To explore whether combined treatments with daptomycin and gentamicin can prevent the development of Staphylococcus aureus resistance, and whether the possible restriction is associated with changes in antibiotic mutant prevention concentrations (MPCs), the enrichment of daptomycin- and gentamicin-resistant mutants was studied by simulating 5-day single and combined treatments in an in vitro dynamic model. The MPCs of the antibiotics in the combination were determined at concentration ratios equal to the ratios of 24 h areas, under the concentration–time curve (AUCs) of the antibiotics, as simulated in pharmacodynamic experiments. The MPCs of both daptomycin and gentamicin decreased in the presence of each other; this led to an increase in the time when antibiotic concentrations were above the MPC (T_>MPC). The increases in T_>MPCs were concurrent with increases of the anti-mutant effects of the combined antibiotics. When anti-mutant effects of the antibiotics in single and combined treatments were plotted against the T_>MPCs, significant sigmoid relationships were obtained. These findings suggest that (1) daptomycin–gentamicin combinations prevent the development of S. aureus resistance to each antibiotic; (2) the anti-mutant effects of antibiotic combinations can be predicted using MPCs determined at pharmacokinetic-based antibiotic concentration ratios; (3) T_>MPC is a reliable predictor of the anti-mutant efficacy of antibiotic combinations.

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基于 MPC 的抗生素组合抗突变有效性预测：达托霉素和庆大霉素对金黄色葡萄球菌的体外模型研究

为了探讨达托霉素和庆大霉素联合治疗是否能阻止金黄色葡萄球菌耐药的发展，以及可能的限制是否与抗生素突变预防浓度（MPCs）的变化有关，通过模拟达托霉素和庆大霉素耐药突变体的富集进行了研究。体外动态模型中的 5 天单次和联合治疗。在药效学实验中模拟抗生素的浓度-时间曲线 (AUC) 下，以等于 24 小时面积比的浓度比确定组合中抗生素的 MPC。达托霉素和庆大霉素的MPCs在彼此存在下均降低；这导致抗生素浓度高于 MPC 的时间增加（T _{> MPC}）。在增加Ť _{> MPC}小号是同步用的联合应用抗生素的抗突变作用增加。当针对T _{> MPC}绘制抗生素在单一和联合治疗中的抗突变作用时，获得了显着的 sigmoid 关系。这些发现表明 (1) 达托霉素-庆大霉素组合可防止金黄色葡萄球菌对每种抗生素产生耐药性；(2) 可以使用基于药代动力学的抗生素浓度比确定的 MPC 来预测抗生素组合的抗突变作用；(3) T _{> MPC}是抗生素组合抗突变功效的可靠预测因子。