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Antimicrob Agents Chemother. 1990 December; 34(12): 2318-2326

Comparative in vitro and in vivo activities of six new monofluoroquinolone and difluoroquinolone 3-carboxylic acids with a 7-azetidin ring substituent.

Department of Sanitary Microbiology and Parasitology, Faculty of Pharmacy, University of Barcelona, Spain.

ABSTRACT

E-4502, E-4501, E-4500, E-4480, E-4474, and E-4441 are new monofluorinated or difluorinated quinolone agents that are chemically characterized by the presence of an azetidin ring, with different C'-3 substituents, at position 7 of the molecular structure. The MICs of the difluorinated compounds E-4501, E-4474, and E-4441 for 90% of isolates were 0.06 to 1, 0.06 to 1, and 0.12 to 1 microgram/ml, respectively, against gram-positive organisms (staphylococci, streptococci, and Enterococcus faecalis); 0.0015 to 0.12, 0.015 to 0.12, and 0.03 to 0.12 microgram/ml, respectively, against members of the family Enterobacteriaceae except Providencia spp.; and 1, 1, and 2 micrograms/ml, respectively, against Pseudomonas aeruginosa. E-4501, E-4474, and E-4441 inhibited all anaerobic bacteria at concentrations of 1, 2, and 4 micrograms/ml, respectively. Difluorinated compounds were significantly more active than the corresponding monofluorinated analogs E-4502, E-4500, and E-4480 against aerobic and facultatively anaerobic organisms, as well as against anaerobes. Considering monofluorinated and difluorinated compounds, activity in moderate ascending order was observed in quinolones containing an amine and a methyl group (E-4441 and E-4480), an amine group (E-4474 and E-4500), and a methylamine group (E-4501 and E-4502) in the C'-3 position of the azetidin ring. E-4501, E-4474, and E-4441 were more active than norfloxacin and DR-3355 [S-(-)-ofloxacin], had activities comparable to or slightly lower than that of ciprofloxacin against gram-negative bacteria, and were more active than all the reference quinolones against gram-positive organisms and anaerobes. E-4502 and E-4501, which were used to determine the effect of pH, were less active in acidic medium. In general, E-4502, E-4501, E-4500, E-4480, E-4474, and E-4441 activities were not affected or increased in medium containing serum but decreased in the presence of 10 mM Mg2+ or in human urine at pH 5.5. The protective effect of E-4501, E-4474, and E-4441 after oral administration against systemic infections with Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa in mice was greater than that of ciprofloxacin.

This article has been cited by other articles:

• Gargallo-Viola, D., Ferrer, S., Tudela, E., Robert, M., Coll, R., Roser, R., Guinea, J. (2001). Antibacterial Activities and Pharmacokinetics of E-4767 and E-5065, Two New 8-Chlorofluoroquinolones with a 7-Azetidin Ring Substituent. Antimicrob. Agents Chemother. 45: 3113-3121 [Abstract] [Full Text]