Varying fitness cost associated with resistance to fluoroquinolones governs clonal dynamic of methicillin-resistant Staphylococcus aureus

  • A. Horváth
  • O. Dobay
  • S. Kardos
  • Á. Ghidán
  • Á. Tóth
  • J. Pászti
  • E. Ungvári
  • P. Horváth
  • K. Nagy
  • S. Zissman
  • M. FüziEmail author


The purpose of this study was to investigate the impact of fluoroquinolone resistance on the existence and dynamic of MRSA clones. Resistance to ciprofloxacin was induced in strains of community-acquired (CA) MRSA from various sequence types and the fitness cost suffered by mutant derivatives measured in a propagation assay. In addition, the fitness of fluoroquinolone resistant health care-associated (HA) MRSA isolates from major clones prevalent in Hungary were compared with each other and with those of the CA-MRSA derivatives. The genetic background of fluoroquinolone resistance and fitness cost in CA-MRSA was investigated. The fitness cost observed in the CA-MRSA derivatives proved diverse; the derivatives of the ST30-MRSA-IV strain suffered significantly greater fitness cost than those of the ST8-MRSA-IV and ST80-MRSA-IV isolates. Strains from the New York–Japan (ST5-MRSA-II), South German (ST228-MRSA-I) and EMRSA-15 (ST22-MRSA-IV) HA-MRSA clones proved more viable than CA-MRSA derivatives with similar MIC values to ciprofloxacin and HA-MRSA strains from the Hungarian/Brazilian clone (ST239-MRSA-III). Our strains from the New York–Japan, South-German and EMRSA-15 clones seem to have a competitive edge over the tested CA-MRSA isolates in the health care setting. The greater fitness observed in our New York–Japan and South-German strains could account for the replacement by them of the Hungarian/Brazilian clone in Hungary about ten years ago. Alterations in relevant genes were detected. The Ser80 → Phe mutation in the grlA gene may have seriously compromised viability. Surprisingly silent nucleotide substitutions in the grlB gene seemed to impact fitness in derivatives of the ST30-MRSA-IV isolate.


Area Under Curve Fitness Cost Fluoroquinolone Resistance Silent Nucleotide Substitution Japan Strain 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Parts of this material were presented at the 16th International Congress of the Hungarian Society for Microbiology, July 2011 (BOP-9). The study was financially supported by the Hungarian National Scientific Research Fund (OTKA), grant no. PD75660.


  1. 1.
    Deurenberg RH, Stobberingh EE (2008) The evolution of Staphylococcus aureus. Infect Genet Evol 8:747–763PubMedCrossRefGoogle Scholar
  2. 2.
    Harris SR, Feil EJ, Holden MT, Quail MA, Nickerson EK, Chantratita N, Gardete S, Tavares A, Day N, Lindsay JA, Edgeworth JD, de Lencastre H, Parkhill J, Peacock SJ, Bentley SD (2010) Evolution of MRSA during hospital transmission and intercontinental spread. Science 327:469–474PubMedCrossRefGoogle Scholar
  3. 3.
    Grundmann H, Aanensen DM, van den Wijngaard CC, Spratt BG, Harmsen D, Friedrich AW (2010) European Staphylococcal Reference Laboratory Working Group. Geographic distribution of Staphylococcus aureus causing invasive infections in Europe: a molecular-epidemiological analysis. PLoS Med 7:e1000215PubMedCrossRefGoogle Scholar
  4. 4.
    Johnson AP (2011) Methicillin-resistant Staphylococcus aureus: the European landscape. J Antimicrob Chemother 66(Suppl 4):iV43–iV48PubMedCrossRefGoogle Scholar
  5. 5.
    Conceição T, Aires-de-Sousa M, Füzi M, Tóth A, Pászti J, Ungvári E, van Leeuwen WB, van Belkum A, Grundmann H, de Lencastre H (2007) Replacement of methicillin-resistant Staphylococcus aureus clones in Hungary over time: a 10-year surveillance study. Clin Microbiol Infect 13:971–979PubMedCrossRefGoogle Scholar
  6. 6.
    Thouverez M, Muller A, Hocquet D, Talon D, Bertrand X (2003) Relationship between molecular epidemiology and antibiotic susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) in a French teaching hospital. J Med Microbiol 52:801–806PubMedCrossRefGoogle Scholar
  7. 7.
    Foucault ML, Courvalin P, Grillot-Courvalin C (2009) Fitness cost of VanA-type vancomycin resistance in methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 53:2354–2359PubMedCrossRefGoogle Scholar
  8. 8.
    Laurent F, Lelièvre H, Cornu M, Vandenesch F, Carret G, Etienne J, Flandrois JP (2001) Fitness and competitive growth advantage of new gentamicin-susceptible MRSA clones spreading in French hospitals. J Antimicrob Chemother 47:277–283PubMedCrossRefGoogle Scholar
  9. 9.
    Pantosti A, Sanchini A, Monaco M (2007) Mechanisms of antibiotic resistance in Staphylococcus aureus. Future Microbiol 2:323–334PubMedCrossRefGoogle Scholar
  10. 10.
    Oliveira DC, de Lencastre H (2002) Multiplex PCR strategy for rapid identification of structural types and variants of the mec element in methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 46:2155–2161PubMedCrossRefGoogle Scholar
  11. 11.
    Clinical and Laboratory Standards Institute (2005) Performance Standards for Antimicrobial Susceptibility testing; 15th Informational supplement M100-S15. CLSI, Wayne, PA, USA Google Scholar
  12. 12.
    Schmitz FJ, Hofmann B, Hansen B, Scheuring S, Lückefahr M, Klootwijk M, Verhoef J, Fluit A, Heinz HP, Köhrer K, Jones ME (1998) Relationship between ciprofloxacin, ofloxacin, levofloxacin, sparfloxacin and moxifloxacin (BAY 12-8039) MICs and mutations in grlA, grlB, gyrA and gyrB in 116 unrelated clinical isolates of Staphylococcus aureus. J Antimicrob Chemother 41:481–484PubMedCrossRefGoogle Scholar
  13. 13.
    National Epidemiology Centre of Hungary (OEK) (2010) Antibiotic resistance. Based on the data reported in the frame of the national surveillance system. Accessed 28 December 2011
  14. 14.
    Lee SM, Ender M, Adhikari R, Smith JM, Berger-Bächi B, Cook GM (2007) Fitness cost of staphylococcal cassette chromosome mec in methicillin-resistant Staphylococcus aureus by way of continuous culture. Antimicrob Agents Chemother 51:1497–1499PubMedCrossRefGoogle Scholar
  15. 15.
    Collins J, Rudkin J, Recker M, Pozzi C, O'Gara JP, Massey RC (2010) Offsetting virulence and antibiotic resistance costs by MRSA. ISME J 4:577–584PubMedCrossRefGoogle Scholar
  16. 16.
    Hallin M, Denis O, Deplano A, De Ryck R, Crèvecoeur S, Rottiers S, de Mendonça R, Struelens MJ (2008) Evolutionary relationships between sporadic and epidemic strains of healthcare-associated methicillin-resistant Staphylococcus aureus. Clin Microbiol Infect 14:659–669PubMedCrossRefGoogle Scholar
  17. 17.
    Ma XX, Ito T, Chongtrakool P, Hiramatsu K (2006) Predominance of clones carrying Panton-Valentine leukocidin genes among methicillin-resistant Staphylococcus aureus strains isolated in Japanese hospitals from 1979 to 1985. J Clin Microb 44:4515–4527CrossRefGoogle Scholar
  18. 18.
    Velazquez-Meza ME, Aires de Sousa M, Echaniz-Aviles G, Solórzano-Santos F, Miranda-Novales G, Silva-Sanchez J, de Lencastre H (2004) Surveillance of methicillin-resistant Staphylococcus aureus in a pediatric hospital in Mexico City during a 7-year period (1997 to 2003): clonal evolution and impact of infection control. J Clin Microbiol 42:6877–6880CrossRefGoogle Scholar
  19. 19.
    Gagliotti C, Balode A, Baquero F, Degener J, Grundmann H, Gür D, Jarlier V, Kahlmeter G, Monen J, Monnet DL, Rossolini GM, Suetens C, Weist K, Heuer O (2011) Escherichia coli and Staphylococcus aureus: bad news and good news from the European Antimicrobial Resistance Surveillance Network (EARS-Net, formerly EARSS), 2002 to 2009. Eurosurveillance 16:pii:19819Google Scholar
  20. 20.
    Damjanova I, Tóth A, Pászti J, Bauernfeind A, Füzi M (2006) Nationwide spread of clonally related CTX-M-15-producing multidrug-resistant Klebsiella pneumoniae strains in Hungary. Eur J Clin Microbiol Infect Dis 25:275–278PubMedCrossRefGoogle Scholar
  21. 21.
    Damjanova I, Tóth A, Pászti J, Jakab M, Milch H, Bauernfeind A, Füzi M (2007) Epidemiology of SHV-type beta-lactamase-producing Klebsiella spp. from outbreaks in five geographically distant Hungarian neonatal intensive care units: widespread dissemination of epidemic R-plasmids. Int J Antimicrob Agents 29:665–671PubMedCrossRefGoogle Scholar
  22. 22.
    Damjanova I, Tóth A, Pászti J, Hajbel-Vékony G, Jakab M, Berta J, Milch H, Füzi M (2008) Expansion and countrywide dissemination of ST11, ST15 and ST147 ciprofloxacin-resistant CTX-M-15-type beta-lactamase-producing Klebsiella pneumoniae epidemic clones in Hungary in 2005–the new 'MRSAs'? J Antimicrob Chemother 62:978–985PubMedCrossRefGoogle Scholar
  23. 23.
    Szilágyi E, Füzi M, Damjanova I, Böröcz K, Szonyi K, Tóth A, Nagy K (2009) Investigation of extended-spectrum beta-lactamase-producing Klebsiella pneumoniae outbreaks in Hungary between 2005 and 2008. Acta Microbiol Immunol Hung 57:43CrossRefGoogle Scholar
  24. 24.
    Pan XS, Hamlyn PJ, Talens-Visconti R, Alovero FL, Manzo RH, Fisher LM (2002) Small-colony mutants of Staphylococcus aureus allow selection of gyrase-mediated resistance to dual-target fluoroquinolones. Antimicrob Agents Chemother 46:2498–2506PubMedCrossRefGoogle Scholar
  25. 25.
    Holden MT, Feil EJ, Lindsay JA, Peacock SJ, Day NP, Enright MC, Foster TJ, Moore CE, Hurst L, Atkin R, Barron A, Bason N, Bentley SD, Chillingworth C, Chillingworth T, Churcher C, Clark L, Corton C, Cronin A, Doggett J, Dowd L, Feltwell T, Hance Z, Harris B, Hauser H, Holroyd S, Jagels K, James KD, Lennard N, Line A, Mayes R, Moule S, Mungall K, Ormond D, Quail MA, Rabbinowitsch E, Rutherford K, Sanders M, Sharp S, Simmonds M, Stevens K, Whitehead S, Barrell BG, Spratt BG, Parkhill J (2004) Complete genomes of two clinical Staphylococcus aureus strains: evidence for the rapid evolution of virulence and drug resistance. Proc Natl Acad Sci USA 101:9786–9791PubMedCrossRefGoogle Scholar
  26. 26.
    Herron-Olson L, Fitzgerald JR, Musser JM, Kapur V (2007) Molecular correlates of host specialization in Staphylococcus aureus. PLoS One 2:e1120PubMedCrossRefGoogle Scholar
  27. 27.
    Schijffelen MJ, Boel CH, van Strijp JA, Fluit AC (2010) Whole genome analysis of a livestock-associated methicillin-resistant Staphylococcus aureus ST398 isolate from a case of human endocarditis. BMC Genomics 11:376PubMedCrossRefGoogle Scholar
  28. 28.
    Guinane CM, Ben Zakour NL, Tormo-Mas MA, Weinert LA, Lowder BV, Cartwright RA, Smyth DS, Smyth CJ, Lindsay JA, Gould KA, Witney A, Hinds J, Bollback JP, Rambaut A, Penadés JR, Fitzgerald JR (2010) Evolutionary genomics of Staphylococcus aureus reveals insights into the origin and molecular basis of ruminant host adaptation. Genome Biol Evol 2:454–466PubMedCrossRefGoogle Scholar
  29. 29.
    Ikemura T (1981) Correlation between the abundance of Escherichia coli transfer RNAs and the occurrence of the respective codons in its protein genes: a proposal for a synonymous codon choice that is optimal for the E. coli translational system. J Mol Biol 151:389–409PubMedCrossRefGoogle Scholar
  30. 30.
    Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV, Gottesman MM (2007) A "silent" polymorphism in the MDR1 gene changes substrate specificity. Science 315:525–528PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • A. Horváth
    • 1
  • O. Dobay
    • 1
  • S. Kardos
    • 1
  • Á. Ghidán
    • 1
  • Á. Tóth
    • 2
  • J. Pászti
    • 2
  • E. Ungvári
    • 2
  • P. Horváth
    • 1
  • K. Nagy
    • 1
  • S. Zissman
    • 1
  • M. Füzi
    • 1
    Email author
  1. 1.Institute of Medical MicrobiologySemmelweis UniversityBudapestHungary
  2. 2.National Center for EpidemiologyBudapestHungary

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