In vitro activity of Ro 23-6240, a new fluorinated 4-quinolone

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: Resultssupporting

confidence: 68%

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

Asahara

Tsuji

Goto

et al. 1989

“…The drug has shown excellent activity against most members of the family Enterobacteriaceae, inhibiting 90% of isolates per species at concentrations of <1 p.g/ml (2,3). Because of its broad spectrum of activity, fleroxacin may also have use for treating staphylococcal infections; a previous report has shown the in vitro effectiveness of fleroxacin against two species of staphylococci (9).…”

mentioning

confidence: 99%

Susceptibility of Staphylococcus species and subspecies to fleroxacin

Bannerman

Wadiak

Kloos

1991

Twenty-four Staphylococcus species or subspecies were examined for their susceptibilities to the fluoroquinolone fleroxacin (Ro 23-6240) by disk diffusion (5-jig disk) and by agar dilution for the determination of MICs.Resistant strains were further tested for their susceptibilities to oxacillin and the fluoroquinolone ciprofloxacin. Reference strains of the novobiocin-resistant species (Staphylococcus saprophyticus, Staphylococcus cohnii, Staphylococcus xylosus, Staphylococcus arlettae, and Staphylococcus gallinarum) had an intrinsic intermediate susceptibility (MIC,4 ,ug/ml) to fleroxacin. Fleroxacin resistance was not observed in the reference strains of the novobiocin-susceptible species (MIC, 0.5 to 2.0 ,uglml). Clinical isolates of coagulase-negative species were generally less susceptible to fleroxacin than were reference strains. Fleroxacin (Ro 23-6240) is a new orally and intravenously administered trifluoroquinolone with a half-life of 9 to 10 h in humans and peak levels of 2.3 VLg/ml in serum after a single 200-mg oral dose (12). The drug has shown excellent activity against most members of the family Enterobacteriaceae, inhibiting 90% of isolates per species at concentrations of <1 p.g/ml (2, 3). Because of its broad spectrum of activity, fleroxacin may also have use for treating staphylococcal infections; a previous report has shown the in vitro effectiveness of fleroxacin against two species of staphylococci (9). In the current study, 24 Staphylococcus species or subspecies were tested for their susceptibilities to fleroxacin by disk diffusion and by agar dilution for determination of MICs. The resistant strains were further tested for their susceptibilities to oxacillin and to the fluoroquinolone ciprofloxacin.(A preliminary report of this work was presented previ-Reference strains of the 24 Staphylococcus species or subspecies were obtained from our laboratory's collection of isolates from the skin of healthy human volunteers or from animals. Clinical strains used in this study were isolated from April 1989 to February 1990 from a variety of patients at Rex Hospital, Raleigh, N.C. All the clinical strains were identified by using the criteria of Kloos and coworkers (4, 5). The reference and clinical strains were maintained on P agar (11) at 4°C for up to 2 months and preserved by desiccation on steatite fish spine insulator beads at 4°C. These storage conditions do not alter the antibiograms or plasmid compositions of strains tested in this laboratory.Fleroxacin as powder and in 5-,ug disks was kindly provided by Hoffmann-La Roche, Inc. Md.). Disk diffusion susceptibility testing was performed by the procedure outlined by the National Committee for Clinical Laboratory Standards (7). Agar dilution susceptibility tests for fleroxacin and oxacillin were performed by the procedure outlined by the National Committee for Clinical Laboratory Standards (8) with Mueller-Hinton agar. Oxacillin plates were supplemented with 4% NaCl. The plates were inoculated by using the Steers replicator (10). Ciprofloxac...

“…Pyrrolidines at this position offer great potency against gram-positive bacteria, and piperazines introduce excellent activity against gram-negative bacteria. Furthermore, among the variations described at position 7 (1,2,7,12,16), it has been proven that the presence of an azetidine moiety (3,5,6,8,9) yields a broader spectrum and enhanced activity against gram-positive bacteria. On the other hand, the substituent at position 8 controls in vivo efficacy and is largely responsible for the activity against anaerobic bacteria, with halogens being one of the optimal substitution groups at this site.…”

Section: E-4767 {(؊)-7-[3-(r)-amino-2-(s)-methyl-1-azetidinyl]mentioning

confidence: 99%

Antibacterial Activities and Pharmacokinetics of E-4767 and E-5065, Two New 8-Chlorofluoroquinolones with a 7-Azetidin Ring Substituent

Gargallo-Viola

Ferrer

Tudela

et al. 2001

E-4767 {(؊)-7-[3-(R)-amino-2-(S)-methyl-1-azetidinyl]-8-chloro-1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-3-quinolinecarboxylic acid} and E-5065 [(؊)-7-(3-amino-1-azetidinyl)-8-chloro-1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-3-quinolinecarboxylic acid] are two new chlorofluoroquinolones with an azetidine moiety at position 7. Their in vitro activities were evaluated in comparison with those of ciprofloxacin, ofloxacin, fleroxacin, and tosufloxacin, while ciprofloxacin was used as a reference for in vivo studies. Against gram-positive organisms, E-4767 and E-5065 were, in general, eight-and fourfold more active than tosufloxacin, which is the most potent of the reference compounds. E-4767 and E-5065 were also more potent than the reference compounds against all species of enteric bacteria tested. The MICs of E-4767 and E-5065 at which 90% of the isolates tested were inhibited (MIC 90 s) were 0.007 to 0.5 g/ml and 0.03 to 2 g/ml, respectively, for gram-positive organisms and <0.003 to 0.06 g/ml and 0.007 to 0.12 g/ml, respectively, for members of the family Enterobacteriaceae except Serratia marcescens and Providencia spp. (MIC 90 s of E-4767 and E-5065 for these species were <0.5 g/ml and <2 g/ml, respectively). For Pseudomonas aeruginosa both compounds had a MIC 90 of 0.5 g/ml. E-4767 and E-5065 were 356-and 32-fold more potent than ciprofloxacin against Bacteroides spp., and their MIC 90 s for Clostridium spp. were 0.25 and 0.5 g/ml, respectively. Both products showed a remarkable reduction of activity when the pH was below 4.8 and, in general, were less active in the presence of 5 or 10 mM Mg 2؉ . The presence of horse serum or human urine (pH 7.2) decreased the activity of E-4767 and E-5065 only two-to fourfold more than the activity observed in broth. After an oral dose of 50 mg/kg of body weight, the maximum levels in serum (the maximum concentration of drug in serum was reached 30 min postadministration) of E-4767 and E-5065 were approximately threefold higher than that of ciprofloxacin. The area under the concentration-time curve from 0 to 4 h for ciprofloxacin was about two-and fourfold lower than that for E-4767 and E-5065, respectively. These two new chlorofluoroquinolones were as effective as or more effective than ciprofloxacin against all experimental infections evaluated, not only against gram-negative bacteria, such as Escherichia coli or P. aeruginosa, but also against gram-positive pathogens, such as Staphylococcus aureus or Streptococcus pneumoniae. E-4767 was the most effective compound, with a 50% effective dose (ED 50 ) of <17 mg/kg for all strains tested except ciprofloxacin-resistant S. aureus strains. The ED 50 of E-4767 for these strains was <47.5 mg/kg. Against gram-positive experimental infections, the ED 50 values of E-4767 were 3-to 14-fold lower than those of E-5065 and up to 25 times lower than those of ciprofloxacin.Since the discovery of nalidixic and oxolinic acids (10, 13), many modifications have been introduced in the chemical structure of the quinolonic ring, yielding new drug...