Development and Qualification of a Pharmacodynamic Model for the Pronounced Inoculum Effect of Ceftazidime against Pseudomonas aeruginosa
Development and Qualification of a Pharmacodynamic Model for the Pronounced Inoculum Effect of Ceftazidime against Pseudomonas aeruginosa
复制标题
DOI：
10.1128/aac.00489-08
复制
发表时间：
2009-01-01
影响因子：
4.9
通讯作者：
Tsuji, Brian T.
中科院分区：
文献类型：
--
作者：
Bulitta, Juergen B.;Ly, Neang S.;Tsuji, Brian T.
越来越多的证据支持接种效应（即，在大量初始接种物[CFUo]下的缓慢杀灭）。我们的目标是（i）确定铜绿假单胞菌的CFU o对头孢他啶活性的影响，以及（ii）开发和验证适应一系列CFU o的药代动力学/药效学（PKPD）数学模型。使用高达128 mg/L（MIC，2 mg/L）的七种浓度的头孢他啶对铜绿假单胞菌PAO 1进行一式两份的时间-杀灭实验，其中5个CFU 0为105至109 CFU/ml。在24小时内采集样本，并通过NONMEM VI和S-ADAPT 1.55中的候选模型进行拟合（所有数据均为共建模）。外部模型确认整合了来自8项先前发表的研究的数据。头孢他啶在10（6.2）CFU o和4 mg/L（或更高）浓度下显示出约3至4 log（10）CFU/ml的净杀灭作用，在10（7.3）CFU o时杀灭作用小于1.6 log（10）CFU/ml，在10（8.0）CFU o时无杀灭作用，浓度高达128 mg/L。所提出的基于机理的模型成功地描述了接种效果和非浓度依赖性的杀伤滞后时间。平均世代时间为28.3分钟。假设自溶素的作用抑制成功复制。头孢他啶浓度为0.294毫克/升刺激自溶作用的50%。该模型在内部交叉验证中具有预测性，并且对于铜绿假单胞菌ATCC 27853的已发表研究的各种CFUo具有优异的计算机模拟预测性能。所提出的PKPD模型成功地描述和预测了头孢他啶在体外的显著接种效果，并整合了8项文献研究的数据，以支持从时间杀灭实验到体外感染模型的翻译。
Evidence is mounting in support of the inoculum effect (i.e., slow killing at large initial inocula [CFUo]) for numerous antimicrobials against a variety of pathogens. Our objectives were to (i) determine the impact of the CFUo of Pseudomonas aeruginosa on ceftazidime activity and (ii) to develop and validate a pharmacokinetic/pharmacodynamic (PKPD) mathematical model accommodating a range of CFUo. Time-kill experiments using ceftazidime at seven concentrations up to 128 mg/liter (MIC, 2 mg/liter) were performed in duplicate against P. aeruginosa PAO1 at five CFUo from 105 to 109 CFU/ml. Samples were collected over 24 h and fit by candidate models in NONMEM VI and S-ADAPT 1.55 (all data were comodeled). External model qualification integrated data from eight previously published studies. Ceftazidime displayed approximately 3 to 4 log(10) CFU/ml net killing at 10(6.2) CFUo and concentrations of 4 mg/liter (or higher), less than 1.6 log(10) CFU/ml killing at 10(7.3) CFUo, and no killing at 10(8.0) CFUo for concentrations up to 128 mg/liter. The proposed mechanism-based model successfully described the inoculum effect and the concentration-independent lag time of killing. The mean generation time was 28.3 min. The effect of an autolysin was assumed to inhibit successful replication. Ceftazidime concentrations of 0.294 mg/liter stimulated the autolysin effect by 50%. The model was predictive in the internal cross-validation and had excellent in silico predictive performance for published studies of P. aeruginosa ATCC 27853 for various CFUo. The proposed PKPD model successfully described and predicted the pronounced inoculum effect of ceftazidime in vitro and integrated data from eight literature studies to support translation from time-kill experiments to in vitro infection models.