In vitro Synergy and Time-kill Assessment of Interaction between Kanamycin and Metronidazole against Resistant Bacteria

Purpose: To evaluate the in vitro effects of combining kanamycin and metronidazole against resistant bacteria.
Methods: The influence of combining kanamycin and metronidazole against Gram-positive and Gramnegative bacteria was assessed by agar diffusion, checkerboard and time-kill assays.
Results: The test isolates were highly resistant, with minimum inhibitory concentration (MIC) ranging between 15.63 and >250 μg/ml for kanamycin, and 15.63 and 125 μg/ml for metronidazole. The antibacterial combinations resulted in drastic decrease in MIC with increased antibacterial activity that indicated synergistic interaction against all the bacteria except Acinetobacter calcaoceuticus UP, Enterobacter cloacae ATCC 13047 and Shigella flexneri KZN. Fractional inhibitory concentration index (FICI) showed synergy ranging from 0.31 to 0.50, additive interaction with FICI ranging from 0.53 to 1.25 and absence of antagonistic interaction. Escherichia coli ATCC 25922, Enterococcus faecalis ATCC 29212, Bacillus cereus ATCC 10702, Enterobacter cloacae ATCC 13047, Klebsiella pneumoniae ATCC 10031, Acinetobacter calcoaceuticus UP and Micrococcus luteus were totally eliminated by the antibacterial combinations within 24 h of incubation. The lack of antagonism between these antibacterial agents in checkerboard and time-kill assays suggest that kanamycin may be effective in both monotherapy and combination therapy.
Conclusion: The study indicates the potential beneficial value of combining kanamycin and metronidazole in the treatment of microbial infections in clinical settings.

Keywords
Drug-drug interactions; Synergy; Time-kill; Fractional inhibitory concentration index; Kanamycin; Metronidazole; Microbial resistance