effect of rnd-efflux pumps inhibitor on the synergy of different antibiotics combinations against carbapenem-resistant pseudomonas aeruginosa

Introduction: 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 antimicrobial agents is af-fected by the mechanisms of antimicrobial resistance. the aim of the current study was to evaluate the effect of efflux pump inhibition on the synergy of antibiotics against carbapenem-resistant p. aeruginosa.methods: the antibiotics’ minimum inhibitory concentration (mic) was determined by the microbroth dilu-tion method. the synergy effect of antibiotics was determined using the checkerboard assay with-out and with resistance-nodulation- division (rnd) efflux pump inhibitor phenylalanine-arginine beta-naphthylamide (paβn).results: the highest levels of synergistic effects were found between cefepime/tobramycin and meropenem/tobramycin combinations in 35.3% of isolates. after adding paβn, the most frequent synergistic effects were observed between the meropenem/ciprofloxacin and cefepime/ciprofloxacin combinations, found in 64.7% of isolates. the adding paβn led to an increase in the synergy of all combinations except tobramycin/colistin. the highest effect of paβn on the synergy effects of antibiotics combination was observed in meropenem/ciprofloxacin, cefepime/ciprofloxacin, and ciprofloxacin/colistin (an increase of 41.2%). conclusion: rnd efflux pump inhibition has a noticeable effect on the results of synergy tests of some antimi-crobial agent combinations. given the drug- and strain-dependent effects of paβn on synergy re-sults, the effects of efflux pump inhibitors should be studied on different combinations of drugs and a large population of bacterial strains.