Department of Biology, Emory University, Atlanta, Georgia, USA.
Program in Microbiology and Molecular Genetics, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University, Atlanta, Georgia, USA.
Microbiol Spectr. 2023 Jun 15;11(3):e0409122. doi: 10.1128/spectrum.04091-22. Epub 2023 May 3.
The MIC of an antibiotic required to prevent replication is used both as a measure of the susceptibility/resistance of bacteria to that drug and as the single pharmacodynamic parameter for the rational design of antibiotic treatment regimes. MICs are experimentally estimated under conditions optimal for the action of the antibiotic. However, bacteria rarely grow in these optimal conditions. Using a mathematical model of the pharmacodynamics of antibiotics, we make predictions about the nutrient dependency of bacterial growth in the presence of antibiotics. We test these predictions with experiments in broth and a glucose-limited minimal media with Escherichia coli and eight different antibiotics. Our experiments question the sufficiency of using MICs and simple pharmacodynamic functions as measures of the pharmacodynamics of antibiotics under the nutritional conditions of infected tissues. To an extent that varies among drugs: (i) the estimated MICs obtained in rich media are greater than those estimated in minimal media; (ii) exposure to these drugs increases the time before logarithmic growth starts, their lag; and (iii) the stationary-phase density of E. coli populations declines with greater sub-MIC antibiotic concentrations. We postulate a mechanism to account for the relationship between sub-MICs of antibiotics and these growth parameters. This study is limited to a single bacterial strain and two types of culture media with different nutritive content. These limitations aside, the results of our study clearly question the use of MIC as the unique pharmacodynamic parameter to develop therapeutically oriented protocols. For studies of antibiotics and how they work, the most-often used measurement of drug efficacy is the MIC. The MIC is the concentration of an antibiotic needed to inhibit bacterial growth. This parameter is critical to the design and implementation of antibiotic therapy. We provide evidence that the use of MIC as the sole measurement for antibiotic efficacy ignores important aspects of bacterial growth dynamics. Before now, there has not been a nexus between bacteria, the conditions in which they grow, and the MIC. Most importantly, few studies have considered sub-MICs of antibiotics, despite their clinical importance. Here, we explore these concentrations in-depth, and we demonstrate MIC to be an incomplete measure of how an infection will interact with a specific antibiotic. Understanding the critiques of MIC is the first of many steps needed to improve infectious disease treatment.
抗生素的 MIC 用于预防复制，既是衡量细菌对该药物敏感性/耐药性的指标，也是抗生素治疗方案合理设计的唯一药效学参数。MIC 是在抗生素作用的最佳条件下通过实验估计的。然而，细菌很少在这些最佳条件下生长。我们使用抗生素药效学的数学模型来预测在抗生素存在下细菌生长的营养依赖性。我们用大肠杆菌和八种不同抗生素在肉汤和葡萄糖限制的最小培养基中的实验来检验这些预测。我们的实验质疑了在感染组织的营养条件下，使用 MIC 和简单的药效学函数作为抗生素药效学的衡量标准的充分性。在不同程度上：（i）在丰富的培养基中获得的估计 MIC 大于在最小培养基中估计的 MIC；（ii）暴露于这些药物会增加对数生长开始之前的时间，即其滞后时间；（iii）在更高的亚 MIC 抗生素浓度下，大肠杆菌种群的静止期密度下降。我们提出了一个机制来解释抗生素的亚 MIC 与这些生长参数之间的关系。这项研究仅限于单一的细菌菌株和两种具有不同营养含量的培养介质。除了这些限制，我们研究的结果清楚地质疑了将 MIC 作为唯一药效学参数来制定治疗导向方案的用途。对于抗生素及其作用的研究，最常用的药物疗效测量是 MIC。MIC 是抑制细菌生长所需的抗生素浓度。该参数对于抗生素治疗的设计和实施至关重要。我们提供的证据表明，将 MIC 作为抗生素疗效的唯一测量值忽略了细菌生长动力学的重要方面。到目前为止，还没有将细菌、它们生长的条件和 MIC 联系起来。最重要的是，尽管亚 MIC 具有临床重要性，但很少有研究考虑过抗生素的亚 MIC。在这里，我们深入研究这些浓度，并证明 MIC 是衡量感染与特定抗生素相互作用的不完整指标。了解 MIC 的批评意见是改善传染病治疗的许多步骤中的第一步。
