In vitro and in vivo antibacterial activity of AM-833, a new quinolone derivative

Abstract

AM-833 showed potent activity against members of the family Enterobacteriaceae, Neisseria spp., and HaemophUus influenzae and good activity against staphylococci, Pseudomonas aeruginosa, and BranhameUa catarrhalis. Against these bacteria, its activity was roughly comparable to that of norfloxacin and ofloxacin but was slightly less potent than that of ciprofloxacin. This compound also showed good activity against drug-resistant strains such as methicillin-resistant Staphylococcus aureus and gentamicin-resistant Pseudomonas aeruginosa. The protective effects of a single oral dose of AM-833 on systemic bacterial infections in mice were greater than those of norfloxacin. AM-833 was as effective as ofloxacin and ciprofloxacin against systemic infections with Escherichia coli and Pseudomonas aeruginosa, and it showed somewhat higher activity against staphylococcal infections than did the other quinolones. AM-833 exhibited good prophylactic activity against E. coli infections. AM-833 also proved effective against localized infections such as acute pneumonia and ascending urinary tract infections in mice. The excellent therapeutic efficacy of AM-833 against these systemic and local infections may be a result of its good oral absorption and high levels in tissues.Recently, new quinolone derivatives such as norfloxacin (3), ofloxacin (10), and ciprofloxacin (11,12) have been developed, and a few of these compounds have been introduced into the market. New quinolones have a broad spectrum of activity against gram-positive and gram-negative bacteria including Pseudomonas aeruginosa.AMnew quinolone derivative structurally related to norfloxacin (Fig. 1) , abstr. no. 659, 1983). In this study, the in vitro and in vivo activities of AM-833 were compared with those of norfloxacin, ofloxacin, and ciprofloxacin.(This work was presented in part at the 14th International Congress of Chemotherapy, Kyoto, Japan, 23 to 28 June 1985.) MATERIALS AND METHODS Antimicrobial agents. AM-833, norfloxacin, ofloxacin, and ciprofloxacin were synthesized in our laboratories. Nalidixic acid, gentamicin, ampicillin, and methicillin were obtained from commercial sources. The quinolones were dissolved in 0.1 N NaOH before dilution in distilled water to the desired concentration.Microorganisms. Methicillin-resistant Staphylococcus aureus and Branhamella catarrhalis were kindly given to us by T. Yokota, Department of Bacteriology, School of Medicine, Juntendo University, and by K. Matsumoto, Depart-* Corresponding author. ment of Internal Medicine, Institute of Tropical Medicine, Nagasaki University. Clinically isolated strains were obtained from hospitals in several areas in Japan. Escherichia coli ML4707 and Klebsiella pneumoniae 1-220S were kindly provided by S. Mitsuhashi, Episome Institute. The other strains used were stock cultures from our laboratories.Determination of MICs. The antibacterial activities of the compounds were determined by the twofold agar dilution method (3) with Mueller-Hinton agar (Difco Laboratories, Detroit, Mich.) which ...

Clinical isolate of Citrobacter freundii highly resistant to new quinolones

“…Also, C. freundii can rapidly acquire resistance to nalidixic acid; the MIC rose to 1,600 ,ug/ml after five transfers (8). We reported earlier that one of the resistance mechanisms of the spontaneous nalidixic acid-resistant mutant M2-5 was an altered DNA gyrase A subunit (1).…”

Mutations producing resistance to norfloxacin in Pseudomonas aeruginosa

“…Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of outer membrane proteins demonstrated the appearance of a 54,000-dalton protein in the nfxB mutant. These findings suggested that the norfloxacin resistance mechanism in the nfxB mutant might be an alteration in outer membrane permeability to norfloxacin.Norfloxacin and other new 4-quinolones show potent antibacterial activity against gram-negative and grampositive bacteria (11,14,20). They also have high in vitro and in vivo antibacterial activity against Pseudomonas aeruginosa strains that show a strong intrinsic resistance to various antimicrobial agents including older quinolones such as nalidixic acid (11,20,42).…”

“…Norfloxacin and other new 4-quinolones show potent antibacterial activity against gram-negative and grampositive bacteria (11,14,20). They also have high in vitro and in vivo antibacterial activity against Pseudomonas aeruginosa strains that show a strong intrinsic resistance to various antimicrobial agents including older quinolones such as nalidixic acid (11,20,42).…”

“…They also have high in vitro and in vivo antibacterial activity against Pseudomonas aeruginosa strains that show a strong intrinsic resistance to various antimicrobial agents including older quinolones such as nalidixic acid (11,20,42). The high antibacterial activity of new quinolones might be due to their strong inhibitory action against DNA gyrase, a target enzyme of quinolones, which has been isolated from various bacteria including Pseudomonas aeruginosa (5,16,26,28,42).…”

In vitro antibacterial activity of AM-1155, a novel 6-fluoro-8-methoxy quinolone

“…A portion (about 5 [LI) of the dilution was inoculated with an inoculation apparatus (Microplanter; Sakuma Seisakusho, Tokyo, Japan) onto agar plates containing various concentrations of drug. The final inoculum size was approximately 104 CFU per spot.…”