title: When is an outbreak not an outbreak? Fit, divergent strains of Mycobacterium tuberculosis display independent evolution of drug resistance in a large London outbreak.
abstract: OBJECTIVE
  To study the evolutionary relationship of Mycobacterium tuberculosis isolates from 13 patients in a large outbreak of isoniazid-resistant tuberculosis in London.
  
  
  METHODS
  Genotypic and phenotypic susceptibility tests were performed. Molecular genotyping using restriction fragment length polymorphisms and mycobacterial interspersed repetitive units was carried out. Additionally, the generation times of 13 strains of M. tuberculosis from the outbreak were measured to determine relative fitness.
  
  
  RESULTS
  Genotypic and phenotypic susceptibility testing demonstrated variations between isolates. Polymorphisms causing isoniazid resistance varied within clusters of isolates that were indistinguishable by standard genotyping. The measurement of in vitro generation times demonstrated that the fitness of the resistant strains was not significantly different from either wild-type or susceptible isolates in the outbreak, indicating that apparently no fitness cost was associated with the acquisition of drug resistance.
  
  
  CONCLUSIONS
  It appears that this outbreak comprised a heterogeneous collection of closely related strains, which appear to exhibit more variation than would usually be associated with a point source outbreak. These strains appear to have evolved by acquisition of additional antimicrobial resistance mutations while remaining competitive. The acquired resistance and retained competitiveness may be partly responsible for the difficulty in controlling the outbreak.
authors.affiliation: Department of Medical Microbiology,  Royal Free Hospital, London,  UK.
authors.forename: R J
authors.initials: RJ
authors.lastname: Shorten
authors.forename: A C
authors.initials: AC
authors.lastname: McGregor
authors.forename: S
authors.initials: S
authors.lastname: Platt
authors.forename: C
authors.initials: C
authors.lastname: Jenkins
authors.forename: M C I
authors.initials: MC
authors.lastname: Lipman
authors.forename: S H
authors.initials: SH
authors.lastname: Gillespie
authors.forename: B M
authors.initials: BM
authors.lastname: Charalambous
authors.forename: T D
authors.initials: TD
authors.lastname: McHugh
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D004196:Disease Outbreaks; D024881:Drug Resistance, Bacterial; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology; D008131:London / Q000453:epidemiology; D017720:Molecular Epidemiology; D058889:Molecular Typing; D009169:Mycobacterium tuberculosis / Q000145:classification* / Q000187:drug effects* / Q000302:isolation & purification; D012150:Polymorphism, Restriction Fragment Length; D014376:Tuberculosis / Q000453:epidemiology* / Q000382:microbiology*
chemical_list: D000995:Antitubercular Agents; D007538:Isoniazid