Enhancement of vancomycin activity by phenothiazines against vancomycin-resistant Enterococcus faecium in vitro

The antimicrobial and resistance-reversal activities of seven phenothiazine derivatives were evaluated against vancomycin-sensitive Enterococcus faecalis ATCC 29212, vancomycin resistant E. faecalis ATCC 51299 and ten vancomycin-resistant E. faecium strains originating from human infections. Minimum inhibitory concentrations (MIC) of the compounds were determined by agar dilution method, and synergy between phenothiazines and vancomycin was investigated using Checkerboard (microbroth dilution) technique. We found that all enterococci strains, regardless of their susceptibility to vancomycin, were inhibited by phenothiazines at concentrations varying from 8 to 256 microg/ml, with thiethylperazine being the most potent inhibitory agent. Besides, all the phenothiazines showed partial synergy with vancomycin and could lessen MIC of vancomycin from 512 to 8 microg/ml at their sub-inhibitory concentrations. The highest reduction in MIC was observed with chlorpromazine (32 times); however, thiethylperazine and promethazine stood next (24 times). Although resistance modification was observed at concentrations higher than those that phenothiazines reach in vivo, the potential offered by non-antibiotics justify further animal experiments as well as clinical trials to establish their clinical relevance.