title: Evolution of antibiotic resistance is linked to any genetic mechanism affecting bacterial duration of carriage.
abstract: 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.
authors.affiliation: Oxford Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7LF United Kingdom; s.lehtinen@imperial.ac.uk.|Department of Infectious Disease Epidemiology, Imperial College London, London W2 1PG United Kingdom.
authors.forename: Sonja
authors.initials: S
authors.lastname: Lehtinen
authors.affiliation: Department of Infectious Disease Epidemiology, Imperial College London, London W2 1PG United Kingdom.
authors.forename: François
authors.initials: F
authors.lastname: Blanquart
authors.affiliation: Department of Infectious Disease Epidemiology, Imperial College London, London W2 1PG United Kingdom.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Croucher
authors.affiliation: Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot 63110, Thailand.|Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Turner
authors.affiliation: Center for Communicable Disease Dynamics, Harvard T. H. Chan School of Public Health, Boston, MA 02115.|Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA 02115.|Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115.
authors.forename: Marc
authors.initials: M
authors.lastname: Lipsitch
authors.affiliation: Oxford Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7LF United Kingdom.
authors.forename: Christophe
authors.initials: C
authors.lastname: Fraser
mesh_terms: D002353:Carrier State / Q000382:microbiology*; D004352:Drug Resistance, Microbial / Q000235:genetics*; D004843:Epistasis, Genetic; D006801:Humans; D015810:Linkage Disequilibrium; D008957:Models, Genetic; D011008:Pneumococcal Infections / Q000382:microbiology*; D012641:Selection, Genetic; D065288:Serogroup; D013296:Streptococcus pneumoniae / Q000145:classification / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D013997:Time Factors
keywords: Streptococcus pneumoniae; antibiotic resistance; coexistence; epistasis; multistrain model