In vitro antibacterial properties of AT-2266, a new pyridonecarboxylic acid

The in vitro susceptibilities of 1,310 clinical isolates to QA-241, a novel tricyclic quinolone, were evaluated in comparison with susceptibilities to norfloxacin, ofloxacin, enoxacin, and ciprofloxacin. The MICs of QA-241 for 90% of staphylococci, Enterococcus faecalis isolates, and streptococcal species ranged from 1.56 to 6.25 ,ug/ml, and the activity of QA-241 was similar to those of norfloxacin and enoxacin but two to four times less potent than those of ofloxacin and ciprofloxacin. At the concentration of -.1.56 ,ug/ml, QA-241 inhibited 90% of Haemophilus influenzae, Bordetella pertussis, Neisseria gonorrhoeae, and gram-negative enteric bacteria except for Serratia marcescens and Citrobacterfreundii. QA-241 was moderately active (MIC for 90% of strains tested, 6.25 to 12.5 ,ug/ml) against S. marcescens, Pseudomonas aeruginosa, Xanthomonas maltophilia, and Bacteroidesfragilis. The antibacterial activity of QA-241 was roughly comparable to that of enoxacin but two to four times less potent than that of ofloxacin. In systemic infections in mice with gram-positive cocci and gram-negative rods, the efficacy of QA-241 was generally greater than that of norfloxacin and similar to those of ofloxacin and ciprofloxacin. In urinary tract infections in mice with Escherichia coli or Pseudomonas aeruginosa, QA-241 was as active as ofloxacin and more active than norfloxacin but less active than ciprofloxacin. In pulmonary infections in mice with Klebsiella pneumoniae, the effectiveness of QA-241 was similar to that of ofloxacin.Recently, new quinolone antimicrobial agents such as norfloxacin (4), ofloxacin (10), enoxacin (7), and ciprofloxacin (14) have been developed and used in the therapy of bacterial infections. These new quinolones have a broad spectrum of antimicrobial activity against gram-positive and gram-negative bacteria, including Pseiudomonas aeruoginosa.QA-241, (-+)-9-fluoro-6,7-dihydro-5-methyl-8-(4-methyl-1-piperazinyl) -1,7 -dioxo -1H,5H-benzo[ij]quinolidine -2 -carboxylic acid hydrochloride hydrate, was synthesized by Tokyo Tanabe Research Laboratories. QA-241 is a novel tricyclic quinolone derivative which is bridged by an oxomethylene group at 1,8 positions of the quinoline ring, possesses methyl and 4-methylpiperazinyl groups, and has a fluorine atom in the structure (Fig. 1) defibrinated horse blood to support the growth of streptococci and enterococci. Brain heart infusion agar (Difco) supplemented with 5% Fildes enrichment (Difco) was used for Haemophilius influenzae; GC agar (Difco) supplemented with 1% hemoglobin (Difco)-2% defined supplement solution (glucose, 20 g; glutamine, 0.5 g; cocarboxylase, 0.001 g in 100 ml of distifled water) was used for Neisseria gonorrhoeae; and Gifu Anaerobic Medium agar (Nissui Pharmaceutical, Tokyo, Japan)

Section: Methodsmentioning

confidence: 99%

“…Recently, new quinolone antimicrobial agents such as norfloxacin (4), ofloxacin (10), enoxacin (7), and ciprofloxacin (14) have been developed and used in the therapy of bacterial infections. These new quinolones have a broad spectrum of antimicrobial activity against gram-positive and gram-negative bacteria, including Pseiudomonas aeruoginosa.…”

mentioning

confidence: 99%

In vitro and in vivo activities of QA-241, a new tricyclic quinolone derivative

Asahara

Tsuji

Goto

et al. 1989

“…Appearance of these strains has prompted a search for alternative antimicrobial agents with activity against vibrios. Norfloxacin is a new carboxyquinoline derivative that has in vitro activity against a number of enteric pathogens, including campylobacter, salmonella, shigella, toxigenic Escherichia coli, yersinia, and, in testing involving a limited number of strains, V. parahaemolyticus and V. cholerae (4,8,11,13). In vitro activity against V. cholerae 01 would make norfloxacin an attractive drug for further study in areas with tetracycline-resistant cholera.…”

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confidence: 99%

In vitro susceptibility of pathogenic Vibrio species to norfloxacin and six other antimicrobial agents

Morris¹,

Tenney²,

Drusano³

1985

The in vitro activity of norfloxacin and six other antimicrobial agents was tested against 93 vibrio strains representing the currently described pathogenic Vibrio species. Norfloxacin had excellent activity against all species, with the following MICs for 90% of the strains: 0.016 ,ug/ml for Vibrio cholerae (including tetracycline-resistant V. cholerae 01 strains), 0.25 ,ug/ml for V. parahaemolyticus, and 0.063 ,ig/ml for V.vulnificus.Tetracycline is currently the drug of choice for serious vibrio infections (10,14). Since 1978, however, an increasing number of Vibrio cholerae 01 strains have been identified that have plasmid-mediated resistance to multiple antibiotics, including tetracycline. These strains have been responsible for major epidemics in Tanzania (9) and Bangladesh (7) and are currently endemic in parts of Africa (J. G. Morris 503, 1984). Appearance of these strains has prompted a search for alternative antimicrobial agents with activity against vibrios. Norfloxacin is a new carboxyquinoline derivative that has in vitro activity against a number of enteric pathogens, including campylobacter, salmonella, shigella, toxigenic Escherichia coli, yersinia, and, in testing involving a limited number of strains, V. parahaemolyticus and V. cholerae (4,8,11,13). In vitro activity against V. cholerae 01 would make norfloxacin an attractive drug for further study in areas with tetracycline-resistant cholera. Demonstration of activity against the other known pathogenic Vibrio species would also enhance the potential usefulness of norfloxacin as a broad-spectrum agent for treatment of bacterial gastroenteritis. In this study we compared the in vitro activity of norfloxacin to that of nalidixic acid, tetracycline, chloramphenicol, ampicillin, trimethoprim-sulfamethoxazole, and gentamicin against 93 vibrio strains representing all known pathogenic Vibrio species (10).( Results of the microtiter MIC assays are given in Tables 1 and 2. All vibrio strains tested were susceptible to norfloxacin, with MICs of .0.5 pLg/ml. V. cholerae strains were very susceptible to the drug, with MICs of 0.016 ,ug/ml for 90% of the strains tested. The presence of an R factor did not influence the norfloxacin MICs. Only one V. cholerae strain had a norfloxacin MIC of >0.016 ,ug/ml: the MIC for this strain was 0.25 ,ug/ml, with a corresponding MIC of nalidixic acid of 32 jLg/ml. A significant inoculum effect was observed for one of the four V. cholerae 01 strains tested, with MICs of <0.008 ,ug/ml at 103 and 105 organisms per ml and 1.0 ,ug/ml at 107 organisms per ml. For one of the two V. parahaemolyticus strains tested, the MIC increased from 0.25 to 1.0 ,ug/ml with an increase in the inoculum from 105 to 107 organisms per ml. The MIC for the V. vulnificus strain increased from 0.031 ,ug/ml at 103 organisms per ml to 0.125 ,ug/ml at 105 organisms per ml and 1 ,ug/ml at 107 organisms per ml.Our data indicate that norfloxacin may be a useful agent for treatment of cholera. Peak stool concentrations of the drug after a single 400-mg o...

“…Interest in new quinoline derivatives norfloxacin (8,9,13) and, more recently, enoxacin CI-919 (1,11) as an alternate group of antibacterial agents has been expanded with the introduction of ciprofloxacin (BAY o 9867). Ciprofloxacin was shown to have activity against a wide range of bacteria and was particularly effective against the Enterobacteriaceae (2,6,16,17).…”

mentioning

confidence: 99%

Antimicrobial activity of ciprofloxacin against Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus determined by the killing curve method: antibiotic comparisons and synergistic interactions

Chalkley¹,

Koornhof²

1985

135

A derivative of quinolinecarboxylic acid, ciprofloxacin (BAY o 9867) was found to be an effective bactericidal agent against Pseudomonas aeruginosa and Escherichia coli. A bactericidal effect was achieved immediately after the addition of ciprofloxacin. At a concentration of 0.5 ,ug/ml, culture viability was reduced from 5 x 10 to about S x 103 CFU/ml within 15 min, and at 0.1 ,ug/ml, a >10-fold reduction in viability resulted during the first hour after exposure. This bactericidal activity observed during the lag phase in Mueller-Hinton broth was also demonstrated in a nongrowing system. The antibiotics used in comparative studies, i.e., tobramycin, aztreonam, cefotaxime, and azlocillin, did not show this initial bactericidal activity, and ciprofloxacin prevented culture regrowth at lower concentrations. Staphylococcus aureus was not as susceptible to ciprofloxacin; killing occurred at a concentration of 0.5 ,Ig/ml only after the onset of exponential growth in the control culture. Synergistic interactions were observed wtih ciprofloxacin in combination with tobramycin and azlociilin against P. aeruginosa and with cefotaxime and tobramycin against E. coli.