Evidence of bisphosphonate-conjugated sitafloxacin eradication of established methicillin-resistant S. aureus infection with osseointegration in murine models of implant-associated osteomyelitis.
Youliang RenJason WeeksThomas XueJoshua RainboltKaren L de Mesy BentleyYe ShuYuting LiuElysia A MastersPhilip CherianCharles E McKennaJeffrey NeighborsFrank H EbetinoEdward M SchwarzShuting SunZhao XiePublished in: Bone research (2023)
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.
Keyphrases
- methicillin resistant staphylococcus aureus
- staphylococcus aureus
- bone loss
- drug delivery
- candida albicans
- high fat diet induced
- biofilm formation
- healthcare
- soft tissue
- randomized controlled trial
- photodynamic therapy
- acute kidney injury
- minimally invasive
- early stage
- machine learning
- stem cells
- adipose tissue
- mesenchymal stem cells
- lipopolysaccharide induced
- escherichia coli
- type diabetes
- body composition
- newly diagnosed
- artificial intelligence
- percutaneous coronary intervention
- clinical trial
- bone mineral density
- quality improvement
- postmenopausal women
- coronary artery disease
- helicobacter pylori
- cancer therapy
- coronary artery bypass
- smoking cessation
- pain management