Abstract

Epidemic C. difficile (027/BI/NAP1) has rapidly emerged in the past decade as the leading cause of antibiotic-associated diarrhea worldwide. However, the key events in evolutionary history leading to its emergence and the subsequent patterns of global spread remain unknown. Here, we define the global population structure of C. difficile 027/BI/NAP1 using whole-genome sequencing and phylogenetic analysis. We show that two distinct epidemic lineages, FQR1 and FQR2, not one as previously thought, emerged in North America within a relatively short period after acquiring the same fluoroquinolone resistance–conferring mutation and a highly related conjugative transposon. The two epidemic lineages showed distinct patterns of global spread, and the FQR2 lineage spread more widely, leading to healthcare-associated outbreaks in the UK, continental Europe and Australia. Our analysis identifies key genetic changes linked to the rapid transcontinental dissemination of epidemic C. difficile 027/BI/NAP1 and highlights the routes by which it spreads through the global healthcare system.

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Acknowledgements

We are grateful to members of the European Study Group of Clostridium difficile (ESGCD), a working group of ESCMID (European Society of Clinical Microbiology and Infectious Diseases), including F. Barbut, T. Eckmanns, M.L. Lambert, F. Fitzpatrick, C. Wiuff, H. Pituch, P. Reichert, A.F. Widmer, F. Allerberger, D.W. Notermans, M. Delmée, R. Frei, O. Lyytikäinen, A. Ingebretsen and I.R. Poxton. We thank the Wellcome Trust Sanger Institute sequencing and informatics teams. This project was funded by the Wellcome Trust (grants 098051 and 086418), a Medical Research Council New Investigator Research Grant (T.D.L.; grant 93614) and the Scottish Infection Research Network. We acknowledge funding from the National Institute for Health Research (NIHR) Biomedical Research Centre in Liverpool. Both F.M. and P.R. were supported by the Liverpool BRC (Biomedical Research Centre). M.P. is an NIHR Senior Investigator.

Author information

Affiliations

  1. Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

    • Miao He
    • , Louise Ellison
    • , Derek J Pickard
    • , Thomas R Connor
    • , Simon R Harris
    • , Sharon J Peacock
    • , Gordon Dougan
    • , Julian Parkhill
    •  & Trevor D Lawley
  2. Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.

    • Fabio Miyajima
    • , Paul Roberts
    •  & Munir Pirmohamed
  3. University of Liverpool and Royal Liverpool and Broadgreen University Hospital National Health Service (NHS) Trust, Liverpool, UK.

    • Fabio Miyajima
    • , Paul Roberts
    •  & Munir Pirmohamed
  4. Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, London, UK.

    • Melissa J Martin
    •  & Brendan W Wren
  5. Belfast Health and Social Trust, Belfast, UK.

    • Derek Fairley
  6. Department of Infectious Diseases and Immunity, Imperial College London, London, UK.

    • Kathleen B Bamford
    •  & Stephanie D'Arc
  7. Department of Bacteriology, Imperial College Healthcare NHS Trust, London, UK.

    • Kathleen B Bamford
    •  & Stephanie D'Arc
  8. Anaerobic Reference Laboratory, Cardiff, UK.

    • Jon Brazier
  9. Scottish Salmonella, Shigella and Clostridium difficile Reference Laboratory, Glasgow, UK.

    • Derek Brown
    • , John E Coia
    •  & Gill Douce
  10. Hines VA Hospital, Hines, Illinois, USA.

    • Dale Gerding
  11. College of Medicine, Yonsei University, Seoul, South Korea.

    • Hee Jung Kim
  12. Department of Pathology, Singapore General Hospital, Singapore.

    • Tse Hsien Koh
  13. Department of Bacteriology, National Institute of Infectious Diseases, Tokyo, Japan.

    • Haru Kato
    •  & Mitsutoshi Senoh
  14. Department of Microbiology, Immunology & Infectious Diseases, University of Calgary, Calgary, Alberta, Canada.

    • Tom Louie
  15. College of Life and Environmental Sciences, University of Exeter, Exeter, UK.

    • Stephen Michell
    •  & Emma Butt
  16. Department of Medicine, University of Cambridge, Cambridge, UK.

    • Sharon J Peacock
  17. Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

    • Sharon J Peacock
    •  & Nick M Brown
  18. Health Protection Agency, London, UK.

    • Sharon J Peacock
    •  & Nick M Brown
  19. School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, Western Australia, Australia.

    • Tom Riley
  20. Department of Veterinary Microbiology and Preventive Medicine, Iowa State University, Ames, Iowa, USA.

    • Glen Songer
  21. Healthcare Associate Infection Research Group, University of Leeds, Leeds, UK.

    • Mark Wilcox
  22. Department of Experimental Microbiology, Leiden University Medical Centre, Leiden, The Netherlands.

    • Ed Kuijper
  23. School of Immunity and Infection, University of Birmingham, Birmingham, UK.

    • Peter Hawkey

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Contributions

M.H. analyzed the data. T.D.L., M.H., G. Dougan, B.W.W. and J.P. were involved in the study design. F.M., P.R., L.E., D.J.P., M.J.M., D.F., K.B.B., S.D., J.B., D.B., J.E.C., G. Douce, D.G., H.J.K., T.H.K., H.K., M.S., T.L., S.M., E.B., S.J.P., N.M.B., T.R., G.S., M.W., M.P., E.K., P.H. and B.W.W. were involved in isolate collection and DNA extraction. T.R.C. contributed to Bayesian analysis. M.H., J.P., T.D.L., G. Dougan, T.R.C. and S.R.H. contributed to data interpretation. M.H., J.P., T.D.L. and G. Dougan wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Julian Parkhill or Trevor D Lawley.

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DOI

https://doi.org/10.1038/ng.2478

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