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JAC Advance Access originally published online on October 3, 2006
Journal of Antimicrobial Chemotherapy 2006 58(6):1264-1267; doi:10.1093/jac/dkl398
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

High-level resistance to moxifloxacin and gatifloxacin associated with a novel mutation in gyrB in toxin-A-negative, toxin-B-positive Clostridium difficile

Denise Drudy1,*, Teresa Quinn1, Rebecca O'Mahony1, Lorraine Kyne2, Peadar Ó'Gaora3 and Séamus Fanning1

1 Centre for Food Safety, School of Agriculture Food Science and Veterinary Medicine, University College Dublin, Belfield, Dublin 4, Ireland 2 Department of Medicine for the Older Person Mater Misericordiae University Hospital, Dublin 7, Ireland 3 UCD Conway Institute of Biomolecular and Biomedical Research University College Dublin, Dublin 4, Ireland

Received 16 June 2006; returned 24 July 2006; revised 22 August 2006; accepted 11 September 2006

*Corresponding author. Tel: +353-1-716-6268; Fax: +353-1-716-6091; E-mail: denise.drudy{at}ucd.ie

Objectives: To determine the mechanism of high-level resistance to fluoroquinolone antimicrobials in toxin-A-negative, toxin-B-positive (A–B+) Clostridium difficile isolates.

Methods: Following culture 16–23S PCR ribotyping was used to determine genomic relationships between A–B+ C. difficile isolates. Antimicrobial susceptibilities were determined using Etests in the presence and absence of the efflux pump inhibitors reserpine (20 µg/mL), L-phenylalanine-L-arginine-ß-naphthylamide (PAßN; 20 µg/mL) and verapamil (100 µg/mL). Genomic regions including the quinolone-resistance-determining-region (QRDR) of gyrA and gyrB were amplified and characterized.

Results: PCR ribotyping profiles identified one major cluster of A–B+ C. difficile, universally resistant to the fluoroquinolones tested (ofloxacin, ciprofloxacin, levofloxacin, moxifloxacin and gatifloxacin; MICs > 32 mg/L). All isolates with high-level resistance had a transversion mutation (A->T) resulting in the amino acid substitution Asp-426->Val in gyrB. Non-clonal isolates were susceptible to moxifloxacin and gatifloxacin (MICs 0.3 and 0.4 mg/L, respectively) with reduced susceptibility to levofloxacin (MIC 3 mg/L) consistent with the wild-type genotype. The MICs for resistant isolates were not significantly affected by the addition of any of the efflux pump inhibitors. No amino acid substitutions were identified in the QRDR of gyrA.

Conclusions: High-level resistance to fluoroquinolones in A–B+ C. difficile is associated with a novel transversion mutation in gyrB. The emergence of universal resistance in different C. difficile strain types may be a factor promoting outbreaks in hospitals.

Keywords: fluoroquinolone resistance , A–B+ C. difficile , transversion mutation


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