Comparison of synergistic effects of antimicrobial agents on carbapenem-resistant Pseudomonas aeruginosa isolates in the presence and absence of RND-type efflux pump inhibitors

Abstract

The high-level antimicrobial resistance particularly carbapenem resistance in Pseudomonas aeruginosa is a global health challenge. The combination of antibiotics and synergy effects is beneficial in control of drug-resistant P. aeruginosa. The synergic interaction of drugs combinations is affected by the mechanisms of antimicrobial resistance. The present study aimed to evaluate the effect of the inhibition of RND efflux pumps on the antibiotic’s combination in carbapenem-resistant P. aeruginosa. Methods: Seventeen efflux-mediated carbapenem resistant P. aeruginosa isolates were selected using the phenotypic methods. The minimum inhibitory concentrations (MICs) of antibiotics including cefepime, colistin, meropenem, ciprofloxacin, and tobramycin were determined by the broth microdilution method. Synergy effect of antibiotics was determined using the checkerboard assay in the absence and presence of RND efflux pump inhibitor phenylalanine-arginine betanaphthylamide (PAβN). Results: The most frequent synergistic effects found between cefepime/tobramycin and meropenem/tobramycin combinations in 35.3% of isolates. After adding PAβN, the most frequent synergistic effects between meropenem/ciprofloxacin and cefepime/ciprofloxacin combinations were found in 64.7%. The adding PAβN led to an increase in the synergy of all combination except tobramycin/colistin. The highest effect of PaβN on synergy effects of antibiotics combination was observed in meropenem/ciprofloxacin, cefepime/ciprofloxacin and ciprofloxacin/colistin (increasing of 41.2%).