Evidence of bisphosphonate-conjugated sitafloxacin eradication of established methicillin-resistant S. aureus infection with osseointegration in murine models of implant-associated osteomyelitis
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 t...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-10-01
|
| Series: | Bone Research |
| Online Access: | https://doi.org/10.1038/s41413-023-00287-4 |
| _version_ | 1797577523800834048 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Youliang Ren |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T22:09:32Z |
| format | Article |
| id | doaj.art-96b573a5a803436d94a93195b6f70cb2 |
| institution | Directory Open Access Journal |
| issn | 2095-6231 |
| language | English |
| last_indexed | 2024-03-10T22:09:32Z |
| publishDate | 2023-10-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Bone Research |
| spelling | doaj.art-96b573a5a803436d94a93195b6f70cb22023-11-19T12:39:48ZengNature Publishing GroupBone Research2095-62312023-10-0111111310.1038/s41413-023-00287-4Evidence of bisphosphonate-conjugated sitafloxacin eradication of established methicillin-resistant S. aureus infection with osseointegration in murine models of implant-associated osteomyelitisYouliang Ren0Jason Weeks1Thomas Xue2Joshua Rainbolt3Karen L. de Mesy Bentley4Ye Shu5Yuting Liu6Elysia Masters7Philip Cherian8Charles E. McKenna9Jeffrey Neighbors10Frank H. Ebetino11Edward M. Schwarz12Shuting Sun13Chao Xie14Center for Musculoskeletal Research, University of Rochester Medical CenterCenter for Musculoskeletal Research, University of Rochester Medical CenterCenter for Musculoskeletal Research, University of Rochester Medical CenterCenter for Musculoskeletal Research, University of Rochester Medical CenterCenter for Musculoskeletal Research, University of Rochester Medical CenterCenter for Musculoskeletal Research, University of Rochester Medical CenterCenter for Musculoskeletal Research, University of Rochester Medical CenterCenter for Musculoskeletal Research, University of Rochester Medical CenterBioVinc, LLCDepartment of Chemistry, University of Southern CaliforniaDepartment of Pharmacology, Pennsylvania State UniversityBioVinc, LLCCenter for Musculoskeletal Research, University of Rochester Medical CenterBioVinc, LLCCenter for Musculoskeletal Research, University of Rochester Medical CenterAbstract 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.https://doi.org/10.1038/s41413-023-00287-4 |
| spellingShingle | 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 Evidence of bisphosphonate-conjugated sitafloxacin eradication of established methicillin-resistant S. aureus infection with osseointegration in murine models of implant-associated osteomyelitis Bone Research |
| title | Evidence of bisphosphonate-conjugated sitafloxacin eradication of established methicillin-resistant S. aureus infection with osseointegration in murine models of implant-associated osteomyelitis |
| title_full | Evidence of bisphosphonate-conjugated sitafloxacin eradication of established methicillin-resistant S. aureus infection with osseointegration in murine models of implant-associated osteomyelitis |
| title_fullStr | Evidence of bisphosphonate-conjugated sitafloxacin eradication of established methicillin-resistant S. aureus infection with osseointegration in murine models of implant-associated osteomyelitis |
| title_full_unstemmed | Evidence of bisphosphonate-conjugated sitafloxacin eradication of established methicillin-resistant S. aureus infection with osseointegration in murine models of implant-associated osteomyelitis |
| title_short | Evidence of bisphosphonate-conjugated sitafloxacin eradication of established methicillin-resistant S. aureus infection with osseointegration in murine models of implant-associated osteomyelitis |
| title_sort | evidence of bisphosphonate conjugated sitafloxacin eradication of established methicillin resistant s aureus infection with osseointegration in murine models of implant associated osteomyelitis |
| url | https://doi.org/10.1038/s41413-023-00287-4 |
| work_keys_str_mv | AT youliangren evidenceofbisphosphonateconjugatedsitafloxacineradicationofestablishedmethicillinresistantsaureusinfectionwithosseointegrationinmurinemodelsofimplantassociatedosteomyelitis AT jasonweeks evidenceofbisphosphonateconjugatedsitafloxacineradicationofestablishedmethicillinresistantsaureusinfectionwithosseointegrationinmurinemodelsofimplantassociatedosteomyelitis AT thomasxue evidenceofbisphosphonateconjugatedsitafloxacineradicationofestablishedmethicillinresistantsaureusinfectionwithosseointegrationinmurinemodelsofimplantassociatedosteomyelitis AT joshuarainbolt evidenceofbisphosphonateconjugatedsitafloxacineradicationofestablishedmethicillinresistantsaureusinfectionwithosseointegrationinmurinemodelsofimplantassociatedosteomyelitis AT karenldemesybentley evidenceofbisphosphonateconjugatedsitafloxacineradicationofestablishedmethicillinresistantsaureusinfectionwithosseointegrationinmurinemodelsofimplantassociatedosteomyelitis AT yeshu evidenceofbisphosphonateconjugatedsitafloxacineradicationofestablishedmethicillinresistantsaureusinfectionwithosseointegrationinmurinemodelsofimplantassociatedosteomyelitis AT yutingliu evidenceofbisphosphonateconjugatedsitafloxacineradicationofestablishedmethicillinresistantsaureusinfectionwithosseointegrationinmurinemodelsofimplantassociatedosteomyelitis AT elysiamasters evidenceofbisphosphonateconjugatedsitafloxacineradicationofestablishedmethicillinresistantsaureusinfectionwithosseointegrationinmurinemodelsofimplantassociatedosteomyelitis AT philipcherian evidenceofbisphosphonateconjugatedsitafloxacineradicationofestablishedmethicillinresistantsaureusinfectionwithosseointegrationinmurinemodelsofimplantassociatedosteomyelitis AT charlesemckenna evidenceofbisphosphonateconjugatedsitafloxacineradicationofestablishedmethicillinresistantsaureusinfectionwithosseointegrationinmurinemodelsofimplantassociatedosteomyelitis AT jeffreyneighbors evidenceofbisphosphonateconjugatedsitafloxacineradicationofestablishedmethicillinresistantsaureusinfectionwithosseointegrationinmurinemodelsofimplantassociatedosteomyelitis AT frankhebetino evidenceofbisphosphonateconjugatedsitafloxacineradicationofestablishedmethicillinresistantsaureusinfectionwithosseointegrationinmurinemodelsofimplantassociatedosteomyelitis AT edwardmschwarz evidenceofbisphosphonateconjugatedsitafloxacineradicationofestablishedmethicillinresistantsaureusinfectionwithosseointegrationinmurinemodelsofimplantassociatedosteomyelitis AT shutingsun evidenceofbisphosphonateconjugatedsitafloxacineradicationofestablishedmethicillinresistantsaureusinfectionwithosseointegrationinmurinemodelsofimplantassociatedosteomyelitis AT chaoxie evidenceofbisphosphonateconjugatedsitafloxacineradicationofestablishedmethicillinresistantsaureusinfectionwithosseointegrationinmurinemodelsofimplantassociatedosteomyelitis |