Cefiderocol, a Siderophore Cephalosporin for Gram-Negative Bacterial Infections: Pharmacokinetics and Safety in Subjects With Renal Impairment.
Cefiderocol, a Siderophore Cephalosporin for Gram-Negative Bacterial Infections: Pharmacokinetics and Safety in Subjects With Renal Impairment.
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DOI：
10.1002/jcph.841
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发表时间：
2017-05
影响因子：
2.9
通讯作者：
Galloway C
中科院分区：
文献类型：
--
作者：
Katsube T;Echols R;Arjona Ferreira JC;Krenz HK;Berg JK;Galloway C
头孢地考是一种新型注射用铁载体头孢菌素抗生素，对革兰氏阴性菌（包括多重耐药铜绿假单胞菌、鲍曼不动杆菌和肺炎克雷伯菌）具有良好的体外和体内活性。头孢地洛主要通过肾脏消除。在单次 1000 mg 静脉输注 1 小时头孢地罗后，评估了肾功能不全受试者中头孢地罗可的药代动力学和安全性。将患有轻度、中度或重度肾功能不全以及需要血液透析的终末期肾病（ESRD）的受试者与人口统计学（年龄、体重指数和性别）匹配的肾功能正常的健康受试者进行比较。还评估了血液透析对头孢地考清除率的影响。血浆总药物清除率 (CL) 和终末半衰期 (t1/2) 与肾功能相关。轻度、中度、重度和 ESRD 组与肾功能正常组相比，从 0 到无穷大的血浆浓度-时间曲线下面积 (AUC) 的比率（90% 置信区间）分别为 1.0（0.8-1.3）、1.5（1.2-1.9）、2.5（2.0-3.3）和 4.1（3.3-5.2）。肾功能不全组和肾功能正常组的最大血浆浓度（Cmax）相似。血液透析3至4小时可去除约60%的头孢地洛考。不同肾功能组之间的血浆蛋白未结合分数相似。不良事件的发生率似乎与肾功能损害的程度没有任何相关性。除 1 名因荨麻疹停药的受试者外，肾功能受损受试者一般对单次 1000 mg 静脉注射头孢地罗耐受性良好。总之，肾功能损害影响 AUC、CL 和 t1/2，但不影响 Cmax。间歇性血液透析可显着去除头孢地洛。
Cefiderocol, a new injectable siderophore cephalosporin antibiotic, has promising in vitro and in vivo activity against Gram‐negative bacteria including multidrug‐resistant Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. Cefiderocol is mainly renally eliminated. The pharmacokinetics and safety of cefiderocol in subjects with renal impairment were assessed following a single 1000‐mg intravenous 1‐hour infusion of cefiderocol. Subjects with mild, moderate, or severe renal impairment and end‐stage renal disease (ESRD) requiring hemodialysis were compared with demographically (age, body mass index, and sex) matched healthy subjects with normal renal function. The effect of hemodialysis on the clearance of cefiderocol was also assessed. Total drug clearance from plasma (CL) and terminal half‐life (t1/2) correlated with renal function. Ratios (90% confidence intervals) of area under the plasma concentration‐time curve from 0 to infinity (AUC) in mild, moderate, severe, and ESRD groups compared to those with normal renal function were 1.0 (0.8‐1.3), 1.5 (1.2‐1.9), 2.5 (2.0‐3.3), and 4.1 (3.3‐5.2), respectively. Maximum plasma concentration (Cmax) was similar between renal‐impairment groups and the normal‐renal‐function group. Approximately 60% of cefiderocol was removed by hemodialysis for 3 to 4 hours. The plasma‐protein‐unbound fraction was similar between various renal function groups. The incidence of adverse events did not appear to have any correlation with the degree of renal impairment. Single 1000‐mg intravenous doses of cefiderocol were generally well tolerated in subjects with impaired renal function except for 1 subject who discontinued due to urticaria. In conclusion, renal impairment impacted AUC, CL, and t1/2 without affecting Cmax. Cefiderocol was significantly removed by intermittent hemodialysis.