The objective of this study was to assess the profile of a variety of dosing regimens for common intravenous antibiotics against contemporary Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa isolates collected in Canada during 2009, using pharmacodynamic modelling techniques. Monte Carlo simulation was conducted for standard and/or prolonged infusion regimens of cefepime, ceftazidime, ceftriaxone, ciprofloxacin, doripenem, ertapenem, meropenem and piperacillin/tazobactam. The cumulative fraction of response (CFR) was calculated using bactericidal targets for each regimen against each species. All cefepime, doripenem, ertapenem and meropenem regimens achieved optimal exposures against Enterobacteriaceae, whereas target attainment was organism and dose dependent for the other agents. These results support that the currently recommended antimicrobial dosing regimens generally attain acceptable exposures to achieve the requisite pharmacodynamic targets against the Enterobacteriaceae species; however, they fall short of obtaining optimal bactericidal exposures against P aeruginosa.BACKGROUND: With diminishing antimicrobial potency, the choice of effective empirical therapy has become more challenging. Thus, the pharmacodynamic evaluation of potential therapies is essential to identify optimal agents, doses and administration strategies.METHODS: Monte Carlo simulation was conducted for standard and/or prolonged infusion regimens of cefepime, ceftazidime, ceftriaxone, ciprofloxacin, doripenem, ertapenem, meropenem and piperacillin/tazobactam. Minimum inhibitory concentrations were obtained for Escherichia coli (n=64 respiratory isolates), Enterobacter cloacae (n=53), Klebsiella pneumoniae (n=75) and Pseudomonas aeruginosa (n=273) throughout Canada. The cumulative fraction of response (CFR) was calculated using bactericidal targets for each regimen against each species. A CFR ≥90% was defined as optimal.RESULTS: All cefepime, doripenem, ertapenem and meropenem regimens achieved optimal exposures against Enterobacteriaceae, whereas target attainment was organism and dose dependent for the other agents. Prolonged infusion doripenem and meropenem 1 g and 2 g every 8 h, along with standard infusion doripenem and meropenem 2 g every 8 h, were the only regimens to attain optimal exposures against P aeruginosa. Ciprofloxacin had the lowest CFR against P aeruginosa, followed by cefepime. Among the P aeruginosa isolates collected in the intensive care unit (ICU) compared with the wards, differences of 0.5% to 10% were noted in favour of non-ICU isolates for all agents; however, marked differences (10% to 15%) in CFR were observed for ciprofloxacin in favour of ICU isolates.CONCLUSION: Standard dosing of cefepime, doripenem, ertapenem and meropenem has a high likelihood of obtaining optimal pharmacodynamic indexes against these Enterobacteriaceae. For P aeruginosa, aggressive treatment with high-dose and/or prolonged infusion regimens are likely required to address the elevated resistance rates of respiratory isolates from Canada.

中文翻译：

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对来自加拿大医院的革兰氏阴性呼吸道分离株的抗菌药物的药效学分析。

这项研究的目的是评估针对当代阴沟肠杆菌、大肠杆菌、肺炎克雷伯菌和铜绿假单胞菌的常见静脉注射抗生素的各种给药方案的概况。2009 年在加拿大收集的分离株，使用药效学建模技术。对头孢吡肟、头孢他啶、头孢曲松、环丙沙星、多利培南、厄他培南、美罗培南和哌拉西林/他唑巴坦的标准和/或延长输注方案进行了蒙特卡罗模拟。使用针对每个物种的每个方案的杀菌目标计算响应的累积分数 (CFR)。所有头孢吡肟、多利培南、厄他培南和美罗培南方案均实现了对肠杆菌科细菌的最佳暴露，而其他药物的目标实现是生物体和剂量依赖性的。这些结果支持目前推荐的抗菌剂给药方案通常可以达到可接受的暴露量，以达到针对肠杆菌科物种所需的药效学目标；然而，铜绿假单胞菌 背景：随着抗菌效力的减弱，选择有效的经验疗法变得更具挑战性。因此，潜在疗法的药效学评估对于确定最佳药物、剂量和给药策略至关重要。 方法：对头孢吡肟、头孢他啶、头孢曲松、环丙沙星、多利培南、厄他培南、美罗培南和哌拉西林/他唑巴坦。获得了对大肠杆菌（n=64 呼吸道分离株）、阴沟肠杆菌（n=53）、肺炎克雷伯菌（n=75）和铜绿假单胞菌的最低抑菌浓度(n=273) 遍及加拿大。使用针对每个物种的每个方案的杀菌目标计算响应的累积分数 (CFR)。CFR ≥ 90% 被定义为最佳。结果：所有头孢吡肟、多利培南、厄他培南和美罗培南方案均实现了对肠杆菌科细菌的最佳暴露，而目标的实现与生物体和其他药物的剂量有关。延长输注多利培南和美罗培南每 8 小时 1 g 和 2 g，以及每 8 小时标准输注多利培南和美罗培南 2 g，是获得最佳铜绿假单胞菌暴露量的唯一方案。环丙沙星对铜绿假单胞菌的病死率最低，其次是头孢吡肟。在绿脓杆菌中在重症监护病房 (ICU) 收集的分离株与病房相比，注意到所有药物的非 ICU 分离株均存在 0.5% 至 10% 的差异；然而，观察到环丙沙星的 CFR 有显着差异（10% 至 15%），有利于 ICU 分离株。结论：头孢吡肟、多利培南、厄他培南和美罗培南的标准剂量极有可能获得针对这些肠杆菌科细菌的最佳药效学指标。对于铜绿假单胞菌，可能需要采用高剂量和/或延长输注方案进行积极治疗，以解决来自加拿大的呼吸道分离株耐药率升高的问题。