Antibacterial Activities and Pharmacokinetics of E-4767 and E-5065, Two New 8-Chlorofluoroquinolones with a 7-Azetidin Ring Substituent

Abstract

E-4767 {(؊)-7-[3-(R)-amino-2-(S)-methyl-1-azetidinyl]-8-chloro-1-cyclopropyl-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 azetidine moiety at position 7. Their in vitro activities were evaluated in comparison with those of ciprofloxacin, ofloxacin, fleroxacin, and tosufloxacin, while ciprofloxacin was used as a reference for in vivo studies. Against gram-positive organisms, E-4767 and E-5065 were, in general, eight-and fourfold more active than tosufloxacin, which is the most potent of the reference compounds. E-4767 and E-5065 were also more potent than the reference compounds 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 90 s) were 0.007 to 0.5 g/ml and 0.03 to 2 g/ml, respectively, for gram-positive organisms and <0.003 to 0.06 g/ml and 0.007 to 0.12 g/ml, respectively, for members of the family Enterobacteriaceae except Serratia marcescens and Providencia spp. (MIC 90 s of E-4767 and E-5065 for these species were <0.5 g/ml and <2 g/ml, respectively). For Pseudomonas aeruginosa both compounds had a MIC 90 of 0.5 g/ml. E-4767 and E-5065 were 356-and 32-fold more potent than ciprofloxacin against Bacteroides spp., and their MIC 90 s for Clostridium spp. were 0.25 and 0.5 g/ml, respectively. Both products showed a remarkable reduction of activity when the pH was below 4.8 and, in general, were less active in the presence of 5 or 10 mM Mg 2؉ . The presence of horse serum or 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 concentration of drug in serum was reached 30 min postadministration) of E-4767 and E-5065 were approximately threefold higher than that of ciprofloxacin. The 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, respectively. These two new chlorofluoroquinolones were as effective as or more effective than ciprofloxacin against all experimental infections evaluated, not only against gram-negative bacteria, such as Escherichia coli or P. aeruginosa, but also against gram-positive pathogens, such as Staphylococcus aureus or Streptococcus pneumoniae. E-4767 was the most effective compound, with a 50% effective dose (ED 50 ) of <17 mg/kg for all strains tested except ciprofloxacin-resistant S. aureus strains. The ED 50 of E-4767 for these strains was <47.5 mg/kg. Against gram-positive experimental infections, the ED 50 values of E-4767 were 3-to 14-fold lower than those of E-5065 and up to 25 times lower than those of ciprofloxacin.Since the discovery of nalidixic and oxolinic acids (10, 13), many modifications have been introduced in the chemical structure of the quinolonic ring, yielding new drug...

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