BMS-284756 in experimental cephalosporin-resistant pneumococcal meningitis.
BMS-284756 is a novel des-fluoro(6) quinolone with a broad antimicrobial activity, including Streptococcus pneumoniae. The purpose of this study was to 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 intracisternal 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 vancomycin were 0.06 and 0.06, 4 and 4, and 0.25 and 0.25 microg/ml, respectively. After single doses of 10, 20, and 30 mg/kg, the maximum concentrations in cerebrospinal fluid (CSF) (mean +/- standard deviation) were 0.32 +/- 0.12, 0.81 +/- 0.38, and 1.08 +/- 0.43 microg/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 Deltalog(10) CFU/ml/h. The BKR(0-5) of the divided regimens (10 mg/kg twice and 20 mg/kg followed by 10 mg/kg) was -0.82 +/- 0.52 and -1.24 +/- 0.34 Deltalog(10) CFU/ml/h, respectively. The BKR(0-5) of the combined therapy with vancomycin and ceftriaxone was -1.09 +/- 0.39 Deltalog(10) CFU/ml/h. The penetration of BMS-284756 into purulent CSF relative to plasma was 14 to 25%. The bactericidal effect of BMS-284756 in CSF was concentration dependent. BMS-284756 at 30 mg/kg as a single or divided dose was as effective as standard therapy with vancomycin and ceftriaxone.
Rodriguez-Cerrato
V
V
Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9063, USA. rodriguez_cerrato@yahoo.com
Ghaffar
F
F
Saavedra
J
J
Michelow
I C
IC
Hardy
R D
RD
Iglehart
J
J
Olsen
K
K
McCracken
G H
GH
D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D000890:Anti-Infective Agents / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002443:Ceftriaxone / Q000494:pharmacology / Q000627:therapeutic use; D018550:Cephalosporin Resistance; D024841:Fluoroquinolones; D007211:Indoles; D008297:Male; D008586:Meningitis, Pneumococcal / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D010403:Penicillin Resistance; D015363:Quinolones; D011817:Rabbits; D014640:Vancomycin / Q000627:therapeutic use
D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D007211:Indoles; D015363:Quinolones; D014640:Vancomycin; D002443:Ceftriaxone; C419689:garenoxacin