Evidence of bisphosphonate-conjugated sitafloxacin eradication of established methicillin-resistant S. aureus infection with osseointegration in murine models of implant-associated osteomyelitis.

Autor: Ren Y; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, 14642, USA.; Department of Orthopaedics, University of Rochester Medical Center, Rochester, NY, 14642, USA., Weeks J; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, 14642, USA.; Department of Orthopaedics, University of Rochester Medical Center, Rochester, NY, 14642, USA., Xue T; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, 14642, USA.; Department of Orthopaedics, University of Rochester Medical Center, Rochester, NY, 14642, USA., Rainbolt J; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, 14642, USA.; Department of Orthopaedics, University of Rochester Medical Center, Rochester, NY, 14642, USA., de Mesy Bentley KL; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, 14642, USA.; Department of Orthopaedics, University of Rochester Medical Center, Rochester, NY, 14642, USA.; Department of Pathology and Center for Advanced Research Technologies, University of Rochester Medical Center, Rochester, NY, 14642, USA., Shu Y; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, 14642, USA.; Department of Orthopaedics, University of Rochester Medical Center, Rochester, NY, 14642, USA., Liu Y; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, 14642, USA.; Department of Orthopaedics, University of Rochester Medical Center, Rochester, NY, 14642, USA., Masters E; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, 14642, USA.; Department of Orthopaedics, University of Rochester Medical Center, Rochester, NY, 14642, USA., Cherian P; BioVinc, LLC, Pasadena, CA, 91107, USA., McKenna CE; Department of Chemistry, University of Southern California, Los Angeles, CA, 90089, USA., Neighbors J; Department of Pharmacology, Pennsylvania State University, Hershey, PA, 17033, USA., Ebetino FH; BioVinc, LLC, Pasadena, CA, 91107, USA.; Department of Chemistry, University of Rochester, Rochester, NY, 14642, USA., Schwarz EM; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, 14642, USA.; Department of Orthopaedics, University of Rochester Medical Center, Rochester, NY, 14642, USA., Sun S; BioVinc, LLC, Pasadena, CA, 91107, USA. shuting.sun@biovinc.com., Xie C; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, 14642, USA. chao_xie@urmc.rochester.edu.; Department of Orthopaedics, University of Rochester Medical Center, Rochester, NY, 14642, USA. chao_xie@urmc.rochester.edu.
Jazyk: angličtina
Zdroj: Bone research [Bone Res] 2023 Oct 18; Vol. 11 (1), pp. 51. Date of Electronic Publication: 2023 Oct 18.
DOI: 10.1038/s41413-023-00287-4
Abstrakt: Eradication of MRSA osteomyelitis requires elimination of distinct biofilms. To overcome this, we developed bisphosphonate-conjugated sitafloxacin (BCS, BV600072) and hydroxybisphosphonate-conjugate sitafloxacin (HBCS, BV63072), which achieve "target-and-release" drug delivery proximal to the bone infection and have prophylactic efficacy against MRSA static biofilm in vitro and in vivo. Here we evaluated their therapeutic efficacy in a murine 1-stage exchange femoral plate model with bioluminescent MRSA (USA300LAC::lux). Osteomyelitis was confirmed by CFU on the explants and longitudinal bioluminescent imaging (BLI) after debridement and implant exchange surgery on day 7, and mice were randomized into seven groups: 1) Baseline (harvested at day 7, no treatment); 2) HPBP (bisphosphonate control for BCS) + vancomycin; 3) HPHBP (hydroxybisphosphonate control for HBCS) + vancomycin; 4) vancomycin; 5) sitafloxacin; 6) BCS + vancomycin; and 7) HBCS + vancomycin. BLI confirmed infection persisted in all groups except for mice treated with BCS or HBCS + vancomycin. Radiology revealed catastrophic femur fractures in all groups except mice treated with BCS or HBCS + vancomycin, which also displayed decreases in peri-implant bone loss, osteoclast numbers, and biofilm. To confirm this, we assessed the efficacy of vancomycin, sitafloxacin, and HBCS monotherapy in a transtibial implant model. The results showed complete lack of vancomycin efficacy while all mice treated with HBCS had evidence of infection control, and some had evidence of osseous integrated septic implants, suggestive of biofilm eradication. Taken together these studies demonstrate that HBCS adjuvant with standard of care debridement and vancomycin therapy has the potential to eradicate MRSA osteomyelitis.
(© 2023. West China School of Stomatology Sichuan University.)
Databáze: MEDLINE
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