title: Combinatory antibiotic therapy increases rate of bacterial kill but not final outcome in a novel mouse model of Staphylococcus aureus spinal implant infection.
abstract: BACKGROUND
  Management of spine implant infections (SII) are challenging. Explantation of infected spinal hardware can destabilize the spine, but retention can lead to cord compromise and biofilm formation, complicating management. While vancomycin monotherapy is commonly used, in vitro studies have shown reduced efficacy against biofilm compared to combination therapy with rifampin. Using an established in vivo mouse model of SII, we aim to evaluate whether combination therapy has increased efficacy compared to both vancomycin alone and infected controls.
  
  
  METHODS
  An L-shaped, Kirschner-wire was transfixed into the L4 spinous process of 12-week-old C57BL/6 mice, and inoculated with bioluminescent Staphylococcus aureus. Mice were randomized into a vancomycin group, a combination group with vancomycin plus rifampin, or a control group receiving saline. Treatment began on post-operative day (POD) 7 and continued through POD 14. In vivo imaging was performed to monitor bioluminescence for 35 days. Colony-forming units (CFUs) were cultured on POD 35.
  
  
  RESULTS
  Bioluminescence peaked around POD 7 for all groups. The combination group had a 10-fold decrease in signal by POD 10. The vancomycin and control groups reached similar levels on POD 17 and 21, respectively. On POD 25 the combination group dropped below baseline, but rebounded to the same level as the other groups, demonstrating a biofilm-associated infection by POD 35. Quantification of CFUs on POD 35 confirmed an ongoing infection in all three groups.
  
  
  CONCLUSIONS
  Although both therapies were initially effective, they were not able to eliminate implant biofilm bacteria, resulting in a rebound infection after antibiotic cessation. This model shows, for the first time, why histologic-based, static assessments of antimicrobials can be misleading, and the importance of longitudinal tracking of infection. Future studies can use this model to test combinations of antibiotic therapies to see if they are more effective in eliminating biofilm prior to human trials.
authors.affiliation: Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California Los Angeles, Santa Monica, California, United States of America.
authors.forename: Yan
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California Los Angeles, Santa Monica, California, United States of America.
authors.forename: Vishal
authors.identifier: http://orcid.org/0000-0001-6665-0442
authors.initials: V
authors.lastname: Hegde
authors.affiliation: Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California Los Angeles, Santa Monica, California, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Johansen
authors.affiliation: Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California Los Angeles, Santa Monica, California, United States of America.
authors.forename: Amanda H
authors.initials: AH
authors.lastname: Loftin
authors.affiliation: Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California Los Angeles, Santa Monica, California, United States of America.
authors.forename: Erik
authors.initials: E
authors.lastname: Dworsky
authors.affiliation: Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California Los Angeles, Santa Monica, California, United States of America.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Zoller
authors.affiliation: Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California Los Angeles, Santa Monica, California, United States of America.
authors.forename: Howard Y
authors.initials: HY
authors.lastname: Park
authors.affiliation: Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California Los Angeles, Santa Monica, California, United States of America.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Hamad
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: George E
authors.initials: GE
authors.lastname: Nelson
authors.affiliation: Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California Los Angeles, Santa Monica, California, United States of America.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Francis
authors.affiliation: Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California Los Angeles, Santa Monica, California, United States of America.
authors.forename: Anthony
authors.initials: A
authors.lastname: Scaduto
authors.affiliation: Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California Los Angeles, Santa Monica, California, United States of America.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Bernthal
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D018441:Biofilms / Q000187:drug effects; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019736:Prostheses and Implants / Q000382:microbiology*; D013131:Spine / Q000601:surgery; D013203:Staphylococcal Infections / Q000188:drug therapy*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000472:pathogenicity*; D014640:Vancomycin / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D014640:Vancomycin