BMS-284756 (T-381 1ME) a new fluoroquinolone: in vitro activity against Legionella, efficacy in a guinea pig model of L-pneumophila pneumonia and pharmacokinetics in guinea pigs

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 MIC50 of 22 different L egionella spp. strains was 0.008 mg/L, compared with 0.016 and 0.125 mg/L f or levofloxacin and azithromycin, respectively. BMS-284756 (1 mg/L) reduced the intracellular concentrations of two L. pneumophila strains grown in gu inea 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 th e same drug concentrations. Efficacy studies of BMS-284756, levofloxacin an d azithromycin were performed in guinea pigs with L. pneumophila pneumonia. In infected guinea pigs given BMS-284756 10 mg/kg ip, mean peak plasma lev els were 1.8 mg/L at 0.5 h and 0.7 mg/L at 1 h post-dose. The elimination h alf-life in plasma was 0.5 h, and the AUC(0-24) was 1.7 mg .h/L, about 2% o f the AUC(0-24) for a single 400 mg oral dose in man. Sixteen of 18 L. pneu mophila-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. A ll 12 animals that were treated with levofloxacin 10 mg/kg ip once daily fo r 5 days survived. None of 12 control animals treated with saline survived. Animals treated with BMS-284756 had significantly higher residual lung cou nts of L. pneumophila at the end of therapy than did animals treated with l evofloxacin or azithromycin, which may be attributable to the very low drug concentrations that were obtained. BMS-284756 was more active than erythro mycin against L. pneumophila in infected macrophages, and effectively treat ed animals with experimental L. pneumophila pneumonia. These data support f urther studies of BMS-284756 for the treatment of Legionnaires' disease.