Ilse M Boekhoud1, Igor Sidorov1, Sam Nooij1,2, Céline Harmanus1, Ingrid M J G Bos-Sanders1, Virginie Viprey3, William Spittal3, Emma Clark3, Kerrie Davies3,4, Jane Freeman3,4, Ed J Kuijper1,4,5, Wiep Klaas Smits1,2,4. 1. Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands. 2. Center for Microbiome Analyses and Therapeutics, Leiden University Medical Center, Leiden, The Netherlands. 3. Healthcare Associated Infection Research Group, School of Medicine, University of Leeds, Leeds, UK. 4. European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Study Group for Clostridioides difficile (ESGCD), Basel, Switzerland. 5. National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
Abstract
BACKGROUND: 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. OBJECTIVES: To identify factors that contribute to plasmid-independent metronidazole resistance of C. difficile. METHODS: 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. RESULTS: 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 >2 mg/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. CONCLUSIONS: Our data demonstrate that haem is crucial for medium-dependent metronidazole resistance in C. difficile.
BACKGROUND: Until recently, metronidazole was the first-line treatment for Clostridioides difficileinfection and it is still commonly used. Though resistance has been reported due to the plasmid pCD-METRO, this does not explain all cases. OBJECTIVES: To identify factors that contribute to plasmid-independent metronidazole resistance of C. difficile. METHODS: 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. RESULTS: 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 >2 mg/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. CONCLUSIONS: Our data demonstrate that haem is crucial for medium-dependent metronidazole resistance in C. difficile.
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