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Efflux pump inhibitors may overcome antibiotic resistance in multi-resistant bacteria by increasing intracellular drug concentration

Abstract number: O101

Leitner I., Nemeth J., Abrahim A., Lagler H., Erker T., Zeitlinger M.

Introduction: Multi drug resistance (MDR) of bacteria is an increasing problem in clinical practice of antimicrobial therapy. Inhibition of bacterial efflux mechanisms appears to be a promising target in order to restore antimicrobial susceptibility in MDR bacteria. Previous in-vitro studies have shown that inhibitors of bacterial efflux pumps may improve the antimicrobial effect of fluoroquinolons. However, for most substances concentrations necessary to restore antimicrobial susceptibility were too high for clinical use, which might be ascribed to insufficient increase of intracellular concentrations of antimicrobials. The present study set out to investigate the potency of various efflux pump inhibitors (EPI) to overcome MDR and to explore changes of intracellular concentrations of ciprofloxacin for the most potent substances.

Methods: Two previously described EPIs, 1-(1-naphthylmethyl)-piperazine (NMP) and phenyl-arginine-beta-naphthylamide (PAbN) and with two novel, specific p-glycoprotein (PGP) inhibitors, tariquidar and elacridar, were investigated in terms of effects on in vitro antibacterial activity. Antimicrobial susceptibility to ciprofloxacin in the absence and presence of EPIs were tested in the following strains: Staphylococcus aureus ATCC 29213 (SA), ciprofloxacin resistant S. aureus SA-1199B (rSA), Pseudomonas aeruginosa ATCC 27853 (PS) and MDR Stenotrophomonas maltophilia ATCC BAA-85 (SM). Changes in intracellular concentrations of ciprofloxacin were determined by use of [14C]Ciprofloxacin.

Results: Inhibition of PGP mediated drug efflux by tariquidar and elacridar reduced MICs of ciprofloxacin for rSA from 16 mg/l to 2 mg/l in a dose depended manner, whereas only minor effects were observed for SA and Gram-negative strains. Addition of MNP and PAbN at high concentrations increased susceptibility towards ciprofloxacin in all resistant strains tested. By addition of tariquidar and elacridar a dose dependent increase of intracellular [14C]Ciprofloxacin was detected.

Conclusions: Our findings suggest that tariquidar and elacridar are potent inhibitors of PGP mediated bacterial efflux. Both substances may restore susceptibility for PGP over expressing pathogens by dose dependent increase of intracellular ciprofloxacin. MDR in Stenotrophomonas maltophilia could not be overcome by specific PGP inhibitors but susceptibility could be increased by addition of high doses of MNP and PAbN.

Session Details

Date: 19/04/2008
Time: 00:00-00:00
Session name: 18th European Congress of Clinical Microbiology and Infectious Diseases
Subject:
Location: Barcelona, Spain
Presentation type:
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