Cefiderocol is a novel siderophore cephalosporin with antibacterial activity against Gram-negative bacteria, including carbapenem-resistant strains. The standard dosing regimen of cefiderocol is 2 g administered every 8 hours over 3 hours infusion in patients with creatinine clearance (CrCL) of 60 to 119 ml/min, and it is adjusted for patients with <60 ml/min or ≥120 ml/min CrCL. A population pharmacokinetic (PK) model was constructed using 3,427 plasma concentrations from 91 uninfected subjects and 425 infected patients with pneumonia, bloodstream infection/sepsis (BSI/sepsis), and complicated urinary tract infection (cUTI). Plasma cefiderocol concentrations were adequately described by the population PK model, and CrCL was the most significant covariate. No other factors, including infection sites and mechanical ventilation, were clinically relevant, although the effect of infection sites was identified as a statistically significant covariate in the population PK analysis. No clear pharmacokinetic/pharmacodynamic relationship was found for any of the microbiological outcome, clinical outcome, or vital status. This is because the estimated percentage of time for which free plasma concentrations exceed the minimum inhibitory concentration (MIC) over dosing interval (%fT_>MIC) was 100% in most of the enrolled patients. The probability of target attainment (PTA) for 100% fT_>MIC was >90% against MICs of ≤4 μg/ml for all infection sites and renal function groups except for BSI/sepsis patients with normal renal function (85%). These study results support adequate plasma exposure can be achieved at the cefiderocol recommended dosing regimen for the infected patients, including the patients with augmented renal function, ventilation, and/or severe illness.

中文翻译：

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头孢菌素（一种肠外铁载体头孢菌素）在肺炎、血流感染/脓毒症或复杂性尿路感染患者中的群体药代动力学和药代动力学/药效学分析


Cefiderocol 是一种新型铁载体头孢菌素，对革兰氏阴性菌（包括碳青霉烯类耐药菌株）具有抗菌活性。肌酐清除率（CrCL）为 60 至 119 ml/min 的患者，头孢地罗考的标准给药方案为每 8 小时 2 g，输注时间为 3 小时，对于 <60 ml/min 或≥120 ml/min 的患者进行调整。最低 CrCL。使用来自 91 名未感染受试者和 425 名肺炎、血流感染/脓毒症 (BSI/脓毒症) 和复杂性尿路感染 (cUTI) 感染患者的 3,427 个血浆浓度构建了群体药代动力学 (PK) 模型。群体 PK 模型充分描述了血浆头孢地考浓度，CrCL 是最显着的协变量。尽管感染部位的影响在群体 PK 分析中被确定为具有统计学意义的协变量，但没有其他因素（包括感染部位和机械通气）具有临床相关性。对于任何微生物学结果、临床结果或生命状态，都没有发现明确的药代动力学/药效学关系。这是因为在大多数入组患者中，在给药间隔内游离血浆浓度超过最低抑菌浓度 (MIC) 的估计时间百分比 (% f T _>MIC ) 为 100%。对于所有感染部位和肾功能组，100% f T _>MIC的目标达到概率 (PTA) 为 >90%，而 MIC ≤ 4 μg/ml，肾功能正常的 BSI/脓毒症患者除外 (85%)。 这些研究结果支持感染患者（包括肾功能增强、通气和/或重症患者）采用头孢地罗推荐给药方案可以实现足够的血浆暴露。