BMS-284756 in experimental cephalosporin-resistant pneumococcal meningitis

BMS-284756 is a novel des-fluoro(6) quinolone with a broad antimicrobial ac tivity, including Streptococcus pneumoniae. The purpose of this study was t o evaluate the pharmacodynamic profile and effectiveness of BMS-284756 for therapy of experimental meningitis caused by penicillin- and cephalosporin- resistant S. pneumoniae (CRSP). Meningitis was induced in rabbits by intrac isternal inoculation of CRSP. BMS-284756 was given intravenously 16 h after intracisternal inoculation in single doses of 2.5 (n = 5 animals), 5 (n = 6), 10 (n = 6), 20 (n = 8), and 30 mg/kg (n = 6), in two doses of 10 mg/kg each separated by 5 h (n = 4), and as a 20-mg/kg dose followed 5 h later by 10 mg/kg (n = 5). The MICs and MBCs of BMS-284756, ceftriaxone, and vancom ycin were 0.06 and 0.06, 4 and 4, and 0.25 and 0.25 mug/ml, respectively. A fter single doses of 10, 20, and 30 mg/kg, the maximum concentrations in ce rebrospinal fluid (CSF) (mean +/- standard deviation) were 0.32 +/- 0.12, 0 .81 +/- 0.38, and 1.08 +/- 0.43 mug/ml, respectively; the elimination half- life in CSF was 4.5 to 6.3 h. The CSF bacterial killing rates (BKR) at 5 h of the single-dose regimens of 10, 20 and 30 mg/kg were -0.84 +/- 0.48, -1. 09 +/- 0.32, and -1.35 +/- 0.05 Delta log(10) CFU/ml/h. The BKR0-5 of the d ivided regimens (10 mg/kg twice and 20 mg/kg followed by 10 mg/kg) was -0.8 2 +/- 0.52 and -1.24 +/- 0.34 Delta log(10) CFU/ml/h, respectively. The BKR 0-5 of the combined therapy with vancomycin and ceftriaxone was -1.09 +/- 0 .39 Delta log(10). CFU/ml/h. The penetration of BMS-284756 into purulent CS F relative to plasma was 14 to 25%. The bactericidal effect of BMS-284756 i n CSF was concentration dependent. BMS-284756 at 30 mg/kg as a single or di vided dose was as effective as standard therapy with vancomycin and ceftria xone.