title: Efficacies of ABT-719 and related 2-pyridones, members of a new class of antibacterial agents, against experimental bacterial infections.
abstract: 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 quinolone-sensitive 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.
authors.affiliation: Anti-Infective Research Division, Abbott Laboratories, Abbott Park, Illinois, USA.
authors.forename: J
authors.initials: J
authors.lastname: Alder
authors.forename: J
authors.initials: J
authors.lastname: Clement
authors.forename: J
authors.initials: J
authors.lastname: Meulbroek
authors.forename: N
authors.initials: N
authors.lastname: Shipkowitz
authors.forename: M
authors.initials: M
authors.lastname: Mitten
authors.forename: K
authors.initials: K
authors.lastname: Jarvis
authors.forename: A
authors.initials: A
authors.lastname: Oleksijew
authors.forename: T
authors.initials: T
authors.lastname: Hutch
authors.forename: L
authors.initials: L
authors.lastname: Paige
authors.forename: B
authors.initials: B
authors.lastname: Flamm
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001424:Bacterial Infections / Q000188:drug therapy*; D002939:Ciprofloxacin / Q000627:therapeutic use; D005260:Female; D051379:Mice; D011728:Pyridones / Q000627:therapeutic use; D059005:Topoisomerase II Inhibitors
chemical_list: D000900:Anti-Bacterial Agents; D011728:Pyridones; D059005:Topoisomerase II Inhibitors; D002939:Ciprofloxacin; C093440:ABT 719