JAC Advance Access originally published online on July 12, 2006
Journal of Antimicrobial Chemotherapy 2006 58(3):543-548; doi:10.1093/jac/dkl278
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Clinical significance of overexpression of multiple RND-family efflux pumps in Bacteroides fragilis isolates
1 Greater Los Angeles Veterans Administration Healthcare Systems 691/151J, 11301 Wilshire Blvd., Los Angeles, CA 90073, USA 2 Department of Medicine, University of California Los Angeles, CA 90024, USA
Received 8 March 2006; returned 1 June 2006; revised 7 June 2006; accepted 8 June 2006
*Corresponding author. Tel: +1-310-268-3404; Fax: +1-310-268-4458; E-mail: hwexler{at}ucla.edu
Objectives: The aim of the present study was to determine correlation between bmeB efflux pump overexpression and resistance to fluoroquinolones and ß-lactams in Bacteroides fragilis clinical isolates (n = 51) and the effects of broad-spectrum efflux pump inhibitors (EPIs) on the MICs of the test antibiotics.
Methods: Susceptibility to garenoxacin, levofloxacin, moxifloxacin, cefoxitin and faropenem ± EPIs (CCCP, MC-207,110, reserpine and verapamil) was determined. Expression of bmeB efflux pumps was measured, topoisomerase genes were sequenced and ß-lactamase production was determined.
Results: Isolates were grouped into categories based on susceptibility patterns, topoisomerase sequence and efflux pump expression. Panel I isolates (19/51, 37.3%) were highly resistant to fluoroquinolones and cefoxitin (resistance to all agents was significantly reduced by EPIs, P < 0.05), had a point mutation in gyrA (C
T) causing a Ser-82Phe substitution, and overexpressed bmeB4 and bmeB15. Panel II isolates (7/51; 13.7%) had intermediate-level resistance to fluoroquinolones and cefoxitin and a GyrA substitution. Panel IIIA isolates (21/51; 41.2%) had intermediate-level fluoroquinolone resistance and high-level cefoxitin resistance [resistance to all agents was significantly reduced by EPIs (P < 0.05)] and overexpressed bmeB4 and bmeB15. Panel IIIB isolates (4/51; 7.8%) had low-level fluoroquinolone resistance and high-level resistance to cefoxitin [cefoxitin resistance was significantly reduced by EPIs (P < 0.05)] and overexpressed bmeB4, bmeB6, bmeB10 and bmeB14. All isolates were ß-lactamase-positive.
Conclusions: These data suggest that bmeB efflux pump overexpression can (i) cause low- to intermediate-level clinically relevant fluoroquinolone resistance; (ii) be coupled with GyrA substitutions to cause high-level fluoroquinolone resistance; (iii) contribute to high-level clinically relevant resistance to ß-lactams.
Keywords: cross-resistance , therapy , susceptibility
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