title: In vitro evaluation of A-56619 (difloxacin) and A-56620: new aryl-fluoroquinolones.
abstract: The in vitro antibacterial potencies of A-56619 and A-56620, two new aryl-fluoroquinolones, were compared with the potency of norfloxacin against a broad spectrum of organisms. Cefotaxime, aztreonam, piperacillin, imipenem, penicillin, and gentamicin were also tested for reference purposes. The MICs required to inhibit at least 90% of the strains tested ranged from 0.25 to 4 micrograms/ml for A-56619 and from 0.06 to 0.5 microgram/ml for A-56620 for members of the Enterobacteriaceae. A-56619 was generally twofold less potent and A-56620 was twofold more potent than norfloxacin against most aerobic gram-negative bacilli, including members of the Enterobacteriaceae and Pseudomonas aeruginosa. Against indole-positive Proteus, Morganella, Providencia rettgeri, and Serratia strains, A-56619 was at least 8- to 16-fold less potent than norfloxacin. A-56619 and A-56620 were four- to eightfold more potent than norfloxacin against Staphylococcus aureus and equally potent to fourfold more potent against Streptococcus species, Haemophilus influenzae, and Neisseria gonorrhoeae. The MICs of A-56619 and A-56620 were only slightly affected by increased inoculum size or by the addition of various cations at physiologic concentrations. A-56619 was three- to fivefold less active at pH 8.0 than at pH 6.5 or 7.2. A-56620 was twofold less active at pH 6.5 than at pH 8.0 or 7.2 against members of the Enterobacteriaceae and Pseudomonas aeruginosa; similar pH variations did not affect A-56620 activity against gram-positive cocci. The potencies of A-56619, A-56620, and norfloxacin were less in urine than in Mueller-Hinton broth; however, this effect was more pronounced with norfloxacin. Human serum at a concentration of 50% caused a 4- to 64- fold decrease in the potency of A-56619 and an average 4-fold decrease in the potency of A-56620, compared with no effect on the potency of norfloxacin. A-56619, A-56620, and norfloxacin were bactericidal and, at four times the MIC, reduced the viable cell counts of Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa by approximately 99.9% within 2 h. A-56619, A-56620, and norfloxacin showed no significant synergistic activity and no antagonism when they were aminoglycoside or beta-lactam antimicrobial agents.
mesh_terms: D000890:Anti-Infective Agents; D001398:Aztreonam / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects*; D002439:Cefotaxime / Q000494:pharmacology; D002939:Ciprofloxacin / Q000031:analogs & derivatives*; D004338:Drug Combinations; D004755:Enterobacteriaceae / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D024841:Fluoroquinolones; D005839:Gentamicins / Q000494:pharmacology; D006193:Haemophilus influenzae / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D015378:Imipenem; D008826:Microbial Sensitivity Tests; D009344:Neisseria gonorrhoeae / Q000187:drug effects; D009643:Norfloxacin / Q000494:pharmacology; D010406:Penicillins / Q000494:pharmacology; D010878:Piperacillin / Q000494:pharmacology; D010879:Piperazines / Q000097:blood / Q000494:pharmacology* / Q000652:urine; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D011804:Quinolines / Q000097:blood / Q000494:pharmacology* / Q000652:urine; D013211:Staphylococcus aureus / Q000187:drug effects; D013291:Streptococcus / Q000187:drug effects; D013845:Thienamycins / Q000494:pharmacology
chemical_list: D000890:Anti-Infective Agents; D004338:Drug Combinations; D024841:Fluoroquinolones; D005839:Gentamicins; D010406:Penicillins; D010879:Piperazines; D011804:Quinolines; D013845:Thienamycins; D002939:Ciprofloxacin; C047225:difloxacin; D015378:Imipenem; D001398:Aztreonam; D009643:Norfloxacin; D002439:Cefotaxime; C047224:sarafloxacin; D010878:Piperacillin