Mutators among CTX-M β-lactamase-producing Escherichia coli and risk for the emergence of fosfomycin resistance

Matthew J. Ellington*, David M. Livermore, Tyrone L. Pitt, Lucinda M.C. Hall, Neil Woodford

*Corresponding author for this work

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43 Citations (Scopus)

Abstract

Objectives: Fosfomycin is a possible oral treatment for lower urinary tract infections caused by Escherichia coli with CTX-M extended-spectrum β-lactamases but is vulnerable to mutational resistance. Hypermutability among natural E. coli populations might facilitate the emergence of resistance to fosfomycin. We therefore examined the prevalence of mutators amongst urinary isolates of E. coli producing CTX-M β-lactamases. Methods: Urinary E. coli isolates with CTX-M & beta;-lactamases (n = 220) were screened for resistance to both rifampicin and fosfomycin, as well as a mutator phenotype, by rifampicin and fosfomycin disc assays. Mutation frequencies for 10 isolates, identified as mutators by the initial disc screen, were determined in triplicate on agar with rifampicin or fosfomycin at 4× MIC and with fosfomycin or nitrofurantoin at 256 mg/L. Results: The disc screen identified 10 likely mutators and quantitative tests indicated that 9 of these had mutation frequencies of 8.0 × 10-6-1.5 × 10-4 for fosfomycin and 0.1-2.3 × 10-6 for rifampicin. These mutators were diverse in terms of PFGE type and 4 of the 10 were confirmed as strong mutators with rifampicin and fosfomycin. Only the strongest mutator isolate and hypermutable MutS- control strain consistently gave single-step mutants resistant to 256 mg/L fosfomycin. No nitrofurantoin-resistant mutants were selected from any isolate, although they could be selected from the hypermutable MutS- control strain. Conclusions: Mutator phenotypes were found among E. coli expressing CTX-M β-lactamases and were independent of strain type. These had an increased propensity to fosfomycin resistance.

Original languageEnglish
Pages (from-to)848-852
Number of pages5
JournalJournal of Antimicrobial Chemotherapy
Volume58
Issue number4
DOIs
Publication statusPublished - 15 Oct 2006

Bibliographical note

Funding Information:
We would like to thank Russell Hope (Antibiotic Resistance Monitoring and Reference Laboratory) for nitrofurantoin and fosfomycin susceptibility data. Funding was provided by the Department of Health, UK, through grant no. 91 of the Resistance to Antibiotics and other Antimicrobial Agents Research Programme. Parts of this work were presented at the Sixteenth European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), Nice, France, 1–4 April 2006 (Ellington MJ, Livermore DM, Pitt TL et al. Mutators among CTX-M b-lactamase-producing E. coli pose a risk for the emergence of fosfomycin resistance. Clin Microbiol Infect 2006; 12 Suppl 4: Abstract P1236).

Keywords

  • Hypermutators
  • Nitrofurantoin
  • UTIs

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