Harvard Medical School; Department of Medicine, Mount Auburn Hospital, 330 Mount Auburn Street, Cambridge, MA 02138, USA.
Department of Pharmacokinetics & Pharmacodynamics, Gause Institute of New Antibiotics, 11 Bolshaya Pirogovskaya Street, Moscow 119021, Russia.
J Antimicrob Chemother. 2021 Jun 18;76(7):1832-1839. doi: 10.1093/jac/dkab095.
To explore whether linezolid/daptomycin combinations can restrict Staphylococcus aureus resistance and if this restriction is associated with changes in the mutant prevention concentrations (MPCs) of the antibiotics in combination, the enrichment of resistant mutants was studied in an in vitro dynamic model.
Two MRSA strains, vancomycin-intermediate resistant ATCC 700699 and vancomycin-susceptible 2061 (both susceptible to linezolid and daptomycin), and their linezolid-resistant mutants selected by passaging on antibiotic-containing medium were used in the study. MPCs of antibiotics in combination were determined at a linezolid-to-daptomycin concentration ratio (1:2) that corresponds to the ratio of 24 h AUCs (AUC24s) actually used in the pharmacokinetic simulations. Each S. aureus strain was supplemented with respective linezolid-resistant mutants (mutation frequency 10-8) and treated with twice-daily linezolid and once-daily daptomycin, alone and in combination, simulated at therapeutic and sub-therapeutic AUC24s.
Numbers of linezolid-resistant mutants increased at therapeutic and sub-therapeutic AUC24s, whereas daptomycin-resistant mutants were enriched only at sub-therapeutic AUC24 in single drug treatments. Linezolid/daptomycin combinations prevented the enrichment of linezolid-resistant S. aureus and restricted the enrichment of daptomycin-resistant mutants. The pronounced anti-mutant effects of the combinations were attributed to lengthening the time above MPC of both linezolid and daptomycin as their MPCs were lowered.
The present study suggests that (i) the inhibition of S. aureus resistant mutants using linezolid/daptomycin combinations can be predicted by MPCs determined at pharmacokinetically derived antibiotic concentration ratios and (ii) T>MPC is a reliable predictor of the anti-mutant efficacy of antibiotic combinations as studied using in vitro dynamic models.
探讨利奈唑胺/达托霉素联合用药是否能抑制金黄色葡萄球菌耐药性的产生，如果能，这种抑制作用是否与联合用药时抗生素的突变预防浓度（MPC）变化有关，本研究采用体外动态模型研究了耐药突变体的富集情况。
本研究使用了耐万古霉素中介的 ATCC 700699 和万古霉素敏感的 2061 （两者均对利奈唑胺和达托霉素敏感）两种 MRSA 菌株及其通过在含抗生素培养基上传代选择的利奈唑胺耐药突变体。联合用药时抗生素的 MPC 是根据药代动力学模拟中实际使用的 24 小时 AUC（AUC24）比值来确定的，利奈唑胺与达托霉素的浓度比为 1:2。在治疗和亚治疗 AUC24 时，每种金黄色葡萄球菌菌株均添加相应的利奈唑胺耐药突变体（突变频率为 10-8），单独及联合使用每日两次利奈唑胺和每日一次达托霉素进行治疗。
在治疗和亚治疗 AUC24 时，利奈唑胺耐药突变体的数量增加，而在单药治疗时，仅在亚治疗 AUC24 时才富集达托霉素耐药突变体。利奈唑胺/达托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，并限制达托霉素耐药突变体的富集。联合用药的明显抗突变作用归因于延长了利奈唑胺和达托霉素的 MPC 时间，因为它们的 MPC 降低了。
本研究表明：（i）通过在药代动力学衍生的抗生素浓度比值下确定 MPC 可预测利奈唑胺/达托霉素联合用药抑制金黄色葡萄球菌耐药突变体的效果；（ii）在体外动态模型研究中，T>MPC 是抗生素联合用药抗突变疗效的可靠预测指标。
