Comparative antibacterial activities of temafloxacin hydrochloride (A-62254) and two reference fluoroquinolones

Hardy, Dwight J.; Swanson, R. N.; Hensey, Dena M.; Ramer, N.; Bower, R. R.; Hanson, Charles W.; Chu, Daniel T. W.; Fernandes, Prabhavathi

doi:10.1128/aac.31.11.1768

Cited by 109 publications

(65 citation statements)

References 14 publications

(24 reference statements)

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“…For the L. monocytogenes infection, therapy was delayed for 24 h to allow establishment of an intracellular infection, and compounds were administered 24 and 28 h postinoculation. Mortality and/or morbidity was recorded for 7 days, and the mean effective dose sufficient to protect 50% of the mice (ED 50 ) was calculated from the cumulative mortality by trimmed-logit analysis (19,32). There were 10 mice per dosage group.…”

Section: Methodsmentioning

confidence: 99%

Efficacies of ABT-773, a New Ketolide, against Experimental Bacterial Infections

Mitten

Meulbroek

Nukkala

et al. 2001

Antimicrob Agents Chemother

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ABT-773 is a novel ketolide effective against antibacterial-resistant respiratory tract pathogens. The pharmacokinetic profile of ABT-773 was studied in rats and consisted of a mean peak concentration in plasma of 1.07 g/ml and an area under the concentration-time curve (AUC) of 12.03 g ⅐ h/ml when the compound was delivered at a dose of 25 mg/kg of body weight. It concentrated in rat lung tissue, with a lung tissue-to-plasma ratio of 29 based on the AUC. In acute systemic infections in mice, ABT-773 showed efficacy against macrolidesusceptible strains of Staphylococcus aureus, Streptococcus pneumoniae, S. pyogenes, and Listeria monocytogenes. Additionally, ABT-773 improved the survival of mice infected with resistant S. pneumoniae containing either the ermB gene, the mefE gene, or altered penicillin binding protein genes. In a rat lung model of infection, ABT-773 demonstrated 50% effective doses lower than those of comparator macrolides when evaluated against the following strains of S. pneumoniae: a macrolide-lincosamide-streptogramin B-susceptible strain, an ermB strain, and an mefE strain. ABT-773 was also effective against Haemophilus influenzae lung infections in rats. Thus, ABT-773 may prove to be a useful new antibacterial agent for the treatment of respiratory tract infections.

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Section: Methodsmentioning

confidence: 99%

Efficacies of ABT-773, a New Ketolide, against Experimental Bacterial Infections

Mitten

Meulbroek

Nukkala

et al. 2001

Antimicrob Agents Chemother

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“…For the L. monocytogenes and S. typhimurium infections, the drugs were administered at 16 and 21 h postinoculation. Mortality was recorded for 7 days, and the mean effective dose sufficient to protect 50% of the mice (ED 50 ) was calculated from the cumulative mortality by trimmed-logit analysis (10). There were 10 mice per dosage group.…”

Section: Methodsmentioning

confidence: 99%

“…The efficacies of the 2-pyridones were determined in mouse models of acute bacterial infection as described previously (4,10). In brief, CF1 female mice (Charles River, Wilmington, Mass.)…”

Section: Methodsmentioning

confidence: 99%

Efficacies of ABT-719 and related 2-pyridones, members of a new class of antibacterial agents, against experimental bacterial infections

Alder

Clement

Meulbroek

et al. 1995

Antimicrob Agents Chemother

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The 2-pyridones are a new class of broad-spectrum orally bioavailable antibacterial agents. These compounds are potent bacterial DNA gyrase inhibitors which differ from fluoroquinolones by placement of the nitrogen atom in the ring juncture. ABT-719 is an S isomer and a representative 2-pyridone. ABT-719 administered orally or subcutaneously was 4-to 10-fold more effective than ciprofloxacin against Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes infections in normal mice. ABT-719 was equivalent in efficacy to ciprofloxacin for treatment of gram-negative bacterial infections caused by Pseudomonas aeruginosa or Escherichia coli. The racemate and R forms of ABT-719 produced similar results against gram-positive and gram-negative bacterial infections. The 50% effective doses of ABT-719 were at least threefold lower than those of ciprofloxacin for therapy of intracellular infections caused by Salmonella typhimurium or Listeria monocytogenes. In immunosuppressed mice, ABT-719 was more effective than ciprofloxacin against quinolonesensitive S. aureus, Enterococcus faecalis, and Enterococcus faecium. The pharmacokinetic properties of ABT-719 were consistent with its relative efficacy. The 2-pyridones are potent, orally available antibacterial agents with efficacy against gram-positive and gram-negative bacterial infections in mice.The 2-pyridones are a class of antibacterial agents recently synthesized at Abbott Laboratories (Fig. 1). ABT-719, 8-(3(S)-aminopyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4H-4-oxo-quinolizine-3-carboxylic acid hydrochloride monohydrate, is a representative 2-pyridone which exhibits potent, broadspectrum in vitro activity (7). The 2-pyridones differ structurally from the fluoroquinolones by placement of the nitrogen atom at the ring juncture. Like the fluoroquinolones, the 2-pyridones are inhibitors of bacterial DNA gyrase.There is a need to improve upon the fluoroquinolones in clinical use. Fluoroquinolones have limited activity against gram-positive bacteria, particularly Streptococcus pneumoniae (1,19) and Staphylococcus aureus (2). Infections caused by methicillin-resistant S. aureus (MRSA) and coagulase-negative staphylococci have caused concern regarding fluoroquinolone use because of the emergence of resistance (3,13,20). Fluoroquinolone use has generally been most effective against gram-negative infections (11).The efficacies of the R, S, and racemate forms of a representative 2-pyridone against systemic infections caused by salient gram-positive and gram-negative bacteria were investigated. The efficacy of the potent S isomer, ABT-719, was determined in additional trials with normal and immunocompromised mice. ABT-719 had efficacy against gram-positive, gram-negative, and intracellular bacterial infections in mice, demonstrating potential as a broad-spectrum agent. MATERIALS AND METHODSAntimicrobial agents. The 2-pyridones ABT-719, A-86719.0, A-86504.1, and A-87092.1 were synthesized at Abbott Laboratories, Abbott Park, Ill. A-86504.1 is the racemate ...

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“…It possesses excellent activity against both Gram-positive and Gram-negative bacteria (6). The general synthetic methods for the introduction of an N-l substituent require the alkylation of 1,4-dihydro-4-oxoquinoline-3-carboxylic ester with a reactive alkyl halide.…”

Section: Introductionmentioning

confidence: 99%

An alternative synthesis of temafloxacin, a potent antibacterial agent

Chu¹,

Lico²,

Claiborne³

et al. 1992

Can. J. Chem.

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An alternative synthesis of (±)-7-(3-methylpiperazin-1-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride 4, a potent antibacterial agent, was developed. The method was characterized by regiospecific displacement of the 4-fluoro of the 2,4,5-trifluoroacetophenone by 2-methylpiperazine to produce the key intermediate, 2,5-difluoro-4-(3-methylpiperazin-1-yl)acetophenone 12, which was subsequently converted to 4 via an intramolecular nucleophilic displacement cyclization reaction.

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Comparative antibacterial activities of temafloxacin hydrochloride (A-62254) and two reference fluoroquinolones

Cited by 109 publications

References 14 publications

Efficacies of ABT-773, a New Ketolide, against Experimental Bacterial Infections

Efficacies of ABT-773, a New Ketolide, against Experimental Bacterial Infections

Efficacies of ABT-719 and related 2-pyridones, members of a new class of antibacterial agents, against experimental bacterial infections

An alternative synthesis of temafloxacin, a potent antibacterial agent

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