Abstract
Metronidazole was until recently used as a first-line treatment for potentially life-threatening Clostridioides difficile (CD) infection. Although cases of metronidazole resistance have been documented, no clear mechanism for metronidazole resistance or a role for plasmids in antimicrobial resistance has been described for CD. Here, we report genome sequences of seven susceptible and sixteen resistant CD isolates from human and animal sources, including isolates from a patient with recurrent CD infection by a PCR ribotype (RT) 020 strain, which developed resistance to metronidazole over the course of treatment (minimal inhibitory concentration [MIC] = 8 mg L−1). Metronidazole resistance correlates with the presence of a 7-kb plasmid, pCD-METRO. pCD-METRO is present in toxigenic and non-toxigenic resistant (n = 23), but not susceptible (n = 563), isolates from multiple countries. Introduction of a pCD-METRO-derived vector into a susceptible strain increases the MIC 25-fold. Our finding of plasmid-mediated resistance can impact diagnostics and treatment of CD infections.
Highlights
Metronidazole was until recently used as a first-line treatment for potentially life-threatening Clostridioides difficile (CD) infection
Metronidazole resistance appears to be more frequent in non-toxigenic strains such as those belonging to RT010, which have a 7–9-fold increase in Minimal Inhibitory Concentration (MIC) values compared to RT001, RT027 and RT07821,26
The patient was subsequently diagnosed with Clostridioides difficile Infection (CDI) and a toxigenic metronidazole sensitive (MIC = 0.25 mg L−1) RT020 strain was isolated from the fecal material of the patient
Summary
Metronidazole was until recently used as a first-line treatment for potentially life-threatening Clostridioides difficile (CD) infection. Reduced susceptibility and resistance to clinically used antimicrobials, including metronidazole, has been reported and this, combined with the intrinsic multiple drug-resistant nature of C. difficile, stresses the importance for the development of better diagnostics and new effective treatment modalities[8]. Longitudinal surveillance in Europe found that 0.2% of clinical isolates investigated were resistant to metronidazole[19], but reported rates from other studies vary from 0 to 18.3%21–24 These differences may reflect geographic distributions in resistant strains, or differences in testing methodology and breakpoints used[25,26]. Metronidazole is a 5-nitroimidazole prodrug that upon intracellular reductive activation induces cellular damage through nitro-radicals[27] It is used in the treatment of CDI, and an important drug for treating parasitic infections and as prophylactic antimicrobial in for instance abdominal surgery[27,28]. Levels of metronidazole achieved in the colon are generally low and this could be relevant for the selection of resistant strains[31]
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