Department of Clinical Sciences and Administration, University of Houston College of Pharmacy, Houston, Texas, USA.
J Infect Dis. 2010 Mar 15;201(6):889-97. doi: 10.1086/651024.
Combination antimicrobial therapy is clinically used as a last-resort strategy to control multidrug-resistant bacterial infections. However, selection of antibiotics is often empirical, and conventional assessment of combined drug effect has not been correlated to clinical outcomes. Here, we report a quantitative method to assess combined killing of antimicrobial agents against 2 multidrug-resistant bacteria.
Combined time-kill studies were performed using clinically achievable concentrations for each 2-agent combination against clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa. Bacterial burden observed at 24 h was mathematically modeled using a 3-dimensional response surface. Subsequently, a neutropenic murine pneumonia model with simulated clinical dosing exposures was used to validate our quantitative assessment of combined killing.
Different antimicrobial combinations were found to have varying efficacy against the multidrug-resistant bacteria. As predicted by our quantitative method, cefepime plus amikacin was found to be the most superior combination, which was evidenced by a reduction in tissue bacterial burden and prolonged survival of infected animals.
The consistency between the predictions of the mathematical model and in vivo observations substantiated the robustness of our quantitative method. These data highlighted a novel and promising method to guide rational selection of antimicrobial combination in the clinical setting.
联合抗菌疗法临床上被用作控制多重耐药菌感染的最后手段。然而，抗生素的选择通常是经验性的，常规的联合药物效果评估与临床结果没有相关性。在这里，我们报告了一种评估抗菌药物对 2 种多重耐药菌联合杀伤作用的定量方法。
采用临床可达到的浓度，对鲍曼不动杆菌和铜绿假单胞菌的临床分离株进行联合时间杀伤研究。使用三维响应面数学模型对 24 小时观察到的细菌负荷进行建模。随后，使用模拟临床剂量暴露的中性粒细胞减少性肺炎小鼠模型验证我们对联合杀伤的定量评估。
不同的抗菌组合对多重耐药菌的疗效不同。正如我们的定量方法所预测的那样，头孢吡肟加阿米卡星是最有效的组合，这一点从组织细菌负荷的减少和感染动物存活时间的延长得到了证实。
数学模型的预测与体内观察结果的一致性证实了我们定量方法的稳健性。这些数据突出了一种新的有前途的方法，可以指导临床合理选择抗菌药物组合。
