Balancing access to antibiotics with the control of antibiotic resistance is a global public health priority. At present, antibiotic stewardship is informed by a ‘use it and lose it’ principle, in which antibiotic use by the population is linearly related to resistance rates. However, theoretical and mathematical models suggest that use–resistance relationships are nonlinear. One explanation for this is that resistance genes are commonly associated with ‘fitness costs’ that impair the replication or transmissibility of the pathogen. Therefore, resistant genes and pathogens may only gain a survival advantage where antibiotic selection pressures exceed critical thresholds. These thresholds may provide quantitative targets for stewardship—optimizing the control of resistance while avoiding over-restriction of antibiotics. Here, we evaluated the generalizability of a nonlinear time-series analysis approach for identifying thresholds using historical prescribing and microbiological data from five populations in Europe. We identified minimum thresholds in temporal relationships between the use of selected antibiotics and incidence rates of carbapenem-resistant Acinetobacter baumannii (Hungary), extended-spectrum β-lactamase-producing Escherichia coli (Spain), cefepime-resistant E. coli (Spain), gentamicin-resistant Pseudomonas aeruginosa (France) and methicillin-resistant Staphylococcus aureus (Northern Ireland) in different epidemiological phases. Using routinely generated data, our approach can identify context-specific quantitative targets for rationalizing population antibiotic use and controlling resistance. Prospective intervention studies that restrict antibiotic consumption are needed to validate these thresholds.

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We acknowledge D. L. Monnet, from the European Centre for Disease Prevention and Control for his continuous support, guidance and intellectual contributions to the THRESHOLDS project. J.-M.L.-L. acknowledges the continuous support of the management team of the Hospital Vega Baja, the technical support of C. Quiles (Cabosoft SL) in the development of TSA techniques in the field of antimicrobial resistance and the WebResist project (www.webresist.org), which provided a framework for the development of this study. G.K. was supported by a Bolyai Research Scholarship of the Hungarian Academy of Sciences. T.L. was supported by the Wellcome Trust. J.R.B. and P.R. received funding for research from Plan Nacional de I+D+i 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (RD16/0016/0001), co-financed by European Development Regional Fund ‘A way to achieve Europe’, Operative Programme Intelligent Growth 2014–2020.

Author information


  1. Medicine Preventive-Infection Control Team, Hospital Vega Baja, Orihuela, Spain

    • José-María López-Lozano
    •  & José-María López-Lozano
  2. The Wellcome Trust Liverpool-Glasgow Centre for Global Health Research, Liverpool, UK

    • Timothy Lawes
    •  & Timothy Lawes
  3. Centro Universitario de la Defensa de San Javier, Murcia, Spain

    • César Nebot
    •  & César Nebot
  4. Departamento de Métodos Cuantitativos para la Economía y la Empresa, University of Murcia, Murcia, Spain

    • Arielle Beyaert
    •  & Arielle Beyaert
  5. Laboratoire Chrono-environnement, Université de Bourgogne-Franche-Comté, Besançon, France

    • Xavier Bertrand
    • , Didier Hocquet
    • , Xavier Bertrand
    • , Didier Hocquet
    •  & Michelle Thouverez
  6. Centre Hospitalier Régional Universitaire de Besançon, Besançon, France

    • Xavier Bertrand
    • , Didier Hocquet
    • , Xavier Bertrand
    •  & Didier Hocquet
  7. School of Pharmacy and Pharmaceutical Science, Ulster University, Coleraine, UK

    • Mamoon Aldeyab
    •  & Mamoon Aldeyab
  8. Pharmacy Department, Northern Health and Social Care Trust and Regional Medicines Optimisation Innovation Centre, Antrim, UK

    • Michael Scott
    • , Geraldine Conlon-Bingham
    • , Michael Scott
    •  & Geraldine Conlon-Bingham
  9. Department of Medical Microbiology, Antrim Area Hospital, Antrim, UK

    • David Farren
    •  & David Farren
  10. Department of Medical Microbiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

    • Gábor Kardos
    • , Gábor Kardos
    •  & Hajnalka Tóth
  11. Clinical Pharmacy, University of Debrecen, Debrecen, Hungary

    • Adina Fésűs
    •  & Adina Fésus
  12. Infectious Diseases and Clinical Microbiology Unit, Hospital Universitario Virgen Macarena, Seville, Spain

    • Jesús Rodríguez-Baño
    • , Pilar Retamar
    • , Jesús Rodríguez-Baño
    •  & Pilar Retamar
  13. Department of Medicine, Instituto de Biomedicina de Sevilla, University of Sevilla, Seville, Spain

    • Jesús Rodríguez-Baño
    • , Pilar Retamar
    • , Jesús Rodríguez-Baño
    •  & Pilar Retamar
  14. Medical Microbiology Department, Hospital Vega Baja, Orihuela, Spain

    • Nieves Gonzalo-Jiménez
    •  & Nieves Gonzalo-Jiménez
  15. Medical Microbiology Department, Aberdeen Royal Infirmary, Aberdeen, UK

    • Ian M. Gould
    •  & Ian M. Gould
  16. Hospital Virgen de la Macarena, Seville, Spain

    • María Núñez-Núñez
    •  & Ana I. Suárez
  17. Hospital Vega Baja, Orihuela, Spain

    • María Navarro-Cots
    • , Emilio Borrajo
    • , Carlos Devesa
    • , Joan Gregori
    • , Inmaculada García-Cuello
    • , Isabel Pacheco
    •  & María Cerón


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  1. THRESHOLDS study group


J.-M.L.-L., T.L., C.N., A.B. and I.M.G. proposed the original idea and designed the study. X.B., D.H., M.A., G.C.-B., M.S., D.F., G.K., J.R.B., P.R. and N.G.J. collated centre-specific data, situational analysis and hypotheses. J.-M.L.-L., T.L., C.N. and A.B. contributed to statistical analysis; C.N. and A.B. were the principal analysts. All authors discussed the results and commented on the manuscript.

Competing interests

I.M.G. is in receipt of payments for consultancies and lectures from numerous pharmaceutical firms developing new antimicrobials. The other authors declare no competing interests.

Corresponding authors

Correspondence to Timothy Lawes or Timothy Lawes.

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