Population Density Modulates Drug Inhibition and Gives Rise to Potential Bistability of Treatment Outcomes for Bacterial Infections
Population Density Modulates Drug Inhibition and Gives Rise to Potential Bistability of Treatment Outcomes for Bacterial Infections
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DOI：
10.1371/journal.pcbi.1005098
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发表时间：
2016-10-01
影响因子：
4.3
通讯作者：
Wood, Kevin B.
中科院分区：
文献类型：
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作者：
Karslake, Jason;Maltas, Jeff;Wood, Kevin B.
接种物效应（IE）是抗生素的最低抑菌浓度（MIC）随微生物种群初始大小的增加而增加。IE已在广泛的细菌中观察到，这意味着抗生素疗效可能取决于种群密度。这种密度依赖性可能会对细菌种群动态和潜在的治疗策略产生巨大影响，但作为密度函数的人均增长的明确措施通常是不可用的。相反，IE测量MIC作为初始种群大小的函数，并且种群密度在实验的时间尺度上变化了许多数量级。因此，种群密度和抗生素抑制之间的函数关系通常是未知的，留下了许多关于IE对不同治疗策略的影响的问题没有答案。为了解决这些问题，在这里，我们使用多路计算机自动化培养装置直接测量了在固定人口密度下暴露于抗生素的粪肠球菌种群的实时人均增长。我们发现，密度依赖性生长抑制是普遍的常用抗生素，与一些药物显示出增加抑制和其他降低抑制在高密度。对于几种药物，密度依赖性是由细胞外pH值的变化介导的，这是一种以前与IE无关的社区水平现象。使用一个简单的数学模型，我们证明了这种密度依赖性如何在恒定的药物环境中调节种群动态。然后，我们说明了时间依赖性的剂量策略可以减轻密度依赖性的负面影响。最后，我们表明，这些密度效应导致抗生素治疗的药理学模型中的抗生素浓度范围广泛的治疗结果。因此，超过临界密度的感染通常在其他有效治疗中存活。
The inoculum effect (IE) is an increase in the minimum inhibitory concentration (MIC) of an antibiotic as a function of the initial size of a microbial population. The IE has been observed in a wide range of bacteria, implying that antibiotic efficacy may depend on population density. Such density dependence could have dramatic effects on bacterial population dynamics and potential treatment strategies, but explicit measures of per capita growth as a function of density are generally not available. Instead, the IE measures MIC as a function of initial population size, and population density changes by many orders of magnitude on the timescale of the experiment. Therefore, the functional relationship between population density and antibiotic inhibition is generally not known, leaving many questions about the impact of the IE on different treatment strategies unanswered. To address these questions, here we directly measured real-time per capita growth of Enterococcus faecalis populations exposed to antibiotic at fixed population densities using multiplexed computer-automated culture devices. We show that density-dependent growth inhibition is pervasive for commonly used antibiotics, with some drugs showing increased inhibition and others decreased inhibition at high densities. For several drugs, the density dependence is mediated by changes in extracellular pH, a community-level phenomenon not previously linked with the IE. Using a simple mathematical model, we demonstrate how this density dependence can modulate population dynamics in constant drug environments. Then, we illustrate how time-dependent dosing strategies can mitigate the negative effects of density-dependence. Finally, we show that these density effects lead to bistable treatment outcomes for a wide range of antibiotic concentrations in a pharmacological model of antibiotic treatment. As a result, infections exceeding a critical density often survive otherwise effective treatments.