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Global spread of three multidrug-resistant lineages of Staphylococcus epidermidis

Nature Microbiology volume 3, pages 1175–1185 (2018)Cite this article

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Abstract

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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Fig. 1: Increasing prevalence of multidrug-resistant S. epidermidis (MDRSE).
Fig. 2: Clonal expansion of endemic, multidrug-resistant ST2 and ST23 S. epidermidis lineages resulting in clinical disease within a single institution.
Fig. 3: International clonal expansion of endemic, multidrug-resistant ST2 and ST23 S. epidermidis lineages resulting in clinical disease.
Fig. 4: RpoB mutations confer vancomycin heteroresistance in S. epidermidis.
Fig. 5: RpoB D471E and I527M mutations cause vancomycin heteroresistance in four different S. epidermidis backgrounds.
Fig. 6: Mutants containing dual D471E and I527M RpoB substitutions outcompete WT S. epidermidis in the presence of vancomycin.

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Acknowledgements

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).

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Author notes

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

Authors and Affiliations

  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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Contributions

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.

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Correspondence to Benjamin P. Howden.

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Supplementary Information

Supplementary Information

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

Reporting Summary

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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Lee, J.Y.H., Monk, I.R., Gonçalves da Silva, A. et al. Global spread of three multidrug-resistant lineages of Staphylococcus epidermidis. Nat Microbiol 3, 1175–1185 (2018). https://doi.org/10.1038/s41564-018-0230-7

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