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 101-5 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.
| Original language | English |
|---|---|
| Pages (from-to) | 1268-1273 |
| Number of pages | 6 |
| Journal | Journal of Antimicrobial Chemotherapy |
| Volume | 58 |
| Issue number | 6 |
| DOIs | |
| State | Published - Dec 2006 |
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All Science Journal Classification (ASJC) codes
- Pharmacology
- Microbiology
Cite this
In vitro development of resistance to DX-619 and other quinolones in enterococci. / Wickman, Paul A.; Black, Jennifer A.; Smith Moland, Ellen; Thomson, Kenneth S.; Hanson, Nancy D.
In: Journal of Antimicrobial Chemotherapy, Vol. 58, No. 6, 12.2006, p. 1268-1273.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - In vitro development of resistance to DX-619 and other quinolones in enterococci
AU - Wickman, Paul A.
AU - Black, Jennifer A.
AU - Smith Moland, Ellen
AU - Thomson, Kenneth S.
AU - Hanson, Nancy D.
PY - 2006/12
Y1 - 2006/12
N2 - 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 101-5 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.
AB - 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 101-5 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.
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U2 - 10.1093/jac/dkl421
DO - 10.1093/jac/dkl421
M3 - Article
VL - 58
SP - 1268
EP - 1273
JO - Journal of Antimicrobial Chemotherapy
JF - Journal of Antimicrobial Chemotherapy
SN - 0305-7453
IS - 6
ER -