<i>Streptococcus pneumoniae</i> pneumonia in mice:: Optimal amoxicillin dosing predicted from a pharmacokinetic pharmacodynamic model

作     者：Moine, P Mazoit, JX 

作者机构：Univ Paris 11 Fac Med Kremlin Bicetre CHU Bicetre Dept Anesthesie ReanimatServ & Lab Anesthesie F-94275 Le Kremlin Bicetre France Ctr Hosp Univ Bichat Claude Bernard Contrat Rech Inst Natl Sante & Rech Med CRI 4U 00 Paris France 

出 版 物：《JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS》 (药理学与实验治疗学杂志)

年 卷 期：1999年第291卷第3期

页      面：1086-1092页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学] 

主　　题：阿莫西林/投药和剂量 阿莫西林/药代动力学 阿莫西林/治疗应用 剂量效应关系 药物 肺/代谢 肺/微生物学 微生物敏感性试验 模型 生物学 中性粒细胞减少/并发症 青霉素类/投药和剂量 青霉素类/药代动力学 青霉素类/治疗应用 肺炎球菌感染/药物疗法 肺炎球菌感染/代谢 链球菌 肺炎/药物作用 存活率分析 动物 小鼠 

摘      要：In an attempt to better understand the interaction of amoxicillin with Streptococcus pneumoniae in the lung, and to determine the parameters of therapeutic efficacy of the antimicrobial agent amoxicillin, we used a pharmacokinetic-pharmacodynamic model to describe the overall dose-effect relationship of amoxicillin against 12 strains of S. pneumoniae with penicillin minimum inhibitory concentrations ranging from 0.01 to 16 mu g/ml in a neutropenic murine pneumonia model. We were able to correlate amoxicillin dosing, pharmacokinetics, and the temporal changes in bacterial count in lung. Moreover, survival rates measured in one strain at different dosing were significantly related to the number of bacteria in lung calculated from the pharmacokinetic-pharmacodynamic model. Disappearance of amoxicillin from the effect compartment appeared to be very slow and the rate constant (k(e0)) governing this process was significantly different between strains, ranging from 0.00131 to 0.03945 h(-1). These findings have two major implications: 1) after a single dose of amoxicillin, bacterial counts in lung rapidly decreased and the bacterial growth remained suppressed during a long period of time after cessation of exposure of microorganisms to amoxicillin;and 2) the duration of bacterial growth suppression was related to the intrinsic properties of S. pneumoniae strains rather than to host environment because k(e0) was significantly different between strains. These two premises clearly demonstrate that bacterial growth suppression is related to an in vivo postantibiotic effect. Furthermore, we have shown that the major determinant of amoxicillin in vivo bactericidal activity and therapeutic efficacy appeared to be the dose of amoxicillin because amoxicillin exhibits a rapid dose-dependent killing regardless of the S. pneumoniae strain. Our findings may have implications for the clinical use of amoxicillin. In view of our results, the guidance to increase the amoxicillin-loading d