Evidence of bisphosphonate-conjugated sitafloxacin eradication of established methicillin-resistant S.aureus 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 

机构地区：[1]Center for Musculoskeletal Research,University of Rochester Medical Center,Rochester,NY 14642,USA [2]Department of Orthopaedics,University of Rochester Medical Center,Rochester,NY 14642,USA [3]Department of Pathology and Center for Advanced Research Technologies,University of Rochester Medical Center,Rochester,NY 14642,USA [4]BioVinc,LLC,Pasadena,CA 91107,USA [5]Department of Chemistry,University of Southern California,Los Angeles,CA 90089,USA [6]Department of Pharmacology,Pennsylvania State University,Hershey,PA 17033,USA [7]Department of Chemistry,University of Rochester,Roche

出　　处：《Bone Research》2023年第4期751-763,共13页骨研究（英文版）

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

摘　　要：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 

分 类 号：R681.2[医药卫生—骨科学] R-332[医药卫生—外科学]