The Effects of Population Density on Antibiotic Efficacy in E. Faecalis

Abstract

Resistance to current antibiotics is a major public health issue in the United States and around the world. A better understanding of the complex relationship between the dynamics of bacterial populations and the response of these populations to antibiotics is crucial for mitigating the rapid decline in antibiotic efficacy. While significant research has focused on the molecular mechanisms of antibiotic resistance, relatively little work has addressed the population-level dynamics that arise from interactions between cells. One of the classic manifestations of such community-wide behavior is the inoculum effect, where the starting size of a cell population modulates the efficacy of some antibiotics, with larger inoculums exhibiting higher drug tolerance. The inoculum effect suggests that there is a relationship between bacterial population density and drug efficacy. However, traditional measurements of the inoculum effect are unable to provide an explicit measure of this density-dependence because cell density is itself changing throughout the experiments. As a result, there is debate about the magnitude of the effect, and it is typically ignored in clinical management of infections. Here, we examine the effect of density on drug inhibitory effects through the use of a continuous culture device designed to control cellular population densities. We are able to quantify the effect of density on several classes of important antibiotics. Further, we also investigate possible general mechanisms behind this effect, and determine using mathematical models the how density affect the dynamics of growing populations exposed to antibiotics.