Efficacies of ABT-719 and related 2-pyridones, members of a new class of antibacterial agents, against experimental bacterial infections.
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.
Alder
J
J
Anti-Infective Research Division, Abbott Laboratories, Abbott Park, Illinois, USA.
Clement
J
J
Meulbroek
J
J
Shipkowitz
N
N
Mitten
M
M
Jarvis
K
K
Oleksijew
A
A
Hutch
T
T
Paige
L
L
Flamm
B
B
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
D000900:Anti-Bacterial Agents; D011728:Pyridones; D059005:Topoisomerase II Inhibitors; D002939:Ciprofloxacin; C093440:ABT 719