{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T22:50:33Z","timestamp":1791931833886,"version":"4.3.4"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2021,4,20]],"date-time":"2021-04-20T00:00:00Z","timestamp":1618876800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"The COMBACTE-CDI"},{"name":"Innovative Medicines Initiative 2 Joint Undertaking","award":["777362"],"award-info":[{"award-number":["777362"]}]},{"name":"Vidi fellowship","award":["864.13.003"],"award-info":[{"award-number":["864.13.003"]}]},{"DOI":"10.13039\/501100003246","name":"Netherlands Organisation for Scientific Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005039","name":"Leiden University Medical Center","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005039","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,6,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Until recently, metronidazole was the first-line treatment for Clostridioides difficile infection and it is still commonly used. Though resistance has been reported due to the plasmid pCD-METRO, this does not explain all cases.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To identify factors that contribute to plasmid-independent metronidazole resistance of C. difficile.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Here, we investigate resistance to metronidazole in a collection of clinical isolates of C. difficile using a combination of antimicrobial susceptibility testing on different solid agar media and WGS of selected isolates.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We find that nearly all isolates demonstrate a haem-dependent increase in the MIC of metronidazole, which in some cases leads to isolates qualifying as resistant (MIC &amp;gt;2\u2009mg\/L). Moreover, we find an SNP in the haem-responsive gene hsmA, which defines a metronidazole-resistant lineage of PCR ribotype 010\/MLST ST15 isolates that also includes pCD-METRO-containing strains.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our data demonstrate that haem is crucial for medium-dependent metronidazole resistance in C. difficile.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jac\/dkab097","type":"journal-article","created":{"date-parts":[[2021,3,11]],"date-time":"2021-03-11T15:09:50Z","timestamp":1615475390000},"page":"1731-1740","source":"Crossref","is-referenced-by-count":53,"title":["Haem is crucial for medium-dependent metronidazole resistance in clinical isolates of\n                    <i>Clostridioides difficile<\/i>"],"prefix":"10.1093","volume":"76","author":[{"given":"Ilse M","family":"Boekhoud","sequence":"first","affiliation":[{"name":"Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor","family":"Sidorov","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam","family":"Nooij","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands"},{"name":"Center for Microbiome Analyses and Therapeutics, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9line","family":"Harmanus","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid M J G","family":"Bos-Sanders","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginie","family":"Viprey","sequence":"additional","affiliation":[{"name":"Healthcare Associated Infection Research Group, School of Medicine, University of Leeds, Leeds, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Spittal","sequence":"additional","affiliation":[{"name":"Healthcare Associated Infection Research Group, School of Medicine, University of Leeds, Leeds, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Clark","sequence":"additional","affiliation":[{"name":"Healthcare Associated Infection Research Group, School of Medicine, University of Leeds, Leeds, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerrie","family":"Davies","sequence":"additional","affiliation":[{"name":"Healthcare Associated Infection Research Group, School of Medicine, University of Leeds, Leeds, UK"},{"name":"European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Study Group for Clostridioides difficile (ESGCD), Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Freeman","sequence":"additional","affiliation":[{"name":"Healthcare Associated Infection Research Group, School of Medicine, University of Leeds, Leeds, UK"},{"name":"European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Study Group for Clostridioides difficile (ESGCD), Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ed J","family":"Kuijper","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands"},{"name":"European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Study Group for Clostridioides difficile (ESGCD), Basel, Switzerland"},{"name":"National Institute for Public Health and the Environment, Bilthoven, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7409-2847","authenticated-orcid":false,"given":"Wiep Klaas","family":"Smits","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands"},{"name":"Center for Microbiome Analyses and Therapeutics, Leiden University Medical Center, Leiden, The Netherlands"},{"name":"European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Study Group for Clostridioides difficile (ESGCD), Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the COMBACTE-CDI 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