College of Bioscience and Bioengineering, Jiangxi Agricultural University, Nanchang, 330045, China.
Affiliated Hospital, Jiangxi Agricultural University, Nanchang, 330045, China.
Sci Rep. 2018 May 8;8(1):7237. doi: 10.1038/s41598-018-25714-z.
Antimicrobial resistance seriously threatened human health. Combination therapy is generally an effective strategy to fight resistance, while some data on its effects are conflicting. To explore the reasons, the fractional inhibitory concentration indexes (FICIs) of three designed combinations against methicillin-resistant Staphylococcus aureus (MRSA) were determined using checkerboard method, and their minimal concentrations inhibiting colony formation by 99% (MICs) and mutant prevention concentrations (MPCs) alone or in combinations including different proportions were first determined using agar plates. The results indicated that different proportions of a combination had presented different MPCs and mutant selection window (MSWs), and also showed that the smaller the FICIs of two agents in combinations were, the more probable their MSWs were to close each other. As two agents of a combination had different pharmacokinetic characters, the ratios of two agents in blood and infectious sites were likely different even though a specific proportion was administrated, which would lead to different effects preventing resistance. Thereby, these experimental results theoretically indicated that synergistic combination closing each other's MSWs had a great potency to prevent resistance according to the hypotheses of MSW and MPC, and deduced that in vivo synergistic validity of a combination was likely a key to prevent resistance. Moreover, a synergistic combination of roxithromycin/doxycycline with the FICIs of 0.26-0.50 and 0.28-0.38 respectively against MRSA 01 and 02 was obtained, and the MSWs of these two agents could be simultaneously closed each other in a certain range of proportions, but for others. Meanwhile, its effect preventing resistance needs to be further verified.
抗菌药物耐药性严重威胁人类健康。联合治疗通常是对抗耐药性的有效策略，但关于其效果的一些数据存在冲突。为了探究原因，采用棋盘法测定了三种设计组合对耐甲氧西林金黄色葡萄球菌（MRSA）的部分抑制浓度指数（FICI），并首次采用琼脂平板法测定了单独或不同比例组合中三种设计组合对 99%菌落形成的最小浓度（MICs）和突变预防浓度（MPCs）。结果表明，不同比例的组合具有不同的 MPC 和突变选择窗（MSW），且组合中两种药物的 FICI 越小，其 MSW 越有可能相互接近。由于两种药物具有不同的药代动力学特征，即使给予特定比例，血液和感染部位的两种药物的比例也可能不同，从而导致预防耐药性的效果不同。因此，这些实验结果从 MSW 和 MPC 的假设理论上表明，相互接近 MSW 的协同组合具有很大的抗耐药潜力，并推断出组合在体内的协同有效性可能是预防耐药的关键。此外，还获得了罗红霉素/强力霉素对 MRSA01 和 02 的 FICI 分别为 0.26-0.50 和 0.28-0.38 的协同组合，这两种药物的 MSW 可以在一定比例范围内相互接近，但对于其他比例则不行。同时，其预防耐药性的效果还需要进一步验证。
