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.