Cheatham S Christian, Kays Michael B, Smith David W, Wack Matthew F, Sowinski Kevin M
Department of Pharmacy, St. Francis Hospital, Beech Grove, Indiana, USA.
Pharmacotherapy. 2008 Jun;28(6):691-8. doi: 10.1592/phco.28.6.691.
To evaluate the steady-state pharmacokinetics and pharmacodynamics of meropenem 500 mg every 6, 8, and 12 hours, based on renal function, in hospitalized patients.
Prospective, open-label, steady-state pharmacokinetic study.
One tertiary care medical center and one community hospital.
Twenty adult patients (12 men, 8 women) with suspected or documented bacterial infections requiring antimicrobial therapy.
Patients received 30-minute infusions of meropenem 500 mg every 6 hours (group 1), every 8 hours (group 2), or every 12 hours (group 3) based on estimated creatinine clearances greater than 60, 40-60, or 10-39 ml/minute, respectively.
Serial blood samples were collected after 2 or more days of therapy. Meropenem concentrations were determined by high-performance liquid chromatography, and pharmacokinetic data were analyzed by noncompartmental methods. Monte Carlo simulations (10,000 patients) were performed to calculate the cumulative fraction of response (CFR) for a percentage of the dosing interval that free drug concentrations remain above the minimum inhibitory concentration (fT>MIC) of 40% by using pharmacokinetic data for each group and MIC data for seven gram-negative pathogens from the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC, 2004-2005) database. Maximum and minimum serum concentrations (mean +/- SD) were 29.2+/-9.8 and 2.4+/-1.1 microg/ml, 33.2+/-8.5 and 3.8+/-2.7 microg/ml, and 33.5+/-4.7 and 4.9+/-1.6 microg/ml for groups 1, 2, and 3, respectively. The half-life values were 2.5+/-0.9, 3.4+/-1.3, and 6.1+/-1.4 hours, and the values for volume of distribution at steady state were 29.3+/-8.7, 23.8+/-8.1, and 28.7+/-8.6 L for groups 1, 2, and 3, respectively. For all three groups, the CFR was greater than 90% for the enteric pathogens and Pseudomonas aeruginosa and 82.4-85.2% for Acinetobacter species.
Pharmacodynamic analyses suggest that regimens of meropenem 500 mg every 6, 8, or 12 hours, adjusted for renal function, are acceptable for treatment of infections caused by enteric gram-negative pathogens and P. aeruginosa. However, more aggressive dosing or alternative dosing strategies may be necessary for Acinetobacter species.
评估住院患者中，根据肾功能每6、8和12小时静脉滴注500毫克美罗培南后的稳态药代动力学和药效学。
前瞻性、开放标签、稳态药代动力学研究。
一家三级医疗中心和一家社区医院。
20名成年患者（12名男性，8名女性），疑似或确诊细菌感染且需要抗菌治疗。
根据估计的肌酐清除率分别大于60、40 - 60或10 - 39毫升/分钟，患者分别接受每6小时（第1组）、每8小时（第2组）或每12小时（第3组）30分钟静脉滴注500毫克美罗培南。
治疗2天或更长时间后采集系列血样。通过高效液相色谱法测定美罗培南浓度，采用非房室模型方法分析药代动力学数据。利用每组的药代动力学数据和来自美罗培南年度药敏试验信息收集数据库（MYSTIC，2004 - 2005）中7种革兰氏阴性病原体的MIC数据，进行蒙特卡洛模拟（10,000例患者），计算当游离药物浓度在给药间隔的一定百分比（fT > MIC）保持高于最低抑菌浓度（MIC）40%时的累积反应分数（CFR）。第1、2和3组的血清最大和最小浓度（平均值±标准差）分别为29.2±9.8和2.4±1.1微克/毫升、33.2±8.5和3 .8±2.7微克/毫升、33.5±4.7和4.9±1.6微克/毫升。半衰期值分别为2.5±0.9、3.4±1.3和6.1±1.4小时，稳态分布容积值分别为29.3±8.7、23.8±8.1和28.7±8.6升。对于所有三组，肠道病原体和铜绿假单胞菌的CFR均大于90%，不动杆菌属的CFR为82.4 - 85.2%。
药效学分析表明，根据肾功能调整为每6、每8或每12小时静脉滴注500毫克美罗培南的方案，对于治疗肠道革兰氏阴性病原体和铜绿假单胞菌引起的感染是可接受的。然而，对于不动杆菌属感染，可能需要更积极的给药方案或替代给药策略。
