Staphylococcus epidermidis is a conspicuous member of the human microbiome, widely present on healthy skin. Here we show that S. epidermidis has also evolved to become a formidable nosocomial pathogen. Using genomics, we reveal that three multidrug-resistant, hospital-adapted lineages of S. epidermidis (two ST2 and one ST23) have emerged in recent decades and spread globally. These lineages are resistant to rifampicin through acquisition of specific rpoB mutations that have become fixed in the populations. Analysis of isolates from 96 institutions in 24 countries identified dual D471E and I527M RpoB substitutions to be the most common cause of rifampicin resistance in S. epidermidis, accounting for 86.6% of mutations. Furthermore, we reveal that the D471E and I527M combination occurs almost exclusively in isolates from the ST2 and ST23 lineages. By breaching lineage-specific DNA methylation restriction modification barriers and then performing site-specific mutagenesis, we show that these rpoB mutations not only confer rifampicin resistance, but also reduce susceptibility to the last-line glycopeptide antibiotics, vancomycin and teicoplanin. Our study has uncovered the previously unrecognized international spread of a near pan-drug-resistant opportunistic pathogen, identifiable by a rifampicin-resistant phenotype. It is possible that hospital practices, such as antibiotic monotherapy utilizing rifampicin-impregnated medical devices, have driven the evolution of this organism, once trivialized as a contaminant, towards potentially incurable infections.

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The authors thank D. Kotsanas (Monash Health), M. Hickey (Ireland), A. Boulos (Northern Ireland) and K. E. Greenwood Quaintance, S. M. Schmidt-Malan and Y. M. Wi (United States) for their submission of isolates used in this study. This project was supported by the Royal Australasian College of Physicians, Basser Research Entry Scholarship/Australian Government Research Training Program Scholarship (to J.Y.H.L.), a National Institutes of Health, National Institute of Allergy and Infectious Diseases Project Grant to R.P. (R21 AI125870), a National Health and Medical Research Council of Australia (NHMRC) Project Grant (GNT1066791), an NHMRC Senior Research Fellowship to T.P.S. (GNT1105525) and an NHMRC Practitioner Fellowship to B.P.H. (GNT1105905).

Author information

Author notes

  1. These authors contributed equally to this work: Timothy P. Stinear, Benjamin P. Howden


  1. Department of Microbiology and Immunology, The University of Melbourne at The Doherty Institute for Infection and Immunity, Melbourne, Australia

    • Jean Y. H. Lee
    • , Ian R. Monk
    •  & Timothy P. Stinear
  2. Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology, The University of Melbourne at The Doherty Institute for Infection and Immunity, Melbourne, Australia

    • Anders Gonçalves da Silva
    •  & Benjamin P. Howden
  3. Doherty Applied Microbial Genomics, Department of Microbiology and Immunology, The University of Melbourne at The Doherty Institute for Infection and Immunity, Melbourne, Australia

    • Anders Gonçalves da Silva
    • , Torsten Seemann
    • , Timothy P. Stinear
    •  & Benjamin P. Howden
  4. Melbourne Bioinformatics, The University of Melbourne, Melbourne, Australia

    • Torsten Seemann
  5. Department of Microbiology, Austin Health, Melbourne, Australia

    • Kyra Y. L. Chua
  6. AMRHAI Reference Unit, National Infection Service, Public Health England, London, UK

    • Angela Kearns
    • , Robert Hill
    •  & Neil Woodford
  7. Department of Clinical Microbiology, Hvidovre University Hospital, Hvidovre, Denmark

    • Mette D. Bartels
  8. National Reference Centre for Staphylococci and Enterococci, Division Nosocomial Pathogens and Antibiotic Resistances, Department of Infectious Diseases, Robert Koch Institute, Wernigerode Branch, Wernigerode, Germany

    • Birgit Strommenger
  9. Department of Bacteriology, Institute for Infectious Agents, French National Reference Centre for Staphylococci, International Centre for Infectiology Research, Institute for Pharmaceutical and Biological Sciences Of Lyon, University of Lyon, Lyon, France

    • Frederic Laurent
  10. National Reference Centre for Staphylococci, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium

    • Magali Dodémont
    •  & Ariane Deplano
  11. Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, and Division of Infectious Diseases, Department of Medicine, Mayo Clinic, Rochester, USA

    • Robin Patel
  12. Reference Laboratory for Antimicrobial Resistance and Staphylococci, Statens Serum Institut, Copenhagen, Denmark

    • Anders R. Larsen
  13. Monash Infectious Diseases, Centre for Inflammatory Diseases, Monash University, Melbourne, Australia

    • Tony M. Korman
  14. Infectious Diseases Department, Austin Health, Melbourne, Australia

    • Benjamin P. Howden


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B.P.H. and T.P.S. conceived the project, which was supervised by B.P.H., T.P.S. and I.R.M. J.Y.H.L. performed all experimental work, with assistance from I.R.M. J.Y.H.L., A.G.d.S., T.S., T.P.S. and B.P.H. analysed data, including analysis of genome sequence data. K.Y.L.C., A.K., R.H., N.W., M.D.B., B.S., F.L., M.D., A.D., R.P., A.R.L. and T.M.K. established and analysed clinical and reference isolate data sets and performed susceptibility testing. J.Y.H.L., I.R.M., B.P.H. and T.P.S. drafted the manuscript. All authors reviewed and contributed to the final manuscript.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Benjamin P. Howden.

Supplementary Information

  1. Supplementary Information

    Supplementary Figures 1–6, Supplementary Tables 1–3, Supplementary References.

  2. Reporting Summary

  3. Supplementary Table 1

    Isolate metadata. Sheet A: clinical metadata. Sheet B: accession information. Sheet C: sequencing and assembly statistics. Sheet D: resistome data. Sheet E: SRA strain metadata.

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