Staphylococcus aureus is a major human pathogen causing serious implant–associated infections. Combination treatment with rifampin (10 to 15 mg/kg per day), which has dose-dependent activity, is recommended to treat S. aureus orthopedic implant–associated infections. Rifampin, however, has limited bone penetration. Here, dynamic ¹¹C-rifampin positron emission tomography (PET) performed in prospectively enrolled patients with confirmed S. aureus bone infection (n = 3) or without orthopedic infection (n = 12) demonstrated bone/plasma area under the concentration-time curve ratio of 0.14 (interquartile range, 0.09 to 0.19), exposures lower than previously thought. PET-based pharmacokinetic modeling predicted rifampin concentration-time profiles in bone and facilitated studies in a mouse model of S. aureus orthopedic implant infection. Administration of high-dose rifampin (human equipotent to 35 mg/kg per day) substantially increased bone concentrations (2 mg/liter versus <0.2 mg/liter with standard dosing) in mice and achieved higher bacterial killing and biofilm disruption. Treatment for 4 weeks with high-dose rifampin and vancomycin was noninferior to the recommended 6-week treatment of standard-dose rifampin with vancomycin in mice (risk difference, −6.7% favoring high-dose rifampin regimen). High-dose rifampin treatment ameliorated antimicrobial resistance (0% versus 38%; P = 0.04) and mitigated adverse bone remodeling (P < 0.01). Last, whole-genome sequencing demonstrated that administration of high-dose rifampin in mice reduced selection of bacterial mutations conferring rifampin resistance (rpoB) and mutations in genes potentially linked to persistence. These data suggest that administration of high-dose rifampin is necessary to achieve optimal bone concentrations, which could shorten and improve treatments for S. aureus orthopedic implant infections.

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动态 PET 辅助建模和高剂量利福平治疗金黄色葡萄球菌骨科植入物相关感染

金黄色葡萄球菌是一种主要的人类病原体，可引起严重的植入物相关感染。建议与利福平（每天 10 至 15 毫克/千克）联合治疗，其活性具有剂量依赖性，建议用于治疗金黄色葡萄球菌骨科植入物相关感染。然而，利福平的骨渗透性有限。在此，对前瞻性入组的确诊金黄色葡萄球菌骨感染 ( n = 3) 或无骨科感染 ( n = 12)的患者进行动态¹¹ C-利福平正电子发射断层扫描 (PET) ，显示浓度-时间曲线下的骨/血浆面积比率为0.14（四分位数范围，0.09至0.19），暴露程度低于之前的预期。基于 PET 的药代动力学模型预测了骨中利福平的浓度-时间曲线，并促进了金黄色葡萄球菌骨科植入物感染小鼠模型的研究。给予高剂量利福平（人体等效剂量为每天 35 毫克/公斤）显着增加小鼠骨浓度（标准剂量为 2 毫克/升，标准剂量<0.2 毫克/升），并实现更高的细菌杀灭和生物膜破坏。在小鼠中，用高剂量利福平和万古霉素治疗 4 周并不劣于推荐的标准剂量利福平与万古霉素 6 周治疗（风险差异，-6.7% 有利于高剂量利福平方案）。高剂量利福平治疗改善了抗菌药物耐药性（0% vs 38%；P = 0.04）并减轻了不良骨重塑（P < 0.01）。最后，全基因组测序表明，给小鼠施用高剂量利福平会减少对利福平耐药性（rpoB）的细菌突变的选择，以及可能与持久性相关的基因突变。这些数据表明，施用高剂量利福平对于达到最佳骨浓度是必要的，这可以缩短和改善金黄色葡萄球菌骨科植入物感染的治疗。