BMS-284756 (T-3811ME) a new fluoroquinolone: in vitro activity against Legionella, efficacy in a guinea pig model of L. pneumophila pneumonia and pharmacokinetics in guinea pigs
Abstract
The activity of BMS-284756 was studied against extracellular Legionella spp. and intracellular Legionella pneumophila, and for the treatment of guinea pigs with L. pneumophila pneumonia. The BMS-284756 MIC(50) of 22 different Legionella spp. strains was 0.008 mg/L, compared with 0.016 and 0.125 mg/L for levofloxacin and azithromycin, respectively. BMS-284756 (1 mg/L) reduced the intracellular concentrations of two L. pneumophila strains grown in guinea pig alveolar macrophages by c. 1.5 log(10 )cfu/mL, and was more active than erythromycin, but less active than azithromycin or levofloxacin at the same drug concentrations. Efficacy studies of BMS-284756, levofloxacin and azithromycin were performed in guinea pigs with L. pneumophila pneumonia. In infected guinea pigs given BMS-284756 10 mg/kg ip, mean peak plasma levels were 1.8 mg/L at 0.5 h and 0.7 mg/L at 1 h post-dose. The elimination half-life in plasma was 0.5 h, and the AUC(0-24 )was 1.7 mg*h/L, about 2% of the AUC(0-24 )for a single 400 mg oral dose in man. Sixteen of 18 L. pneumophila-infected guinea pigs treated with BMS-284756 10 mg/kg ip once daily for 5 days survived for 7 days post-antimicrobial therapy, as did 11 of 12 guinea pigs treated with azithromycin 15 mg/kg ip once daily for 2 days. All 12 animals that were treated with levofloxacin 10 mg/kg ip once daily for 5 days survived. None of 12 control animals treated with saline survived. Animals treated with BMS-284756 had significantly higher residual lung…
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