Pipemidic Acid, a New Antibacterial Agent Active Against Pseudomonas aeruginosa : In Vitro Properties

206

104

AM-715 [1-ethyl-6-fluoro-1 ,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid] is a new nalidixic acid analog. AM-715 has a broad spectrum of antibacterial activity against gram-positive and gram-negative bacteria. The antibacterial activity of AM-715 was greater than those of pipemidic acid and nalidixic acid. AM-715 had higher antibacterial activity against Pseudomonas aeruginosa than did gentamicin. Most nalidixic acid-resistant bacteria were susceptible to AM-715, and cross-resistance was not observed between AM-715 and various antibiotics. The minimal concentration of AM-715 required to inhibit the growth of 75% of the total number of clinical isolates was as follows: Escherichia coli, 0.04 ug/ml; Klebsiella pneumoniae, 0.1 ug/ml; Serratia marcescens, 0.88 ug/ml; Enterobacter spp., 0.076 pg/ml; Staphylococcus aureus, 1.10 pg/ml; P. aeruginosa, 0.38 pug/ml; and nalidixic acid-resistant strains of gramnegative bacteria, 0.62 pg/ml. AM-715 at minimal inhibitory concentrations or at slightly higher concentrations had bactericidal activity against various species of bacteria. The effect of inoculum sizes on minimal inhibitory concentrations and minimal bactericidal concentrations of AM-715 against gram-negative bacteria was smaller than on those of pipemidic acid and nalidixic acid. The dose-response curve of AM-715 indicated a steep gradient, and the 50% inhibited doses of AM-715 were 0.014 pug/ml against E. coli ML4707 and 0.21 pug/ml against P. aeruginosa NC-5.

Section: Nc-5mentioning

confidence: 99%

In Vitro Antibacterial Activity of AM-715, a New Nalidixic Acid Analog

Itô

Hirai

Inoue

et al. 1980

206

104

“…Since nalidixic acid was developed in 1963 (2), many nalidixic acid analogs (e.g., pipemidic acid [9]) have been introduced into clinical use, but they have been used mainly against urinary tract infections. Recently, new quinolones, including norfloxacin (4), ofloxacin (8), enoxacin (5), pefloxacin (10), and ciprofloxacin (3), with improved antibacterial activities and spectra have been developed, expanding their clinical use.…”

mentioning

confidence: 99%

In vitro and in vivo activity of NY-198, a new difluorinated quinolone

Hirose¹,

Okezaki²,

Kato³

et al. 1987

119

-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid hydrochloride] is a new difluorinated quinolone characterized by the presence of a C-methyl group at the 3 position of the piperazine moiety. It has a broad antibacterial spectrum. The in vitro antibacterial activity of (5), pefloxacin (10), and ciprofloxacin (3), with improved antibacterial activities and spectra have been developed, expanding their clinical use. -(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid hydrochloride] was synthesized at Hokuriku Seiyaku Co., Ltd., paying attention to high antibacterial activity, good oral absorption, stability in metabolism, and low toxicity. NY-198 is a new difluorinated quinolone which has a C-methyl group at the 3 position of the piperazine moiety (Fig. 1) Other antimicrobial agents used were obtained from the following sources: pipemidic acid, Dainippon Seiyaku Co., Ltd., Osaka, Japan; norfloxacin, Kyorin Seiyaku, Tokyo, Japan; ofloxacin and nalidixic acid, Daiichi Seiyaku Co., Ltd., Tokyo, Japan; gentamicin, Essex Japan Co., Ltd., Osaka, Japan; ampicillin sodium, Toyama Chemical Co., * Corresponding author. t Present address: Division of Radiation Biology, Faculty of Pharmaceutical Sciences, Kanazawa University, 13-1, Takaramachi, Kanazawa-shi, Ishikawa-ken 920, Japan.Ltd., Tokyo, Japan; methicillin sodium, Banyu Yakuhin Co., Ltd., Tokyo, Japan.Test strains. Bacterial strains used in this study were recent clinical isolates from various hospitals in Japan. All organisms were maintained in the Laboratory of Drug Resistance in Bacteria, School of Medicine, Gunma University.Determination of MICs. MICs were determined by the twofold agar dilution method. The media used for preculture and MIC determination were as follows: brain heart infusion broth (Nissui Seiyaku) and sensitivity test agar (Nissui Seiyaku) supplemented with 10% defibrinated horse blood for streptococci; brain heart infusion broth and agar supplemented with 10 ,ug of hemin (Sigma Chemical Co., St. Louis, Mo.) and 2 ,ug of 3-NAD (Sigma) per ml for Haemophilus influenzae; charcoal medium (Penassay broth, 17.5 g/liter; yeast extract, 2 g/liter; active charcoal, 2 g/liter; agar, 5 g/liter; L-cysteine hydrochloride, 80 mg/liter; iron [III] pyrophosphate, 0.2 g/liter) for Legionella sp.; GC agar (Difco Laboratories, Detroit, Mich.) supplemented with 1% hemoglobin (Difco) and 1% IsoVitaleX (BBL Microbiology Systems, Cockeysville, Md.) for Neisseria gonorrhoeae; GAM broth and agar (Nissui Seiyaku) for obligate anaerobes; and sensitivity test broth and agar for the other microorganisms. An overnight broth culture (about 108 CFU/ml) was diluted 0 F COOH

“…Oral administration of AT-2266 to animals produced concentrations in body fluids and tissues high enough to cover the minimal inhibitory concentrations (MICs) of a large variety of bacterial pathogens (9). Because there was no evidence of cross-resistance with agents such as streptomycin, chloramphenicol, tetracycline, ampicillin, or cephalexin (11,12), AT-2266 might be a potentially useful drug against various pathogens which are now resistant to these antibiotics. To estimate the chemotherapeutic value of AT-2266, we compared its in vitro and in vivo antibacterial activities with those of norfloxacin, pipemidic acid, and nalidixic acid.…”

mentioning

confidence: 99%

In vitro and in vivo antibacterial activity of AT-2266

Kouno¹,

Inoue²,

Mitsuhashi³

1983

AT-2266 [1-ethyl 6fluoro-1,44dihydro4oxo-7-(l-piperazinyl)-1 ,8naphthyridine-3-carboxylic acid] showed a broad spectrum of antibacterial activity against grampositive and gram-negative microorganisms, including Pseudomonas aeruginosa. The in vitro antibacterial activity of AT-2266 was in general comparable to that of norfloxacin, but much higher than that of pipemidic or nalidixic acid. The 90% minimal inhibitory concentrations (MIC90s) of AT-2266 for P. aeruginosa resistant to gentamicin (MIC range, 25 to >200 ,ug/ml) and Enterobacteriaceae resistant to nalidixic acid (25 to >1,600 ,ug/ml) were 3.13 and 12.5 Ijg/ml, respectively. TheMICs of AT-2266 were only slightly affected by the addition of horse serum or sodium cholate, by the pH of the medium, and by inoculum size. AT-2266 was bactericidal at concentrations near its MIC value. The 50%o effective doses of AT-2266 after oral administration against systemic infections in mice were about 1/2 those of norfloxacin, about 1/10 those of pipemidic acid, and between 1/20 and 1/40 those of nalidixic acid.acid] is a new pyridonecarboxylic acid derivative synthesized by Matsumoto et al. (7). This compound, like the structurally related norfloxacin (1-5, 10), has a high order of activity against a broad spectum of gram-positive, gram-negative, and glucose-nonfermenting bacteria. Its activity is in general superior to that of pipemidic acid, nalidixic acid, oxolinic acid, cephalexin, ampicillin, carbenicillin, and gentamicin in vitro and in vivo (11). Oral administration of AT-2266 to animals produced concentrations in body fluids and tissues high enough to cover the minimal inhibitory concentrations (MICs) of a large variety of bacterial pathogens (9). Because there was no evidence of cross-resistance with agents such as streptomycin, chloramphenicol, tetracycline, ampicillin, or cephalexin (11,12), AT-2266 might be a potentially useful drug against various pathogens which are now resistant to these antibiotics. To estimate the chemotherapeutic value of AT-2266, we compared its in vitro and in vivo antibacterial activities with those of norfloxacin, pipemidic acid, and nalidixic acid.MATERIALS AND METHODS Drugs. AT-2266 sesquihydrate and pipemidic acid trihydrate were obtained from Dainippon Pharmaceutical Co., Ltd.; norfloxacin was from Kyorin Pharmaceutical Co., Ltd.; nalidixic acid was from Daiichi Seiyaku Co., Ltd.; and gentamicin was from Shionogi Co., Ltd.Organisms. The organisms used were reference strains stored in our laboratories and recent clinical isolates randomly collected in various hospitals in Japan.Determination of MICs. MICs were determined by the twofold agar dilution method. The media used for preculture and MIC determination were brain heart infusion broth and agar (Difco Laboratories), respectively, for streptococci; brain heart infusion broth and agar (Difco) supplemented with hemin (10 /ml) and P-NAD (Sigma Chemical Co.) for Haemophilus influenzae; GAM broth and agar (Nissui) for obligate anaerobes, and sensitivity test broth and agar (Nissui) ...