The Combination of Colistin and Doripenem Is Synergistic against Klebsiella pneumoniae at Multiple Inocula and Suppresses Colistin Resistance in an In Vitro Pharmacokinetic/Pharmacodynamic Model
The Combination of Colistin and Doripenem Is Synergistic against Klebsiella pneumoniae at Multiple Inocula and Suppresses Colistin Resistance in an In Vitro Pharmacokinetic/Pharmacodynamic Model
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DOI：
10.1128/aac.01064-12
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发表时间：
2012-10-01
影响因子：
4.9
通讯作者：
Nation, Roger L.
中科院分区：
文献类型：
--
作者：
Deris, Zakuan Z.;Yu, Heidi H.;Nation, Roger L.
耐多药（MDR）肺炎的克雷伯菌可能需要组合疗法。我们系统地研究了针对MDR K.肺炎的colistin和多甲基单元和组合疗法的细菌杀死，并杀死了肺炎的出现。在72小时内采用了两种接种物（类似于10（6），类似于10（8）CFU/mL），采用了一种体外药代动力学/药效学模型。 a colistin-heteroresistant reference strain (ATCC 13883) and three clinical isolates (colistin-susceptible FADDI-KP032 [doripenem resistant], colistin-heteroresistant FADDI-KP033, and colistin-resistant FADDI-KP035) were included.研究了利用临床上可实现的浓度的四种组合。通过确定对数的变化和种群分析曲线（对于结肠蛋白抗性的出现）在72小时内检查了微生物的反应。针对抗co菌素敏感和 - 倍耐分离株，结合蛋白的组合（恒定浓度方案为0.5或2 mg/升）加上多甲基（稳态峰浓度[C-max] 2.5或25 mg/升，8小时；半升生命，1.5 h）通常会导致两种incula的细菌杀死。对ATCC 13883，FADDI-KP032和FADDI-KP033在9、9和14例中的FADDI-KP032和FADDI-KP033（在16例中的16例（6、24、48和72 h）中的9个组合为10（6）-CFU// CFU/ ML接种物分别为10（8）-CFU/mL接种物，16例中的14例，11例和12例。最高剂量方案的组合导致在8例中的5例中，在72小时（2个分离物在2个接种物处）在72小时内产生了无法检测到的细菌计数。通过联合疗法，实际上消除了抗colistin敏感和 - 异常抗分离株中抗colis菌素亚群的出现。在低接种物中，对抗抗体蛋白耐药的分离蛋白，以2 mg/升和多叶甲（C-max，25 mg/升）的抗体，改善了细菌杀伤。该研究提供了优化colistin-甲基化学组合组合的重要信息。
Multidrug-resistant (MDR) Klebsiella pneumoniae may require combination therapy. We systematically investigated bacterial killing with colistin and doripenem mono- and combination therapy against MDR K. pneumoniae and emergence of colistin resistance. A one-compartment in vitro pharmacokinetic/pharmacodynamic model was employed over a 72-h period with two inocula (similar to 10(6) and similar to 10(8) CFU/ml); a colistin-heteroresistant reference strain (ATCC 13883) and three clinical isolates (colistin-susceptible FADDI-KP032 [doripenem resistant], colistin-heteroresistant FADDI-KP033, and colistin-resistant FADDI-KP035) were included. Four combinations utilizing clinically achievable concentrations were investigated. Microbiological responses were examined by determining log changes and population analysis profiles (for emergence of colistin resistance) over 72 h. Against colistin-susceptible and -heteroresistant isolates, combinations of colistin (constant concentration regimens of 0.5 or 2 mg/liter) plus doripenem (steady-state peak concentration [C-max] of 2.5 or 25 mg/liter over 8 h; half-life, 1.5 h) generally resulted in substantial improvements in bacterial killing at both inocula. Combinations were additive or synergistic against ATCC 13883, FADDI-KP032, and FADDI-KP033 in 9, 9, and 14 of 16 cases (4 combinations at 6, 24, 48, and 72 h) at the 10(6)-CFU/ml inoculum and 14, 11, and 12 of 16 cases at the 10(8)-CFU/ml inoculum, respectively. Combinations at the highest dosage regimens resulted in undetectable bacterial counts at 72 h in 5 of 8 cases (4 isolates at 2 inocula). Emergence of colistin-resistant subpopulations in colistin-susceptible and -heteroresistant isolates was virtually eliminated with combination therapy. Against the colistin-resistant isolate, colistin at 2 mg/liter plus doripenem (C-max, 25 mg/liter) at the low inoculum improved bacterial killing. This investigation provides important information for optimization of colistin-doripenem combinations.