylamines / Q000008:administration & dosage*; D011859:Radiography; D051381:Rats; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013211:Staphylococcus aureus
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D019485:Bone Morphogenetic Proteins; C000597011:CSA-90; D011278:Pregnanes; D011437:Propylamines