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Understanding how changes in antibiotic consumption affect the prevalence of antibiotic resistance in bacterial pathogens is important for public health. In a number of bacterial species, including Streptococcus pneumoniae, the prevalence of resistance has remained relatively stable despite prolonged selection pressure from antibiotics. The evolutionary processes allowing the robust coexistence of antibiotic sensitive and resistant strains are not fully understood. While allelic diversity can be maintained at a locus by direct balancing selection, there is no evidence for such selection acting in the case of resistance. In this work, we propose a mechanism for maintaining coexistence at the resistance locus: linkage to a second locus that is under balancing selection and that modulates the fitness effect of resistance. We show that duration of carriage plays such a role, with long duration of carriage increasing the fitness advantage gained from resistance. We therefore predict that resistance will be more common in strains with a long duration of carriage and that mechanisms maintaining diversity in duration of carriage will also maintain diversity in antibiotic resistance. We test these predictions in S. pneumoniae and find that the duration of carriage of a serotype is indeed positively correlated with the prevalence of resistance in that serotype. These findings suggest heterogeneity in duration of carriage is a partial explanation for the coexistence of sensitive and resistant strains and that factors determining bacterial duration of carriage will also affect the prevalence of resistance.

Original publication

DOI

10.1073/pnas.1617849114

Type

Journal article

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Date

17/01/2017

Volume

114

Pages

1075 - 1080

Addresses

Oxford Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7LF United Kingdom; s.lehtinen@imperial.ac.uk.

Keywords

Humans, Streptococcus pneumoniae, Pneumococcal Infections, Carrier State, Drug Resistance, Microbial, Epistasis, Genetic, Linkage Disequilibrium, Models, Genetic, Time Factors, Selection, Genetic, Serogroup