Lim Tze-Peng, Ledesma Kimberly R, Chang Kai-Tai, Hou Jing-Guo, Kwa Andrea L, Nikolaou Michael, Quinn John P, Prince Randall A, Tam Vincent H
Singapore General Hospital, Singapore, Singapore.
Antimicrob Agents Chemother. 2008 Aug;52(8):2898-904. doi: 10.1128/AAC.01309-07. Epub 2008 May 27.
Treatment of multidrug-resistant bacterial infections poses a therapeutic challenge to clinicians; combination therapy is often the only viable option for multidrug-resistant infections. A quantitative method was developed to assess the combined killing abilities of antimicrobial agents. Time-kill studies (TKS) were performed using a multidrug-resistant clinical isolate of Acinetobacter baumannii with escalating concentrations of cefepime (0 to 512 mg/liter), amikacin (0 to 256 mg/liter), and levofloxacin (0 to 64 mg/liter). The bacterial burden data in single and combined (two of the three agents with clinically achievable concentrations in serum) TKS at 24 h were mathematically modeled to provide an objective basis for comparing various antimicrobial agent combinations. Synergy and antagonism were defined as interaction indices of <1 and >1, respectively. A hollow-fiber infection model (HFIM) simulating various clinical (fluctuating concentrations over time) dosing exposures was used to selectively validate our quantitative assessment of the combined killing effect. Model fits in all single-agent TKS were satisfactory (r(2) > 0.97). An enhanced combined overall killing effect was seen in the cefepime-amikacin combination (interactive index, 0.698; 95% confidence interval [CI], 0.675 to 0.722) and the cefepime-levofloxacin combination (interactive index, 0.929; 95% CI, 0.903 to 0.956), but no significant difference in the combined overall killing effect for the levofloxacin-amikacin combination was observed (interactive index, 0.994; 95% CI, 0.982 to 1.005). These assessments were consistent with observations in HFIM validation studies. Our method could be used to objectively rank the combined killing activities of two antimicrobial agents when used together against a multidrug-resistant A. baumannii isolate. It may offer better insights into the effectiveness of various antimicrobial combinations and warrants further investigations.
耐多药细菌感染的治疗给临床医生带来了治疗挑战；联合治疗往往是耐多药感染唯一可行的选择。我们开发了一种定量方法来评估抗菌药物的联合杀菌能力。使用一株鲍曼不动杆菌临床耐多药分离株进行时间杀菌研究（TKS），头孢吡肟（浓度范围为0至512毫克/升）、阿米卡星（浓度范围为0至256毫克/升）和左氧氟沙星（浓度范围为0至64毫克/升）的浓度逐步升高。对单药及联合用药（三种药物中的两种，血清中浓度为临床可达到的浓度）24小时的细菌负荷数据进行数学建模，为比较各种抗菌药物组合提供客观依据。协同作用和拮抗作用分别定义为相互作用指数<1和>1。使用模拟各种临床（随时间波动的浓度）给药暴露的中空纤维感染模型（HFIM）来选择性验证我们对联合杀菌效果的定量评估。所有单药TKS的模型拟合均令人满意（r(2)>0.97）。头孢吡肟-阿米卡星组合（相互作用指数，0.698；95%置信区间[CI]，0.675至0.722）和头孢吡肟-左氧氟沙星组合（相互作用指数，0.929；95%CI，0.903至0.956）显示出增强的联合总体杀菌效果，但左氧氟沙星-阿米卡星组合的联合总体杀菌效果未观察到显著差异（相互作用指数，0.994；95%CI，0.982至1.005）。这些评估与HFIM验证研究中的观察结果一致。我们的方法可用于客观地对两种抗菌药物联合对抗耐多药鲍曼不动杆菌分离株时的联合杀菌活性进行排名。它可能为各种抗菌药物组合的有效性提供更好的见解，值得进一步研究。
