Pharmacodynamics of cefiderocol, a novel siderophore cephalosporin, in a Pseudomonas aeruginosa neutropenic murine thigh model
Pharmacodynamics of cefiderocol, a novel siderophore cephalosporin, in a Pseudomonas aeruginosa neutropenic murine thigh model
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DOI：
10.1016/j.ijantimicag.2017.10.008
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发表时间：
2018-02-01
影响因子：
10.8
通讯作者：
Nicolau, David P.
中科院分区：
文献类型：
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作者：
Ghazi, Islam M.;Monogue, Marguerite L.;Nicolau, David P.
头孢地洛是一种含铁载体头孢菌素，在体外对多药耐药(MDR)革兰氏阴性菌具有很强的活性。本研究旨在用剂量范围法描述头孢地洛在中性粒细胞减少的小鼠大腿感染模型中的药代动力学、药效学和24小时疗效。用8株铜绿假单胞菌[最低抑菌浓度0.063~0.5mgg/mL]感染中性粒细胞减少症小鼠(分别在接种前4天和1天注射环磷酰胺150 mg/kg和100 mg/kg)，这些菌株对先前测试的含铁载体的β-内酰胺类抗生素具有不同的体内活性。接种前3天给予5 mg/kg硝酸铀酰控制肾排泄。头孢地洛按8个递增剂量皮下注射[4.2~166.7 mg/kg，每8h 1次，q8h]。在药代动力学研究中，头孢地洛在受试剂量(4、100和250 mg/kg)中表现出相似的药代动力学特征，平均半衰期为0.86h，而在药效学研究中，初始剂量为4.2-166.7 mg/kg q8h时，24 h后CFU的变化范围为+3.4log(10)至-3.1log(10)。这8个分离株的剂量-反应曲线呈典型的S形，随着剂量的增加，CFU减少得更多。着眼于该化合物先前定义的疗效参数FT(>；MIC)(游离药物浓度超过MIC的时间)，停滞目标和减少1个对数(10)和2个对数(10)的目标分别为44.4-94.7、50.2-97.5和62.1-100。头孢地洛对这些耐多药铜绿假单胞菌显示出持续的抗菌作用。这些数据支持临床试验选用的头孢地洛剂量。(C)2017 Elsevier B.V.和国际化疗学会。版权所有。
Cefiderocol is a siderophore cephalosporin that displays potent in vitro activity against multidrug-resistant (MDR) Gram-negative bacteria. This study aimed to describe the pharmacokinetics, pharmacodynamics and 24-h efficacy of cefiderocol using dose-ranging methods in a neutropenic murine thigh infection model. Infection was established in neutropenic mice (administered cyclophosphamide 150 mg/kg and 100 mg/kg at 4 days and 1 day prior to inoculation, respectively) with eight Pseudomonas aeruginosa isolates [minimum inhibitory concentration (MIC) range 0.063-0.5 mu g/mL] that displayed variable in vivo activity against previously tested beta-lactams with siderophore moieties. Renal excretion was controlled by administration of 5 mg/kg uranyl nitrate 3 days prior to inoculation. Cefiderocol was administered subcutaneously in eight escalating doses [4.2-166.7 mg/kg every 8 h (q8h)]. In pharmacokinetic studies, cefiderocol manifested similar pharmacokinetics across tested doses (4, 100 and 250 mg/kg) with a mean half-life of 0.86 h. In pharmacodynamic studies, the change in CFU after 24 h from the initial inoculum ranged from +3.4 to -3.1 log(10) with doses of 4.2-166.7 mg/kg q8h. Dose-response curves for the eight isolates assumed the characteristic sigmoidal shape, with greater CFU reductions as the dose increased. Focusing on the previously defined efficacy parameter of fT (> MIC) (time that the free drug concentration exceeds the MIC) for this compound, targets for stasis and 1 log(10) and 2 log(10) reductions ranged from 44.4-94.7, 50.2-97.5 and 62.1-100, respectively. Cefiderocol displayed sustained antibacterial effects against these MDR P. aeruginosa isolates. These data support the cefiderocol dose selected for clinical trials. (c) 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.