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Density-dependent selection, which promotes contrasting patterns of trait means at different population densities, has a long history in population genetics and ecology. The unifying principle from theory is that density-dependent selection operates on phenotypic traits whose values counter the effects of whatever ecological agent is limiting population growth, be it resource competition, predators, or pathogens. However, the complexity inherent in density dependence means that the same selective process can generate multiple outcomes, depending upon the details of how population density affects vital rates and the age or size structure of a population. Failure to appreciate the potential for multiple outcomes confounded many early studies of the process. Nonetheless, careful empirical work in laboratory studies, long-term field studies, and studies of sexual selection demonstrates the wide reach of density-dependent selection. The inconsistent outcomes observed in these studies call for renewed research into how the details of density dependence channel adaptive responses.
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Population Density Modulates Drug Inhibition and Gives Rise to Potential Bistability of Treatment Outcomes for Bacterial Infections
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.
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- Award ID(s):
- 1553028
- PAR ID:
- 10023242
- Date Published:
- Journal Name:
- PLOS computational biology
- Volume:
- 12
- Issue:
- 10
- ISSN:
- 1553-7358
- Page Range / eLocation ID:
- e1005098
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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