Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia.
Antimicrob Agents Chemother. 2013 Aug;57(8):3738-45. doi: 10.1128/AAC.00703-13. Epub 2013 May 28.
Combination therapy may be required for multidrug-resistant (MDR) Acinetobacter baumannii. This study systematically investigated bacterial killing and emergence of colistin resistance with colistin and rifampin combinations against MDR A. baumannii. Studies were conducted over 72 h in an in vitro pharmacokinetic (PK)/pharmacodynamic (PD) model at inocula of ~10(6) and ~10(8) CFU/ml using two MDR clinical isolates of A. baumannii, FADDI-AB030 (colistin susceptible) and FADDI-AB156 (colistin resistant). Three combination regimens achieving clinically relevant concentrations (constant colistin concentration of 0.5, 2, or 5 mg/liter and a rifampin maximum concentration [C(max)] of 5 mg/liter every 24 hours; half-life, 3 h) were investigated. Microbiological response was measured by serial bacterial counts. Population analysis profiles assessed emergence of colistin resistance. Against both isolates, combinations resulted in substantially greater killing at the low inoculum; combinations containing 2 and 5 mg/liter colistin increased killing at the high inoculum. Combinations were additive or synergistic at 6, 24, 48, and 72 h with all colistin concentrations against FADDI-AB030 and FADDI-AB156 in, respectively, 8 and 11 of 12 cases (i.e., all 3 combinations) at the 10(6)-CFU/ml inoculum and 8 and 7 of 8 cases with the 2- and 5-mg/liter colistin regimens at the 10(8)-CFU/ml inoculum. For FADDI-AB156, killing by the combination was ~2.5 to 7.5 and ~2.5 to 5 log(10) CFU/ml greater at the low inoculum (all colistin concentrations) and high inoculum (2 and 5 mg/liter colistin), respectively. Emergence of colistin-resistant subpopulations was completely suppressed in the colistin-susceptible isolate with all combinations at both inocula. Our study provides important information for optimizing colistin-rifampin combinations against colistin-susceptible and -resistant MDR A. baumannii.
联合治疗可能是多药耐药（MDR）鲍曼不动杆菌所必需的。本研究系统地研究了粘菌素和利福平联合治疗 MDR 鲍曼不动杆菌时的细菌杀菌作用和粘菌素耐药性的产生。在接种量约为 10(6) 和 10(8)CFU/ml 的体外药代动力学（PK）/药效动力学（PD）模型中，使用两种 MDR 临床分离株 FADDI-AB030（粘菌素敏感）和 FADDI-AB156（粘菌素耐药）进行了为期 72 小时的研究。研究了三种达到临床相关浓度的联合方案（固定粘菌素浓度为 0.5、2 或 5mg/L，利福平最大浓度[C(max)]为 5mg/L，每 24 小时一次；半衰期为 3 小时）。通过连续细菌计数测量微生物学反应。种群分析曲线评估了粘菌素耐药性的产生。对于两种分离株，在低接种量时联合治疗的杀菌效果显著提高；在高接种量时，含有 2 和 5mg/L 粘菌素的组合增加了杀菌效果。在 10(6)-CFU/ml 接种量时，所有 3 种联合方案在 12 例中的 8 例（即所有 3 种联合方案）中，在 6、24、48 和 72 小时时，在 FADDI-AB030 和 FADDI-AB156 中，所有 3 种联合方案的粘菌素浓度分别为 6、24、48 和 72 小时，在 10(8)-CFU/ml 接种量时，2mg/L 和 5mg/L 粘菌素方案的 8 例中的 7 例，组合具有相加或协同作用。对于 FADDI-AB156，在低接种量（所有粘菌素浓度）和高接种量（2 和 5mg/L 粘菌素）时，联合治疗的杀菌作用分别比单独使用粘菌素高约 2.5 至 7.5 和 2.5 至 5log(10)CFU/ml。在两种接种量下，所有组合均完全抑制了敏感分离株中粘菌素耐药亚群的产生。本研究为优化粘菌素-利福平联合治疗粘菌素敏感和耐药的多药耐药鲍曼不动杆菌提供了重要信息。
