Antibacterial activities and pharmacokinetics of E-4767 and E-5065, two new 8-chlorofluoroquinolones with a 7-azetidin ring substituent

E-4767 {(-)-7-[3-(R)-amino-2-(S)-methyl-1-azetidinyl]-8-chloro-1-cyclopropy l-1,4-dihydro-6-fluoro-4-oxo-3-quinolinecarboxylic acid} and E-5065 [(-)-7- (3-amino-1-azetidinyl)-8-chloro-1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-3- quinolinecarboxylic acid] are two new chlorofluoroquinolones with an azetid ine moiety at position 7. Their in vitro activities were evaluated in compa rison with those of ciprofloxacin, ofloxacin, fleroxacin, and tosufloxacin, while ciprofloxacin was used as a reference for in vivo studies. Against g ram-positive organisms, E-4767 and E-5065 were, in general, eight- and four fold more active than tosufloxacin, which is the most potent of the referen ce compounds. E-4767 and E-5065 were also more potent than the reference co mpounds against all species of enteric bacteria tested. The MICs of E-4767 and E-5065 at which 90% of the isolates tested were inhibited (MIC,os) were 0.007 to 0.5 mug/ml and 0.03 to 2 mug/ml, respectively, for gram-positive organisms and less than or equal to0.003 to 0.06 mug/ml and 0.007 to 0.12 m ug/ml, respectively, for members of the family Enterobacteriaceae except Se rratia marcescens and Providencia spp. (MIC(90)s of E-4767 and E-5065 for t hese species were less than or equal to0.5 mug/ml and less than or equal to 2 mug/ml, respectively). For Pseudomonas aeruginosa both compounds had a MI C90 of 0.5 mug/ml. E-4767 and E-5065 were 356- and 32-fold more potent than ciprofloxacin against Bacteroides spp., and their MIC90s for Clostridium s pp. were 0.25 and 0.5 mug/ml, respectively. Both products showed a remarkab le reduction of activity when the pH was below 4.8 and, in general, were le ss active in the presence of 5 or 10 mM Mg2+. The presence of horse serum o r human urine (pH 7.2) decreased the activity of E-4767 and E-5065 only two - to fourfold more than the activity observed in broth. After an oral dose of 50 mg/kg of body weight, the maximum levels in serum (the maximum concen tration of drug in serum was reached 30 min postadministration) of E-4767 a nd E-5065 were approximately threefold higher than that of ciprofloxacin. T he area under the concentration-time curve from 0 to 4 h for ciprofloxacin was about two- and fourfold lower than that for E-4767 and E-5065, respecti vely. These two new chlorofluoroquinolones were as effective as or more eff ective than ciprofloxacin against all experimental infections evaluated, no t only against gram-negative bacteria, such as Escherichia coli or P. aerug inosa, but also against gram-positive pathogens, such as Staphylococcus aur eus or Streptococcus pneumoniae. E-4767 was the most effective compound, wi th a 50% effective dose (ED50) of less than or equal to 17 mg/kg for all st rains tested except ciprofloxacin-resistant S. aureus strains. The ED., of E-4767 for these strains was less than or equal to 47.5 mg/kg. Against gram -positive experimental infections, the ED50 values of E-4767 were 3- to 14- fold lower than those of E-5065 and up to 25 times lower than those of cipr ofloxacin.