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

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Bone Research 2023年第4期11卷 751-763页

作者： Youliang Ren Jason Weeks Thomas Xue Joshua Rainbolt Karen L.de Mesy Bentley Ye Shu Yuting Liu Elysia Masters Philip Cherian Charles E.McKenna Jeffrey Neighbors Frank H.Ebetino Edward M.Schwarz Shuting Sun Chao Xie Center for Musculoskeletal Research University of Rochester Medical CenterRochesterNY 14642USA Department of Orthopaedics University of Rochester Medical CenterRochesterNY 14642USA Department of Pathology and Center for Advanced Research Technologies University of Rochester Medical CenterRochesterNY 14642USA BioVinc LLCPasadenaCA 91107USA Department of Chemistry University of Southern CaliforniaLos AngelesCA 90089USA Department of Pharmacology Pennsylvania State UniversityHersheyPA 17033USA Department of Chemistry University of RochesterRoche

Eradication of MRSA osteomyelitis requires elimination of distinct biofilms.To overcome this,we developed bisphosphonateconjugated 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 day7,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.

关键词： implant infection overcome

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