title: Fitness cost: a bacteriological explanation for the demise of the first international methicillin-resistant Staphylococcus aureus epidemic.
abstract: OBJECTIVE
  Denmark and several other countries experienced the first epidemic of methicillin-resistant Staphylococcus aureus (MRSA) during the period 1965-75, which was caused by multiresistant isolates of phage complex 83A. In Denmark these MRSA isolates disappeared almost completely, being replaced by other phage types, predominantly only penicillin resistant. We investigated whether isolates of this epidemic were associated with a fitness cost, and we employed a mathematical model to ask whether these fitness costs could have led to the observed reduction in frequency.
  
  
  METHODS
  Bacteraemia isolates of S. aureus from Denmark have been stored since 1957. We chose 40 S. aureus isolates belonging to phage complex 83A, clonal complex 8 based on spa type, ranging in time of isolation from 1957 to 1980 and with various antibiograms, including both methicillin-resistant and -susceptible isolates. The relative fitness of each isolate was determined in a growth competition assay with a reference isolate.
  
  
  RESULTS
  Significant fitness costs of 2%-15% were determined for the MRSA isolates studied. There was a significant negative correlation between number of antibiotic resistances and relative fitness. Multiple regression analysis found significantly independent negative correlations between fitness and the presence of mecA or streptomycin resistance. Mathematical modelling confirmed that fitness costs of the magnitude carried by these isolates could result in the disappearance of MRSA prevalence during a time span similar to that seen in Denmark.
  
  
  CONCLUSIONS
  We propose a significant fitness cost of resistance as the main bacteriological explanation for the disappearance of the multiresistant complex 83A MRSA in Denmark following a reduction in antibiotic usage.
authors.affiliation: Department of Microbiological Surveillance and Research,  Statens Serum Institut, Ørestads Boulevard 5, 2300 Copenhagen S,  Denmark.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Nielsen
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Pedersen
authors.forename: Klas I
authors.initials: KI
authors.lastname: Udekwu
authors.forename: Andreas
authors.initials: A
authors.lastname: Petersen
authors.forename: Robert L
authors.initials: RL
authors.lastname: Skov
authors.forename: Lars H
authors.initials: LH
authors.lastname: Hansen
authors.forename: Diarmaid
authors.initials: D
authors.lastname: Hughes
authors.forename: Niels
authors.initials: N
authors.lastname: Frimodt-Møller
mesh_terms: D001434:Bacteriophage Typing; D003718:Denmark / Q000453:epidemiology; D004196:Disease Outbreaks; D024901:Drug Resistance, Multiple, Bacterial; D004734:Energy Metabolism; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000254:growth & development / Q000378:metabolism / Q000502:physiology*; D008826:Microbial Sensitivity Tests; D008962:Models, Theoretical; D013203:Staphylococcal Infections / Q000453:epidemiology* / Q000382:microbiology*