Characterization of a clinical Clostridioides difficile isolate with markedly reduced fidaxomicin susceptibility and a V1143D mutation in rpoB.
J Antimicrob Chemother
; 74(1): 6-10, 2019 01 01.
Article
in En
| MEDLINE
| ID: mdl-30247587
ABSTRACT
Objectives:
The identification and characterization of clinical Clostridioides difficile isolates with reduced fidaxomicin susceptibility.Methods:
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 630Δerm. Replication rates, toxin A/B production and spore formation were determined from the strain with reduced fidaxomicin susceptibility.Results:
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 630Δerm, 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.Conclusions:
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
DNA-Directed RNA Polymerases
/
Clostridioides difficile
/
Clostridium Infections
/
Mutation, Missense
/
Fidaxomicin
/
Anti-Bacterial Agents
Limits:
Humans
Language:
En
Journal:
J Antimicrob Chemother
Year:
2019
Type:
Article
Affiliation country:
Germany