INVITRO AND INVIVO ANTIBACTERIAL ACTIVITIES OF E-4497, A NEW 3-AMINE-3-METHYL-AZETIDINYL TRICYCLIC FLUOROQUINOLONE

The in vitro and in vivo antibacterial activities of a new tricyclic fluoroquinolone, E-4497 [S(-)-9-fluoro-3-methyl-10-(3-amine-3-methyl-azetidin-1-yl)-7-oxo-2,3-dihydro-7H-pyrido-(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid], were evaluated in comparison with those of DR-3355 [S-(-)-ofloxacin], norfloxacin, and ciprofloxacin. E-4497 was more potent than norfloxacin and as potent than DR-3355 and ciprofloxacin against Staphylococcus spp., Streptococcus spp., and Enterococcus faecalis. With the exception of Providencia spp., E-4497 inhibited 90% of the Enterobacteriaceae at less-than-or-equal-to 0.25-mu-g/ml. Against enteric bacteria, E-4497 was similar in potency to norfloxacin but less potent than DR-3355 and ciprofloxacin. For Pseudomonas aeruginosa, the MICs of E-4497, DR-3355, norfloxacin, and ciprofloxacin for 90% of strains were 2, 2, 4, and 0.5-mu-g/ml, respectively. Against Clostridium perfringens and Bacteroides fragilis, E-4497 (MICs for 90% of strains, 2 and 8-mu-g/ml, respectively) was two- to fourfold more active than norfloxacin and ciprofloxacin. E-4497 activity decreased moderately in the presence of 10 mM Mg2+. Urine at pH 5.5 caused a significant decrease in activity compared with urine at pH 7.2. However, the presence of serum either had no effect or increased the activity of E-4497. In general, E-4497 was bactericidal at the MIC. In systemic infections with Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli, and Pseudomonas aeruginosa in mice, the protective effect of E-4497 was generally greater than that of norfloxacin and comparable to those of DR-3355 and ciprofloxacin.