title: Fitness Costs of Drug Resistance Mutations in Multidrug-Resistant Mycobacterium tuberculosis: A Household-Based Case-Control Study.
abstract: BACKGROUND
  The projected long-term prevalence of multidrug-resistant (MDR) tuberculosis depends upon the relative fitness of MDR Mycobacterium tuberculosis strains, compared with non-MDR strains. While many experimental models have tested the in vitro or in vivo fitness costs of various drug resistance mutations, fewer epidemiologic studies have attempted to validate these experimental findings.
  
  
  METHODS
  We performed a case-control study comparing drug resistance-associated mutations from MDR M. tuberculosis strains causing multiple cases in a household to matched MDR strains without evidence of secondary household cases.
  
  
  RESULTS
  Eighty-eight multiple-case and 88 single-case household MDR strains were analyzed for 10 specific drug resistance-associated polymorphisms previously associated with fitness effects. We found that the isoniazid-resistant katG Ser315Thr mutation occurred more than twice as frequently in multiple-case households than in single-case households (odds ratio [OR], 2.39; 95% confidence interval [CI], 1.21-4.70), corroborating previous experimental findings. However, strains carrying both the katG Ser315Thr mutation and the rpsL Lys43Arg mutation were less likely to be found in multiple-case households (OR, 0.09; 95% CI, .01-.73), suggesting a negative epistatic interaction which contrasts previous findings.
  
  
  CONCLUSIONS
  The case-control design presents a useful approach for assessing in vivo fitness effects of drug resistance mutations.
authors.affiliation: Department of Epidemiology, Harvard School of Public Health Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Phillip P
authors.initials: PP
authors.lastname: Salvatore
authors.affiliation: Department of Global Health and Social Medicine, Harvard Medical School.
authors.forename: Mercedes C
authors.initials: MC
authors.lastname: Becerra
authors.affiliation: Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut.
authors.forename: Pia
authors.initials: P
authors.lastname: Abel zur Wiesch
authors.affiliation: Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut.
authors.forename: Trevor
authors.initials: T
authors.lastname: Hinkley
authors.affiliation: Massachusetts Supranational TB Reference Laboratory, University of Massachusetts Medical School, Boston.
authors.forename: Devinder
authors.initials: D
authors.lastname: Kaur
authors.affiliation: Massachusetts Supranational TB Reference Laboratory, University of Massachusetts Medical School, Boston.
authors.forename: Alexander
authors.initials: A
authors.lastname: Sloutsky
authors.affiliation: Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut.
authors.forename: Ted
authors.initials: T
authors.lastname: Cohen
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D005191:Family Characteristics; D005260:Female; D056084:Genetic Fitness; D006801:Humans; D008297:Male; D017720:Molecular Epidemiology; D009154:Mutation / Q000235:genetics*; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics*; D010568:Peru / Q000453:epidemiology; D018088:Tuberculosis, Multidrug-Resistant / Q000453:epidemiology / Q000382:microbiology* / Q000635:transmission
keywords: Lima, Peru; MDR M. tuberculosis; antibiotic resistance; case-control study; epistasis; fitness cost; katG; rpsL; molecular epidemiology; transmission