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

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 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

作者机构：Center for Musculoskeletal ResearchUniversity of Rochester Medical CenterRochesterNY 14642USA Department of OrthopaedicsUniversity of Rochester Medical CenterRochesterNY 14642USA Department of Pathology and Center for Advanced Research TechnologiesUniversity of Rochester Medical CenterRochesterNY 14642USA BioVincLLCPasadenaCA 91107USA Department of ChemistryUniversity of Southern CaliforniaLos AngelesCA 90089USA Department of PharmacologyPennsylvania State UniversityHersheyPA 17033USA Department of ChemistryUniversity of RochesterRoche 

出 版 物：《Bone Research》 (骨研究（英文版）)

年 卷 期：2023年第11卷第4期

页      面：751-763页

核心收录：

学科分类：1002[医学-临床医学] 100210[医学-外科学(含：普外、骨外、泌尿外、胸心外、神外、整形、烧伤、野战外)] 10[医学] 

基　　金：supported by grants from the National Institutes of Health(SBIR R44 AI125060 NIAMS P50 AR072000 and NIAMS P30 AR069655) 

主　　题：implant infection overcome 

摘      要：Eradication of MRSA osteomyelitis requires elimination of distinct *** overcome this,we developed bisphosphonateconjugated sitafloxacin(BCS,BV600072)and hydroxybisphosphonate-conjugate sitafloxacin(HBCS,BV63072),which achieve“target-and-releasedrug delivery proximal to the bone infection and have prophylactic efficacy against MRSA static biofilm in vitro and in *** 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+*** confirmed infection persisted in all groups except for mice treated with BCS or HBCS+*** 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 *** confirm this,we assessed the efficacy of vancomycin,sitafloxacin,and HBCS monotherapy in a transtibial implant *** 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 *** together these studies demonstrate that HBCS adjuvant with standard of care debridement and vancomycin therapy has the potential to eradicate MRSA osteomyelitis.