Colistin and doripenem combinations against Pseudomonas aeruginosa: profiling the time course of synergistic killing and prevention of resistance
Colistin and doripenem combinations against Pseudomonas aeruginosa: profiling the time course of synergistic killing and prevention of resistance
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DOI：
10.1093/jac/dku567
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发表时间：
2015-05-01
影响因子：
5.2
通讯作者：
Tsuji, Brian T.
中科院分区：
文献类型：
--
作者：
Ly, Neang S.;Bulitta, Juergen B.;Tsuji, Brian T.
目的：粘菌素是一种“古老”的药物，由于治疗选择有限，正在越来越多地使用。然而，单药治疗期间出现的耐药性令人担忧。在这里，我们的目标是通过分析协同杀灭和预防耐药性的时间过程来优化针对铜绿假单胞菌的粘菌素组合。10天以上的中空纤维感染模型模拟了粘菌素和多利培南对两种异源耐药铜绿假单胞菌菌株（MIC 1 mg/L）和一种耐药（MIC 128 mg/L）菌株（接种物10（9.3）cfu/mL）的临床相关剂量方案。使用S-ADAPT.Results开发了新的基于数学机制的模型（MBMs）：针对异源耐药铜绿假单胞菌菌株，粘菌素单药治疗导致24 h内的初始杀灭（高达2.64 log（10）cfu/mL），随后再生长。高强度联合用药（包括游离稳态黏菌素浓度为5 mg/L）在48 h内达到完全根除（>9.3 log（10）杀灭）。与最有效的单药治疗相比，这些联合治疗可实现高达9.38 log（10）的协同作用。针对粘菌素耐药菌株，该组合产生了显著的初始协同作用，在72小时内细菌减少高达6.11 log（10）cfu/mL，随后再生长。MBMs量化的总和耐药亚群和建议之间的协同作用粘菌素和doripenem.Conclusions：我们的研究结果提供了最佳的抗生素治疗的见解，并可能作为一个框架，新的药物组合和组合建模。
Objectives: Colistin is an 'old' drug, which is being increasingly utilized due to limited therapeutic options. However, resistance emergence during monotherapy is concerning. Here, our objective was to optimize colistin combinations against Pseudomonas aeruginosa by profiling the time course of synergistic killing and prevention of resistance.Methods: Hollow-fibre infection models over 10 days simulated clinically relevant dosage regimens of colistin and doripenem against two heteroresistant P. aeruginosa strains (MIC 1 mg/L) and one resistant (MIC 128 mg/L) strain (inoculum 10(9.3) cfu/mL). New mathematical mechanism-based models (MBMs) were developed using S-ADAPT.Results: Against heteroresistant P. aeruginosa strains, colistin monotherapy resulted in initial killing (up to 2.64 log(10) cfu/mL) within 24 h followed by regrowth. High-intensity combinations involving free steady-state colistin concentrations of 5 mg/L achieved complete eradication (>9.3 log(10) killing) within 48 h. These combinations achieved synergy with up to 9.38 log(10) greater killing compared with the most active monotherapy. Against the colistin-resistant strain, the combination yielded marked initial synergy with up to 6.11 log(10) cfu/mL bacterial reductions within 72 h followed by regrowth. The MBMs quantified total and resistant subpopulations and the proposed synergy between colistin and doripenem.Conclusions: Our findings provide insight into optimal antibiotic treatment and may serve as a framework for new drug combinations and combination modelling.