Antibacterial Activities and Pharmacokinetics of E-4767 and E-5065, Two New 8-Chlorofluoroquinolones with a 7-Azetidin Ring Substituent
Authors: Gargallo-Viola Domingo , Ferrer Santiago , Tudela Encarna , Robert Marta , Coll Ramon , Roser Roberto , Guinea Jesus 
Published: July 2002

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 μg/ml and 0.03 to 2 μg/ml, respectively, for gram-positive organisms and ≤0.003 to 0.06 μg/ml and 0.007 to 0.12 μg/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 μg/ml and ≤2 μg/ml, respectively). For
Pseudomonas aeruginosa
both compounds had a MIC
90
of 0.5 μg/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 μg/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.