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Evolutionary epidemiology of drug-resistance in space.

ABSTRACT: How can we optimize the use of drugs against parasites to limit the evolution of drug resistance? This question has been addressed by many theoretical studies focusing either on the mixing of various treatments, or their temporal alternation. Here we consider a different treatment strategy where the use of the drug may vary in space to prevent the rise of drug-resistance. We analyze epidemiological models where drug-resistant and drug-sensitive parasites compete in a one-dimensional spatially heterogeneous environment. Two different parasite life-cycles are considered: (i) direct transmission between hosts, and (ii) vector-borne transmission. In both cases we find a critical size of the treated area, under which the drug-resistant strain cannot persist. This critical size depends on the basic reproductive ratios of each strain in each environment, on the ranges of dispersal, and on the duration of an infection with drug-resistant parasites. We discuss optimal treatment strategies that limit disease prevalence and the evolution of drug-resistance.

SUBMITTER: Debarre F

PROVIDER: S-EPMC2658742 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Evolutionary epidemiology of drug-resistance in space.

Débarre Florence F Lenormand Thomas T Gandon Sylvain S

PLoS computational biology 20090403 4

How can we optimize the use of drugs against parasites to limit the evolution of drug resistance? This question has been addressed by many theoretical studies focusing either on the mixing of various treatments, or their temporal alternation. Here we consider a different treatment strategy where the use of the drug may vary in space to prevent the rise of drug-resistance. We analyze epidemiological models where drug-resistant and drug-sensitive parasites compete in a one-dimensional spatially he ...[more]

PMID: 19343211

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Project description:The emergence of drug resistant pathogens is a serious public health problem. It is a long-standing goal to predict rates of resistance evolution and design optimal treatment strategies accordingly. To this end, it is crucial to reveal the underlying causes of drug-specific differences in the evolutionary dynamics leading to resistance. However, it remains largely unknown why the rates of resistance evolution via spontaneous mutations and the diversity of mutational paths vary substantially between drugs. Here we comprehensively quantify the distribution of fitness effects (DFE) of mutations, a key determinant of evolutionary dynamics, in the presence of eight antibiotics representing the main modes of action. Using precise high-throughput fitness measurements for genome-wide Escherichia coli gene deletion strains, we find that the width of the DFE varies dramatically between antibiotics and, contrary to conventional wisdom, for some drugs the DFE width is lower than in the absence of stress. We show that this previously underappreciated divergence in DFE width among antibiotics is largely caused by their distinct drug-specific dose-response characteristics. Unlike the DFE, the magnitude of the changes in tolerated drug concentration resulting from genome-wide mutations is similar for most drugs but exceptionally small for the antibiotic nitrofurantoin, i.e., mutations generally have considerably smaller resistance effects for nitrofurantoin than for other drugs. A population genetics model predicts that resistance evolution for drugs with this property is severely limited and confined to reproducible mutational paths. We tested this prediction in laboratory evolution experiments using the "morbidostat", a device for evolving bacteria in well-controlled drug environments. Nitrofurantoin resistance indeed evolved extremely slowly via reproducible mutations-an almost paradoxical behavior since this drug causes DNA damage and increases the mutation rate. Overall, we identified novel quantitative characteristics of the evolutionary landscape that provide the conceptual foundation for predicting the dynamics of drug resistance evolution.

Dataset Information

Evolutionary epidemiology of drug-resistance in space.

Publications

Evolutionary epidemiology of drug-resistance in space.

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