Department of Medicine, Mount Auburn Hospital, Harvard Medical School, 330 Mount Auburn St., Cambridge, Massachusetts 02138, USA.
Department of Pharmacokinetics & Pharmacodynamics, Gause Institute of New Antibiotics, Moscow, 119021, Russia.
Int J Antimicrob Agents. 2018 Dec;52(6):854-860. doi: 10.1016/j.ijantimicag.2018.09.005. Epub 2018 Sep 17.
To explore whether combinations of linezolid with gentamicin restrict Staphylococcus aureus resistance, the enrichment of resistant mutants was studied in an in vitro dynamic model. A clinical isolate S. aureus 10 and its linezolid-resistant mutant selected by passaging on antibiotic-containing media were used in the study. The minimum inhibitory concentration (MIC) and the mutant prevention concentration (MPC) of antibiotics in combination were determined at a linezolid-to-gentamicin concentration ratio corresponding to the ratio of 24-h areas under the concentration-time curve (AUCs) used in the pharmacokinetic simulations. Five-day treatments of S. aureus 10 supplemented with linezolid-resistant mutants (mutation frequency 10) with twice-daily linezolid and once-daily gentamicin, alone and in combination, were simulated at therapeutic and subtherapeutic AUCs. Numbers of linezolid-resistant mutants increased at both therapeutic and subtherapeutic AUCs, whereas gentamicin-resistant mutants were enriched only at the subtherapeutic AUC in single drug treatments. Linezolid-gentamicin combinations prevented the enrichment of linezolid-resistant S. aureus and restricted the enrichment of gentamicin-resistant mutants. The pronounced anti-mutant effect of the combinations was attributed to lengthening the time above MPC of both linezolid and gentamicin as their MPCs were lowered. Unlike resistant S. aureus, killing of the total bacterial burden exposed to linezolid-gentamicin combinations was less than in treatments with gentamicin alone, but greater than with linezolid alone. These findings indicate that (1) the anti-mutant effects of antibiotic combinations can be predicted by MPC determinations at pharmacokinetically-derived concentration ratios, and (2) a given antibiotic combination may be optimal against resistant but not susceptible subpopulations.
为了探索利奈唑胺与庆大霉素联合应用是否能抑制金黄色葡萄球菌耐药性的产生，我们在体外动态模型中研究了耐药突变株的富集情况。本研究使用临床分离的金黄色葡萄球菌 10 及其在含抗生素的培养基上传代选择的利奈唑胺耐药突变株。在与药代动力学模拟中使用的 24 小时浓度-时间曲线下面积（AUC）比值相对应的利奈唑胺-庆大霉素浓度比值下，测定联合用药的抗生素最小抑菌浓度（MIC）和突变选择窗浓度（MPC）。用每日两次利奈唑胺和每日一次庆大霉素对金黄色葡萄球菌 10 进行 5 天的补充治疗，单独和联合应用，模拟治疗和亚治疗 AUC 下的情况。在治疗和亚治疗 AUC 下，无论是单独应用还是联合应用，都能增加利奈唑胺耐药突变株的数量，而在单药治疗中，只有在亚治疗 AUC 下才会富集庆大霉素耐药突变株。利奈唑胺-庆大霉素联合用药可防止利奈唑胺耐药金黄色葡萄球菌的富集，并限制庆大霉素耐药突变株的富集。联合用药的显著抗突变作用归因于其 MPC 降低时，利奈唑胺和庆大霉素的 MPC 之上的时间延长。与耐甲氧西林金黄色葡萄球菌不同，暴露于利奈唑胺-庆大霉素联合用药的总细菌负荷的杀灭作用小于单独应用庆大霉素，但大于单独应用利奈唑胺。这些发现表明：（1）通过在药代动力学衍生的浓度比值下进行 MPC 测定，可以预测抗生素联合用药的抗突变作用；（2）对于耐药而非敏感的亚人群，联合应用特定的抗生素可能是最佳的。
