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
AUTOR(ES)
Edelstein, Paul H.
FONTE
American Society for Microbiology
RESUMO
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 (MIC50) for 20 different Legionella sp. strains was 0.016 μg/ml, whereas the MIC50s of clarithromycin and erythromycin were 0.032 and 0.125 μg/ml, respectively. ABT-773 (1 μg/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 μg/ml at 0.5 h and 0.30 μg/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 (AUC0–24) was 0.65 μg · h/ml. For the same drug dose, mean levels in the lung were 15.9 and 13.2 μg/g at 0.5 and 1 h, respectively, with a half-life of 0.68 h and an AUC0–24 of 37.0 μg · 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.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=90717Documentos Relacionados
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