The discovery of antibiotics more than 80 years ago has led to considerable improvements in human and animal health. Although antibiotic resistance in environmental bacteria is ancient, resistance in human pathogens is thought to be a modern phenomenon that is driven by the clinical use of antibiotics1. Here we show that particular lineages of methicillin-resistant Staphylococcus aureus-a notorious human pathogen-appeared in European hedgehogs in the pre-antibiotic era. Subsequently, these lineages spread within the local hedgehog populations and between hedgehogs and secondary hosts, including livestock and humans. We also demonstrate that the hedgehog dermatophyte Trichophyton erinacei produces two β-lactam antibiotics that provide a natural selective environment in which methicillin-resistant S. aureus isolates have an advantage over susceptible isolates. Together, these results suggest that methicillin resistance emerged in the pre-antibiotic era as a co-evolutionary adaptation of S. aureus to the colonization of dermatophyte-infected hedgehogs. The evolution of clinically relevant antibiotic-resistance genes in wild animals and the connectivity of natural, agricultural and human ecosystems demonstrate that the use of a One Health approach is critical for our understanding and management of antibiotic resistance, which is one of the biggest threats to global health, food security and development.

Advanced Light and Electron Microscopy Robert Koch Institute Berlin Germany

Animal Health Trust Newmarket UK

Antimicrobial Resistance and Healthcare Associated Infections Reference Unit UK Health Security Agency London UK

Bacteriology Department and French National Reference Center for Staphylococci Hospices Civils de Lyon University of Lyon Lyon France

Clinical Microbiology and Public Health Laboratory UK Health Security Agency Addenbrooke's Hospital Cambridge UK

Department of Animal Health and Antimicrobial Strategies National Veterinary Institute Uppsala Sweden

Department of Animal Science and Food Processing Faculty of Tropical AgriSciences Czech University of Life Sciences Prague Prague Czech Republic

Department of Bacteria Parasites and Fungi Statens Serum Institut Copenhagen Denmark

Department of Bacteriology Animal and Plant Health Agency Weybridge UK

Department of Biology and Ecology University of Ostrava Ostrava Czech Republic

Department of Biomedical Science and Veterinary Public Health Swedish University of Agricultural Sciences Uppsala Sweden

Department of Chemistry and Bioscience Aalborg University Aalborg Denmark

Department of Genetics University of Cambridge Cambridge UK

Department of Medicine University of Cambridge Cambridge UK

Department of Microbiology Public Health Agency of Sweden Solna Sweden

Department of Physiology Development and Neuroscience University of Cambridge Cambridge UK

Department of Public Health and Primary Care University of Cambridge Cambridge UK

Department of Veterinary and Animal Sciences Faculty of Health and Medical Sciences University of Copenhagen Frederiksberg Denmark

Department of Veterinary Medicine University of Cambridge Cambridge UK

Department of Zoology Charles University Prague Czech Republic

Dipartimento di Medicina Veterinaria Università degli Studi di Milano Lodi Italy

European Programme for Public Health Microbiology Training Stockholm Sweden

Expert Microbiology Unit Department of Health Security Finnish Institute for Health and Welfare Helsinki Finland

Friedrich Loeffler Institute of Medical Microbiology University Medicine Greifswald Greifswald Germany

Infectious Disease Preparedness Statens Serum Institut Copenhagen Denmark

Institute for Veterinary Food Science Justus Liebig University Giessen Giessen Germany

Institute of Infection and Immunity St George's University of London London UK

Institute of Microbiology and Epizootics Veterinary Faculty Freie Universität Berlin Berlin Germany

Institute of Microbiology University of Veterinary Medicine Vienna Austria

Institute of Veterinary Bacteriology University of Bern Bern Switzerland

Intervacc AB Stockholm Stockholm Sweden

Laboratory for Medical Microbiology Ghent University Hospital Ghent Belgium

Laboratory of Microbiology and Infectious Diseases The Rockefeller University New York NY USA

Laboratory of Molecular Genetics ITQB NOVA Oeiras Portugal

Microbiology Unit Finnish Food Authority Helsinki Finland

National Food Institute Technical University of Denmark Kongens Lyngby Denmark

National Reference Center for Antimicrobial Resistance and Nosocomial Infections Institute for Hygiene Microbiology and Tropical Medicine Ordensklinikum Linz Elisabethinen Linz Austria

National Reference Centre for Staphylococci and Enterococci Division Nosocomial Pathogens and Antibiotic Resistances Department of Infectious Diseases Robert Koch Institute Wernigerode Germany

National Reference Centre Staphylococcus aureus Department of Microbiology Hôpital Erasme Université libre de Bruxelles Brussels Belgium

Norwegian Veterinary Institute Ås Norway

Quality Milk Production Services Animal Health Diagnostic Center Cornell University Ithaca NY USA

Royal Botanic Gardens Kew Richmond UK

School of Life Sciences and Department of Statistics University of Warwick Warwick UK

School of Medicine University of St Andrews St Andrews UK

Scottish MRSA Reference Laboratory NHS Greater Glasgow and Clyde Stobhill Hospital Glasgow UK

Servicio de Microbiología Complejo Asistencial Universitario de Salamanca Salamanca Spain

Servicio de Microbiología Hospital Universitario Lucus Augusti Lugo Spain

SRUC Veterinary Services Inverness UK

The Royal School of Veterinary Studies and Roslin Institute University of Edinburgh Easter Bush UK

Vet Med Labor GmbH Kornwestheim Germany

Wellcome Sanger Institute Hinxton UK

Wildlife Conservation Research Unit Department of Zoology University of Oxford Tubney UK

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Nat Med. 2022 Apr;28(4):638-640. doi: 10.1038/s41591-022-01752-z. PubMed

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Population Pharmacokinetic Analysis Proves Superiority of Continuous Infusion in PK/PD Target Attainment with Oxacillin in Staphylococcal Infections

Host-driven subspeciation in the hedgehog fungus, Trichophyton erinacei, an emerging cause of human dermatophytosis