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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肺炎，血液感染/脓毒症或复杂的尿路感染患者中非肠道铁载体头孢菌素头孢地洛尔的群体药代动力学和药代动力学/药效学分析

头孢地洛尔是一种新型铁载体头孢菌素，对革兰氏阴性细菌（包括对碳青霉烯耐药的菌株）具有抗菌活性。肌酐清除率（CrCL）为60至119 ml / min的患者，头孢地洛尔的标准给药方案为每3小时每8小时注射2 g，并针对<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名感染性肺炎，血液感染/脓毒症（BSI / sepsis）和复杂尿路感染（cUTI）的3,427血浆浓度构建了群体药代动力学（PK）模型。群体头皮动物模型充分描述了血浆头孢地洛尔浓度，而CrCL是最显着的协变量。没有其他因素，包括感染部位和机械通气，尽管在人群PK分析中感染部位的影响被确定为统计学上显着的协变量，但与临床相关。没有发现任何微生物结果，临床结果或生命状态明确的药代动力学/药效关系。这是因为在给药间隔内游离血浆浓度超过最小抑菌浓度（MIC）的估计时间百分比（％在大多数患者中，f T _{> MIC}）为100％。对于肾功能正常的BSI /败血症患者（85％），所有感染部位和肾功能组的MIC≤4μg/ ml时，100％f T _{> MIC}的目标达到（PTA）的可能性均> 90％。这些研究结果表明，对于被感染的患者，包括肾功能增强，通气和/或重症患者，采用头孢地洛尔推荐的给药方案可实现足够的血浆暴露。