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.

根除 MRSA 骨髓炎需要消除不同的生物膜。为了克服这个问题，我们开发了双膦酸盐结合西他沙星（BCS，BV600072）和羟基双膦酸盐结合西他沙星（HBCS，BV63072），它们实现了骨感染附近的“靶向和释放”药物递送，并对MRSA静态生物膜具有预防功效体外和体内。在这里，我们使用生物发光 MRSA (USA300LAC::lux) 评估了它们在小鼠 1 阶段交换股骨板模型中的治疗效果。第7天清创和种植体交换手术后，通过外植体上的CFU和纵向生物发光成像（BLI）证实骨髓炎，将小鼠随机分为七组：1）基线（第7天收获，不进行治疗）；2) HPBP（BCS的双膦酸盐对照）+万古霉素；3) HPHBP（HBCS 的羟基双膦酸盐对照）+万古霉素；4)万古霉素；5) 西他沙星；6)BCS+万古霉素；7) HBCS + 万古霉素。BLI 证实，除了用 BCS 或 HBCS + 万古霉素治疗的小鼠外，所有组中均存在感染。放射学显示，除用 BCS 或 HBCS + 万古霉素治疗的小鼠外，所有组均出现灾难性股骨骨折，这些小鼠也显示种植体周围骨丢失、破骨细胞数量和生物膜减少。为了证实这一点，我们评估了万古霉素、西他沙星和 HBCS 单一疗法在经胫骨植入模型中的疗效。结果显示，万古霉素完全没有疗效，而所有接受 HBCS 治疗的小鼠都有感染控制的证据，有些小鼠有骨整合化脓性植入物的证据，表明生物膜被根除。综上所述，这些研究表明，HBCS 佐剂结合标准护理清创和万古霉素治疗有可能根除 MRSA 骨髓炎。