April 21, 2020  |  

Characterization of a clinical Clostridioides difficile isolate with markedly reduced fidaxomicin susceptibility and a V1143D mutation in rpoB.

Authors: Schwanbeck, Julian and Riedel, Thomas and Laukien, Friederike and Schober, Isabel and Oehmig, Ines and Zimmermann, Ortrud and Overmann, Jörg and Groß, Uwe and Zautner, Andreas E and Bohne, Wolfgang

The identification and characterization of clinical Clostridioides difficile isolates with reduced fidaxomicin susceptibility.Agar dilution assays were used to determine fidaxomicin MICs. Genome sequence data were obtained by single-molecule real-time (SMRT) sequencing in addition to amplicon sequencing of rpoB and rpoC alleles. Allelic exchange was used to introduce the identified mutation into C. difficile 630?erm. Replication rates, toxin A/B production and spore formation were determined from the strain with reduced fidaxomicin susceptibility.Out of 50 clinical C. difficile isolates, isolate Goe-91 revealed markedly reduced fidaxomicin susceptibility (MIC >64?mg/L). A V1143D mutation was identified in rpoB of Goe-91. When introduced into C. difficile 630?erm, this mutation decreased fidaxomicin susceptibility (MIC >64?mg/L), but was also associated with a reduced replication rate, low toxin A/B production and markedly reduced spore formation. In contrast, Goe-91, although also reduced in toxin production, showed normal growth rates and only moderately reduced spore formation capacities. This indicates that the rpoBV1143D allele-associated fitness defect is less pronounced in the clinical isolate.To the best of our knowledge, this is the first description of a pathogenic clinical C. difficile isolate with markedly reduced fidaxomicin susceptibility. The lower-than-expected fitness burden of the resistance-mediating rpoBV1143D allele might be an indication for compensatory mechanisms that take place during in vivo selection of mutants.

Journal: The Journal of antimicrobial chemotherapy
DOI: 10.1093/jac/dky375
Year: 2019

Read publication

Talk with an expert

If you have a question, need to check the status of an order, or are interested in purchasing an instrument, we're here to help.