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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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维普期刊数据库

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Systemic Il-27 administration prevents abscess formation and osteolysis via local neutrophil recruitment and activation

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Bone Research 2022年第4期10卷 826-837页

作者： Yugo Morita Motoo Saito Javier Rangel-Moreno Anthony M.Franchini John R.Owen John C.Martinez John l.Daiss Karen L.de Mesy Bentley Stephen l.Kates Edward M.Schwarz Gowrishankar Muthukrishnan Center for Musculoskeletal Research University of Rochester Medical CenterRochesterNYUSA Division of Allergy Immunology and RheumatologyDepartment of MedicineUniversity of Rochester Medical CenterRochesterNYUSA department of Environmental Medicine University of Rochester School of Medicine and DentistryRochesterNYUSA department of Orthopedic Surgery Virginia Commonwealth UniversityRichmondVAUSA department of Orthopedics University of Rochester Medical CenterRochesterNYUSA department of Pathology and laboratory Medicine University of Rochester Medical CenterRochesterNYUSA

Interleukin-27 is a pleiotropic cytokine whose functions during bacterial infections remain controversial,and its role in patients with S.aureus osteomyelitis is unknown.To address this knowledge gap,we completed a clinical study and observed elevated serum Il-27 levels(20-fold higher,Plthy controls.Remarkably,Il-27 serum levels were 60-fold higher in patients immediately following septic death than in uninfected patients(Ple of Il-27.To test this hypothesis,we evaluated S.aureus osteomyelitis in WT and Il-27Rα^(−/−)mice with and without exogenous Il27 induction by intramuscular injection of rAAV-Il-27p28 or rAAV-GFP,respectively.We found that Il-27 was induced at the surgical site within 1 day of S.aureus infection of bone and was expressed by M0,M1 and M2 macrophages and osteoblasts but not by osteoclasts.Unexpectedly,exogenous Il-27p28(~2 ng·ml^(−1) in serum)delivery ameliorated soft tissue abscesses and periimplant bone loss during infection,accompanied by enhanced local Il-27 expression,significant accumulation of RORγt^(+)neutrophils at the infection site,a decrease in RANK^(+) cells,and compromised osteoclast formation.These effects were not observed in Il-27Rα^(−/−)mice compared with WT mice,suggesting that Il-27 is dispensable for immunity but mediates redundant immune and bone cell functions during infection.In vitro studies and bulk RNA-seq of infected tibiae showed that Il-27 increased nos1,nos2,il17α,il17f,and rorc expression but did not directly stimulate chemotaxis.Collectively,these results identify a novel phenomenon of Il-27 expression by osteoblasts immediately following S.aureus infection of bone and suggest a protective role of systemic Il-27 in osteomyelitis.

关键词： abscess protective immunity

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Evolving concepts in bone infection: redefining “biofilm”,“acute vs. chronic osteomyelitis”, “the immune proteome” and “local antibiotic therapy”

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Bone Research 2019年第3期7卷 225-242页

作者： Elysia A. Masters Ryan P. Trombetta karen l. de mesy bentley Brendan F Boyce Ann lindley Gill Steven R. Gill Kohei Nishitani Masahiro Ishikawa Yugo Morita Hiromu Ito Sheila N. Bello-Irizarry Mark Ninomiya James D. Brodell Jr. Charles C. lee Stephanie P. Hao Irvin Oh Chao Xie Hani A. Awad John l. Daiss John R. Owen Stephen l. Kates Edward M. Schwarz Gowrishankar Muthukrishnan Center for Musculoskeletal Research University of Rochester Medical Center Rochester NY USA department of Biomedical Engineering University of Rochester Medical Center Rochester NY USA department of Pathology and laboratory Medicine University of Rochester Medical Center Rochester NY USA department of Orthopaedics University of Rochester Medical Center Rochester NY USA department of Microbiology & Immunology University of Rochester Medical Center Rochester NY USA department of Orthopaedic Surgery Kyoto University Kyoto Japan department of Orthopaedic Surgery Virginia Commonwealth University Medical Center Richmond VA USA

Osteomyelitis is a devastating disease caused by microbial infection of bone. While the frequency of infection following elective orthopedic surgery is low, rates of reinfection are disturbingly high. Staphylococcus aureus is responsible for the majority of chronic osteomyelitis cases and is often considered to be incurable due to bacterial persistence deep within bone. Unfortunately, there is no consensus on clinical classifications of osteomyelitis and the ensuing treatment algorithm. Given the high patient morbidity,mortality, and economic burden caused by osteomyelitis, it is important to elucidate mechanisms of bone infection to inform novel strategies for prevention and curative treatment. Recent discoveries in this field have identified three distinct reservoirs of bacterial biofilm including: Staphylococcal abscess communities in the local soft tissue and bone marrow, glycocalyx formation on implant hardware and necrotic tissue, and colonization of the osteocyte-lacuno canalicular network(OlCN) of cortical bone. In contrast, S.aureus intracellular persistence in bone cells has not been substantiated in vivo, which challenges this mode of chronic osteomyelitis. There have also been major advances in our understanding of the immune proteome against S. aureus, from clinical studies of serum antibodies and media enriched for newly synthesized antibodies(MENSA), which may provide new opportunities for osteomyelitis diagnosis, prognosis, and vaccine development. Finally, novel therapies such as antimicrobial implant coatings and antibiotic impregnated 3D-printed scaffolds represent promising strategies for preventing and managing this devastating disease. Here, we review these recent advances and highlight translational opportunities towards a cure.

关键词： disease caused by soft tissue necrotic tissuel

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