Gause Institute of New Antibiotics, Moscow, Russian Federation.
Mount Auburn Hospital, Harvard Medical School, Cambridge, MA, USA.
J Antibiot (Tokyo). 2018 May;71(5):514-521. doi: 10.1038/s41429-017-0016-9. Epub 2018 Jan 18.
To explore if the time inside the mutant selection window (T) is a reliable predictor of emergence of bacterial resistance to linezolid, mixed inocula of each of three methicillin-resistant Staphylococcus aureus strains (MIC of linezolid 2 μg ml) and their previously selected resistant mutants (MIC 8 μg ml) were exposed to linezolid pharmacokinetics using an in vitro dynamic model. In five-day treatments simulated over a wide range of the 24-h area under the concentration-time curve (AUC) to the MIC ratio, mutants resistant to 4 × MIC of antibiotic were enriched in a T-dependent manner. With each strain, T relationships with the area under the bacterial mutant concentration-time curve (AUBC) exhibited a hysteresis loop, with the upper portion corresponding to the time above the mutant prevention concentration (MPC; T) of 0 and the lower portion-to the T > 0. Using AUBC related to the maximal value observed with a given strain (normalized AUBC) at T > 0, a strain-independent sigmoid relationship was established between AUBC and T, as well as T (r 0.99 for both). AUC/MIC and AUC/MPC relationships with normalized AUBC for combined data on the three studied S. aureus strains were bell-shaped (r 0.85 and 0.80, respectively). These findings suggest that T at T > 0, T, AUC/MIC and AUC/MPC are useful bacterial strain-independent predictors of the emergence of staphylococcal resistance to linezolid.
为了探究突变选择窗（T）内的时间是否可以可靠地预测细菌对利奈唑胺产生耐药性，我们使用体外动态模型，将三种耐甲氧西林金黄色葡萄球菌（利奈唑胺的 MIC 为 2μg/ml）及其先前选择的耐药突变体（MIC 为 8μg/ml）的混合接种物暴露于利奈唑胺药代动力学中。在模拟的五天治疗过程中，我们考察了 24 小时内浓度-时间曲线下面积（AUC）与 MIC 比值的广泛范围，发现抗生素 4×MIC 的耐药突变体以 T 依赖性方式富集。对于每种菌株，与细菌突变体浓度-时间曲线下面积（AUBC）的 T 关系呈滞后环，上部分对应于突变预防浓度（MPC；T）以上的时间为 0，下部分对应于 T>0。使用 T>0 时与给定菌株相关的 AUBC 的最大值（归一化 AUBC），我们在 AUBC 与 T 之间以及 T 之间建立了一种与菌株无关的 S 形关系（两者的 r 值均为 0.99）。对于三种研究的金黄色葡萄球菌菌株的综合数据，AUC/MIC 和 AUC/MPC 与归一化 AUBC 的关系呈钟形（分别为 r 0.85 和 0.80）。这些发现表明，T>T>0 时、T、AUC/MIC 和 AUC/MPC 是预测金黄色葡萄球菌对利奈唑胺耐药性产生的有用的与菌株无关的预测因子。
