What’s the Matter with MICs: Bacterial Nutrition, Limiting Resources, and Antibiotic Pharmacodynamics

Abstract

ABSTRACT 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 in vitro 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. IMPORTANCE 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.

Keywords

• antibiotics
• minimum inhibitory concentration
• pharmacodynamics
• population biology
• antibiotic resistance
• heteroresistance