Fosfomycin is gaining interest in the treatment of complex osteoarticular infections (OI) due to multidrug-resistant (MDR) pathogens. Our aims were to conduct population pharmacokinetics of fosfomycin in a cohort of OI patients receiving 16 g daily by intermittent (II) or continuous (CI) infusion and to carry out Monte Carlo simulations for dosage optimization in the treatment of these infections. Patients underwent blood sampling on day 5 of therapy (2 to 3 serial samples). Population pharmacokinetics and Monte Carlo simulations were performed to define the probability of target attainment (PTA) of 70% T>MIC and the cumulative fraction of response (CFR) against common OI pathogens with dosages of 8, 12, 16, and 20 g/day administered by II, extended infusion (EI), or CI. Forty-eight patients were recruited. A two-compartment open model with infusion input and first-order elimination was developed. Estimated creatinine clearance (CL_CR) was included as a covariate in the final model. Monte Carlo simulations showed that optimal PTAs and CFRs (≥90%) can be achieved in three different classes of renal function by administering a daily dosage of 2 g every 6 h (q6h) by II against Staphylococcus aureus, Escherichia coli, expanded-spectrum beta-lactamase (ESBL)-producing E. coli, and methicillin-resistant S. aureus; 8 g by CI against coagulase-negative staphylococci, K. pneumoniae, and ESBL-producing K. pneumoniae; 12 g by CI against P. aeruginosa; and 16 g by CI against KPC-producing K. pneumoniae. Our study provides a strong rationale for considering fosfomycin dosages of 8 to 16 g daily by CI in several clinical scenarios for OI patients. The feasibility of administration by CI in an elastomeric pump makes fosfomycin a candidate for OPAT programs.

中文翻译：

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磷霉素治疗无肾功能不全患者骨关节感染剂量优化的群体药代动力学和蒙特卡罗模拟

磷霉素在治疗由多重耐药 (MDR) 病原体引起的复杂骨关节感染 (OI) 方面越来越受到关注。我们的目标是在每天间歇 (II) 或连续 (CI) 输注接受 16 g 磷霉素的一组 OI 患者中进行磷霉素群体药代动力学研究，并进行蒙特卡罗模拟以优化这些感染的治疗剂量。患者在治疗第 5 天接受血液采样（2 至 3 个系列样本）。进行了群体药代动力学和蒙特卡罗模拟来定义 70% T的目标实现概率 (PTA)>MIC 和针对常见 OI 病原体的累积反应分数 (CFR)，剂量为 8、12、16 和 20 g/天，通过 II、延长输注 (EI) 或 CI 给药。招募了四十八名患者。开发了具有输液输入和一级消除的双隔室开放模型。估计的肌酐清除率 (CL _CR ) 作为协变量包含在最终模型中。Monte Carlo 模拟表明，通过 II 每 6 小时 (q6h) 每日剂量 2 g 对金黄色葡萄球菌、大肠杆菌、广谱产 β-内酰胺酶 (ESBL) 的大肠杆菌和耐甲氧西林的金黄色葡萄球菌; 8 g 通过 CI 对抗凝固酶阴性葡萄球菌、肺炎克雷伯菌和产 ESBL肺炎克雷伯菌；CI 对铜绿假单胞菌12 g ；和 16 g 通过 CI 对抗产生 KPC 的肺炎克雷伯菌。我们的研究为在 OI 患者的几种临床情况下通过 CI 考虑每天 8 至 16 g 的磷霉素剂量提供了强有力的依据。在弹性体泵中通过 CI 给药的可行性使磷霉素成为 OPAT 计划的候选药物。