University of Manitoba, Winnipeg, Canada.
J Antimicrob Chemother. 2011 Feb;66(2):343-9. doi: 10.1093/jac/dkq348. Epub 2010 Oct 5.
To evaluate, using Monte Carlo simulation, the pharmacodynamics (PD) of empirical antibiotic monotherapies for serious infections consistent with Canadian intensive care unit (ICU) surveillance data.
Meropenem, piperacillin/tazobactam and cefepime, along with ceftobiprole, a broad-spectrum cephalosporin active against methicillin-resistant Staphylococcus aureus (MRSA), were tested at standard and highest recommended doses with and without prolonged infusion times (t'). Population pharmacokinetic models were used to simulate antibiotic serum concentrations (n = 5000). Cumulative target attainment (CTA) at >50%, >75% and 100% fT( > MIC) (percentage of time free concentrations exceed the MIC) targets were determined based on ICU surveillance data including 4798 pathogens, most commonly methicillin-susceptible S. aureus (20.1%), Escherichia coli (15.2%) and Pseudomonas aeruginosa (12.3%).
With standard doses, ceftobiprole (500 mg every 8 h, t' 2 h) had 0.90 CTA at the >50% fT( > MIC) target while meropenem (1 g every 8 h, t' 0.5 h), piperacillin/tazobactam (3.375 g every 6 h, t' 0.5 h) and cefepime (2 g every 12 h, t' 0.5 h) reached >50% fT( > MIC) in 0.79-0.82 of the population (0.84-0.88 when MRSA was excluded). Piperacillin/tazobactam had the largest reduction in CTA at the >75% and 100% fT( > MIC) targets requiring prolonged infusions to maintain comparable PD. For all agents, prolonged infusions and/or high doses were required to achieve >0.9 CTA at the lowest target, to reach higher targets or to cover less susceptible pathogens such as P. aeruginosa.
This study provides important comparative data on empirical antibiotic monotherapies in an ICU setting including preliminary data on ceftobiprole. Ceftobiprole was most active overall, but similar to meropenem, piperacillin/tazobactam (lowest target only) and cefepime when MRSA was excluded. Prolonged infusions in particular and high doses were effective at improving antibiotic PD.
通过蒙特卡罗模拟评估符合加拿大重症监护病房（ICU）监测数据的严重感染经验性抗生素单药治疗的药效学（PD）。
在标准剂量和最高推荐剂量下，对美罗培南、哌拉西林/他唑巴坦和头孢吡肟以及对耐甲氧西林金黄色葡萄球菌（MRSA）有效的广谱头孢菌素头孢托罗进行了测试，并伴有或不伴有延长输注时间（t'）。使用群体药代动力学模型模拟抗生素血清浓度（n = 5000）。根据包括 4798 种病原体的 ICU 监测数据，包括主要为甲氧西林敏感金黄色葡萄球菌（20.1%）、大肠杆菌（15.2%）和铜绿假单胞菌（12.3%），确定了>50%、>75%和 100% fT（> MIC）（游离浓度超过 MIC 的时间百分比）目标的累积目标达标率（CTA）。
使用标准剂量时，头孢托罗（500 mg 每 8 小时，t' 2 小时）在>50% fT（> MIC）目标的 CTA 为 0.90，而美罗培南（1 g 每 8 小时，t' 0.5 小时）、哌拉西林/他唑巴坦（3.375 g 每 6 小时，t' 0.5 小时）和头孢吡肟（2 g 每 12 小时，t' 0.5 小时）在人群中达到>50% fT（> MIC）的比例为 0.79-0.82（当排除 MRSA 时为 0.84-0.88）。哌拉西林/他唑巴坦在>75%和 100% fT（> MIC）目标的 CTA 下降最大，需要延长输注时间以维持可比的 PD。对于所有药物，需要延长输注时间和/或增加剂量以在最低目标下达到>0.9 的 CTA，以达到更高的目标或覆盖对药物敏感性较低的病原体，如铜绿假单胞菌。
本研究提供了 ICU 环境下经验性抗生素单药治疗的重要比较数据，包括头孢托罗的初步数据。头孢托罗总体上最活跃，但在排除 MRSA 时与美罗培南、哌拉西林/他唑巴坦（仅最低目标）和头孢吡肟相似。延长输注时间，特别是增加剂量，可有效改善抗生素 PD。
