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Original Article | Open Access

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

Youliang Ren1,2, Jason Weeks1,2, Thomas Xue1,2, Joshua Rainbolt1,2, Karen L. de Mesy Bentley1,2,3, Ye Shu1,2, Yuting Liu1,2, Elysia Masters1,2, Philip Cherian4, Charles E. McKenna5, Jeffrey Neighbors6, Frank H. Ebetino4,7, Edward M. Schwarz1,2, Shuting Sun4( ), Chao Xie1,2 ( )
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
BioVinc, LLC, Pasadena, CA 91107, USA
Department of Chemistry, University of Southern California, Los Angeles, CA 90089, USA
Department of Pharmacology, Pennsylvania State University, Hershey, PA 17033, USA
Department of Chemistry, University of Rochester, Rochester, NY 14642, USA
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Abstract

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.

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Bone Research
Volume 11,
December 2023
Article number: 51
DOI: 10.1038/s41413-023-00287-4
Cite this article:
Ren Y, Weeks J, Xue T, et al. Evidence of bisphosphonate-conjugated sitafloxacin eradication of established methicillin-resistant S. aureus infection with osseointegration in murine models of implant-associated osteomyelitis. Bone Research, 2023, 11: 51. https://doi.org/10.1038/s41413-023-00287-4

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Received: 24 April 2023
Revised: 05 August 2023
Accepted: 21 August 2023
Published: 18 October 2023
© The Author(s) 2023

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