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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Synergistic killing of multidrug-resistant Pseudomonas aeruginosa at multiple inocula by colistin combined with doripenem in an in vitro pharmacokinetic/pharmacodynamic model.
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Synergistic killing of multidrug-resistant Pseudomonas aeruginosa at multiple inocula by colistin combined with doripenem in an in vitro pharmacokinetic/pharmacodynamic model.

机译：在体外药代动力学/药效学模型中，大肠菌素与多利培南联合在多个接种物中协同杀死多药耐药的铜绿假单胞菌。

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Combination therapy may be required for multidrug-resistant (MDR) Pseudomonas aeruginosa. The aim of this study was to systematically investigate bacterial killing and emergence of colistin resistance with colistin and doripenem combinations against MDR P. aeruginosa. Studies were conducted in a one-compartment in vitro pharmacokinetic/pharmacodynamic model for 96 h at two inocula (~10(6) and ~10(8) CFU/ml) against a colistin-heteroresistant reference strain (ATCC 27853) and a colistin-resistant MDR clinical isolate (19147 n/m). Four combinations utilizing clinically achievable concentrations were investigated. Microbiological response was examined by log changes and population analysis profiles. Colistin (constant concentrations of 0.5 or 2 mg/liter) plus doripenem (peaks of 2.5 or 25 mg/liter every 8 h; half-life, 1.5 h) substantially increased bacterial killing against both strains at the low inoculum, while combinations containing colistin at 2 mg/liter increased activity against ATCC 27853 at the high inoculum; only colistin at 0.5 mg/liter plus doripenem at 2.5 mg/liter failed to improve activity against 19147 n/m at the high inoculum. Combinations were additive or synergistic against ATCC 27853 in 16 and 11 of 20 cases (4 combinations across 5 sample points) at the 10(6)- and 10(8)-CFU/ml inocula, respectively; the corresponding values for 19147 n/m were 16 and 9. Combinations containing doripenem at 25 mg/liter resulted in eradication of 19147 n/m at the low inoculum and substantial reductions in regrowth (including to below the limit of detection at approximately 50 h) at the high inoculum. Emergence of colistin-resistant subpopulations of ATCC 27853 was substantially reduced and delayed with combination therapy. This investigation provides important information for optimization of colistin-doripenem combinations.
机译：多重耐药性（MDR）铜绿假单胞菌可能需要联合治疗。这项研究的目的是系统地研究针对铜绿假单胞菌的大肠菌素和多烯培南组合的细菌杀灭和大肠菌素抗性的出现。在单室体外药代动力学/药效学模型中，针对大肠菌素-异抗性参考菌株（ATCC 27853）和大肠菌素，以两个接种量（〜10（6）和〜10（8）CFU / ml）进行96小时的研究。耐药的MDR临床分离株（19147 n / m）。研究了利用临床上可达到的浓度的四种组合。通过对数变化和种群分析概况检查了微生物反应。 Colistin（恒定浓度为0.5或2 mg / L）加多利培南（每8小时为2.5或25 mg / L峰值;半衰期为1.5 h）在低接种量下显着提高了对两种菌株的细菌杀灭率，而含有粘菌素在高接种量下，以2 mg / L的浓度对ATCC 27853的活性增加;在高接种量下，只有大肠菌素（0.5 mg / L）和多立培南（2.5 mg / L）不能提高针对19147 n / m的活性。分别在10（6）-和10（8）-CFU / ml接种量的20例病例中的16例和11例中（5个采样点有4种组合），组合与ATCC 27853有协同作用; 19147 n / m的相应值为16和9。含有25 mg /升多立培南的组合可在低接种量时根除19147 n / m，并显着减少再生长（包括在约50 h时降至检出限以下） ）在高接种量下。通过联合治疗，ATCC 27853的大肠菌素抗性亚群的出现显着减少并延迟。这项研究为优化大肠菌素-多利培南组合提供了重要信息。

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