Session: Inhibitors of Bacterial and Fungal Efflux Pumps
Location:
Exhibit Hall
Session Date:
Monday, 9/27/99
Session Time:
3:00 pm - 4:30 pm
Efflux Pump Inhibitors (EPIs) Enhance the Activity of Antimicrobial Agents
against a Broad Selection of Bacteria
J. Blais, D. Cho, K. Tangen, C. Ford, A. Lee, O. Lomovskaya, S. Chamberland
Microcide Pharmaceuticals, Inc.: Mountain View, California
The in vitro activity profile of a series of new agents that are devoid of intrinsic
antimicrobial activity but enhance the activity of several classes of drugs against clinically
relevant pathogens through the inhibition of active efflux is presented. EPIs were
combined with a variety of antibiotics and tested against a wide selection of
gram-negative isolates, including several Enterobacteriaceae and Pseudomonadaceae,
and gram-positive isolates, including Staphylococci, Enterococci, and Streptococci.
Specific pump deletion mutants and mutants overexpressing pumps were used to
characterize the activity of these new agents in combination with several antibiotics
against the Mex pumps in P. aeruginosa, the AcrAB pump system in E. coli and
Salmonella, and Acr homologs in H. influenzae. Significant synergy was observed with
combinations of fluoroquinolones or macrolides and EPIs in Enterobacteriaceae and
Pseudomonadaceae. For example the MIC90 of levofloxacin for a population of 50
clinical isolates of P. aeruginosa was 8-fold lower in the presence of these efflux pump
inhibitors (EPIs), shifting from 8 to 1 µg/ml or from resistant to susceptible according to
the NCCLS susceptibility breakpoints for levofloxacin. In time-kill studies, the
combination of EPIs and levofloxacin was synergistically bactericidal against P.
aeruginosa. EPIs also enhanced the activity of fluoroquinolones and macrolides in
several gram-positive isolates. In summary, EPIs significantly enhance the activity of
antimicrobial agents against several pathogenic bacteria and may be clinically useful
agents. |
