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JAC Advance Access published online on October 24, 2006
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl421
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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
Received June 26, 2006
Revised August 25, 2006
Accepted September 25, 2006

Brief report

In vitro development of resistance to DX-619 and other quinolones in enterococci

Paul A. Wickman 1 *, Jennifer A. Black 1, Ellen Smith Moland 1, Kenneth S. Thomson 1, and Nancy D. Hanson 1

1 Department of Medical Microbiology and Immunology, Center for Research in Anti-Infectives and Biotechnology, Creighton University School of Medicine, 2500 California Plaza, Omaha, NE 68178, USA

* To whom correspondence should be addressed.
Paul A. Wickman, E-mail: pwickman{at}creighton.edu


  Abstract

Objectives: To investigate the molecular events involved in the development of quinolone resistance in enterococci.

Methods: Clinical isolates of Enterococcus faecium and Enterococcus faecalis were exposed to inhibitory and subinhibitory concentrations of DX-619, ciprofloxacin, levofloxacin, gatifloxacin and moxifloxacin. Mutational frequencies were calculated and susceptibility changes were determined. The quinolone resistance determining regions (QRDRs) of gyrA and parC in less-susceptible mutants were amplified by PCR and sequenced.

Results: Single-step mutants of E. faecalis and E. faecium were selected with all drugs. There were no differences in the frequencies of mutant selection among drugs, with frequencies ranging from 10-5 to 10-8. All single-step mutants were inhibited by 0.03-1 mg/L DX-619, 0.25-8 mg/L moxifloxacin, 0.5-8 mg/L gatifloxacin, 1-16 mg/L levofloxacin and 1-32 mg/L ciprofloxacin. No QRDR changes were observed in single-step mutants. Less-susceptible mutants selected after five passages on agar containing subinhibitory quinolone concentrations were inhibited by 0.12-8 mg/L DX-619, 1-64 mg/L moxifloxacin, 2-64 mg/L gatifloxacin and 2-128 mg/L levofloxacin and ciprofloxacin. QRDR changes were detected in only 9 of the 20 fifth-passage mutants, suggesting that mutations outside the purported QRDRs and/or other resistance mechanisms were also involved.

Conclusions: The relatively high frequencies at which single-step mutants were selected with all drugs indicate that caution is necessary if quinolones are to be considered for monotherapy of serious enterococcal infections. DX-619, the most potent quinolone, may have potential as an anti-enterococcal agent if sufficient concentrations can be safely attained in vivo.

Keywords: moxifloxacin; ciprofloxacin; levofloxacin; mutational frequency; gatifloxacin.
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