title: In vitro activity of ABT-773 against Legionella pneumophila, its pharmacokinetics in guinea pigs, and its use to treat guinea pigs with L. pneumophila pneumonia.
abstract: The activity of ABT-773 was studied against extracellular and intracellular Legionella pneumophila and for the treatment of guinea pigs with L. pneumophila pneumonia. The ABT-773 MIC at which 50% of isolates are inhibited (MIC(50)) for 20 different Legionella sp. strains was 0.016 microg/ml, whereas the MIC(50)s of clarithromycin and erythromycin were 0.032 and 0.125 microg/ml, respectively. ABT-773 (1 microg/ml) was bactericidal for two L. pneumophila strains grown in guinea pig alveolar macrophages. In contrast, erythromycin and clarithromycin had easily reversible static activity only. Therapy studies of ABT-773 and erythromycin were performed with guinea pigs with L. pneumophila pneumonia. When ABT-773 was given to infected guinea pigs by the intraperitoneal route (10 mg/kg of body weight), mean peak levels in plasma were 0.49 microg/ml at 0.5 h and 0.30 microg/ml at 1 h postinjection. The terminal half-life phase of elimination from plasma was 0.55 h, and the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) was 0.65 microg. h/ml. For the same drug dose, mean levels in the lung were 15.9 and 13.2 microg/g at 0.5 and 1 h, respectively, with a half-life of 0.68 h and an AUC(0-24) of 37.0 microg. h/ml. Ten of 15 L. pneumophila-infected guinea pigs treated with ABT-773 (15 mg/kg/dose given intraperitoneally once daily) for 5 days survived for 9 days post-antimicrobial therapy, as did 14 of 15 guinea pigs treated with erythromycin (30 mg/kg given intraperitoneally twice daily) for 5 days. All of the ABT-773-treated animals that died appeared to do so because of drug-induced peritonitis rather than overwhelming pneumonia. None of 12 animals treated with saline survived. ABT-773 is as effective as erythromycin against L. pneumophila in infected macrophages and in a guinea pig model of Legionnaires' disease. These data support studies of the clinical effectiveness of ABT-773 for the treatment of Legionnaires' disease.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 3400 Spruce St., Philadelphia, PA 19104-4283. phe@mail.med.upenn.edu
authors.forename: P H
authors.initials: PH
authors.lastname: Edelstein
authors.forename: F
authors.initials: F
authors.lastname: Higa
authors.forename: M A
authors.initials: MA
authors.lastname: Edelstein
mesh_terms: D000818:Animals; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006168:Guinea Pigs; D048628:Ketolides; D016952:Legionella pneumophila / Q000187:drug effects* / Q000254:growth & development; D008297:Male; D008826:Microbial Sensitivity Tests; D018410:Pneumonia, Bacterial / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D048628:Ketolides; D004917:Erythromycin; C405499:cethromycin