Department of Pharmacy, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, USA.
Clin Ther. 2013 Jun;35(6):766-71. doi: 10.1016/j.clinthera.2013.05.004.
Treatment of Pseudomonas aeruginosa infections is increasingly challenging because of escalating resistance. Antimicrobial stewardship programs provide guidance for clinicians regarding use of the most appropriate antimicrobial at the right dose, duration, and route in addition to being cost-effective. Optimizing antimicrobial therapy by using pharmacokinetic/pharmacodynamic principles such as extending time above the MIC is 1 stewardship strategy to reduce antimicrobial resistance.
The goal of this study was to evaluate our current dosing strategy for cefepime and the formulary carbapenem (imipenem) compared with meropenem and doripenem to determine the best dosing strategy for achieving maximal pharmacodynamic activity against an institution-specific population of P aeruginosa isolates.
Consecutive, nonduplicate, blood (n = 39) or bronchial alveolar lavage (n = 25) isolates of P aeruginosa from adult, hospitalized (2009-2010) critically ill patients underwent MIC testing by using broth microdilution. A pharmacokinetic model was developed and used with Monte Carlo simulation to evaluate the ability of imipenem, meropenem, doripenem, and cefepime to achieve optimal bactericidal activity as varying doses infused over standard infusions (SIs; 0.5-1 hour) or prolonged infusions (PIs; 3-4 hours). A regimen was defined as optimal if the cumulative fraction response (CFR) was ≥90%.
None of the imipenem regimens modeled as SI or PI achieved a CFR ≥90%. Meropenem at 1 to 2 g q8h PI achieved a CFR ≥90%. Doripenem 0.5, 1, or 2 g q8h PI achieved a CFR ≥90%. The only cefepime regimen that achieved a CFR ≥90% was 2 g q8h PI. Overall susceptibility rates to P aeruginosa were highest with cefepime (91%), followed by meropenem (83%), doripenem (78%), and imipenem (72%). Our antimicrobial stewardship programs recommended switching from imipenem to doripenem 0.5g q8h PI, which was 36% more costly in drug acquisition costs. Cefepime dosing was increased from 2 g q12h SI to 2 g q8h PI, a 52% increase in drug acquisition cost.
Antimicrobial stewardship programs should consider pharmacodynamic modeling to select the optimal dosing strategies to guide therapy in an era of escalating antimicrobial resistance. Using the percent susceptibility alone can be misleading and ultimately the most expensive if the patient fails to respond.
由于耐药性不断上升，治疗铜绿假单胞菌感染的难度越来越大。抗菌药物管理计划为临床医生提供了指导，包括在成本效益的基础上，以适当的剂量、持续时间和途径使用最合适的抗菌药物。通过使用药代动力学/药效学原则（如延长高于 MIC 的时间）来优化抗菌药物治疗，是减少抗菌药物耐药性的一种管理策略。
本研究的目的是评估我们目前使用头孢吡肟和处方碳青霉烯类（亚胺培南）的剂量策略，并与美罗培南和多利培南进行比较，以确定实现针对特定机构铜绿假单胞菌分离株的最大药效活性的最佳剂量策略。
对 2009-2010 年住院的重症成年患者连续、非重复的血（n=39）或支气管肺泡灌洗液（n=25）铜绿假单胞菌分离株进行肉汤微量稀释法 MIC 检测。开发了一个药代动力学模型，并使用蒙特卡罗模拟来评估亚胺培南、美罗培南、多利培南和头孢吡肟在不同剂量输注（标准输注[SIs]；0.5-1 小时）或延长输注（PIs；3-4 小时）时达到最佳杀菌活性的能力。如果累积分数反应（CFR）≥90%，则定义为最佳方案。
没有一种亚胺培南的 SI 或 PI 方案达到 CFR≥90%。美罗培南 1 至 2 g q8h PI 达到 CFR≥90%。多利培南 0.5、1 或 2 g q8h PI 达到 CFR≥90%。唯一达到 CFR≥90%的头孢吡肟方案是 2 g q8h PI。对铜绿假单胞菌的总体敏感性率以头孢吡肟最高（91%），其次是美罗培南（83%）、多利培南（78%）和亚胺培南（72%）。我们的抗菌药物管理计划建议将用药从亚胺培南切换为多利培南 0.5g q8h PI，这将使药物获取成本增加 36%。头孢吡肟的剂量从 2 g q12h SI 增加到 2 g q8h PI，药物获取成本增加了 52%。
抗菌药物管理计划应考虑使用药效动力学模型来选择最佳的剂量策略，以在抗菌药物耐药性不断上升的时代指导治疗。仅使用药敏率可能会产生误导，并且如果患者治疗失败，最终的成本会最高。
