title: Evaluation of T-3811ME (BMS-284756), a new des-F(6)-quinolone, for treatment of meningitis caused by penicillin-resistant Streptococcus pneumoniae in rabbits.
abstract: T-3811ME (BMS-284756) is a new des-F(6)-quinolone with high levels of activity against gram-positive bacteria, including penicillin-resistant Streptococcus pneumoniae (PRSP) strains. T-3811, the free base of T-3811ME, exhibited potent activity against 28 clinical strains of PRSP isolated clinically (MIC at which 90% of the isolates tested are inhibited, 0.0625 microg/ml). After the intravenous dosing of T-3811ME (20 mg/kg of body weight as T-3811) in rabbits with meningitis caused by PRSP, the area under the concentration-time curve (AUC) of T-3811 in cerebrospinal fluid (CSF) was 5.79 microg. h/ml and was 4.5-fold higher than that of T-3811in the CSF of rabbits without meningitis. In addition, the AUC/MIC for T-3811ME (20 mg/kg as T-3811) in CSF was 185, which was 4.3-fold higher than that for ceftriaxone (administered intravenously at 100 mg/kg). After the administration of any dose of T-3811ME (5, 10, and 20 mg/kg as T-3811), the viable cell counts in CSF decreased in a dose-dependent manner. In particular, after dosing of 20 mg/kg (as T-3811), the viable cell counts in CSF were significantly less than those in the nontreated group (P < 0.01). By histopathological evaluation, 6 h after the administration of T-3811ME (20 mg/kg as T-3811), the thickening of the cerebral meninx and the infiltration of neutrophils into the cerebral meninx were less severe in the treated group than in the nontreated group. T-3811ME (BMS-284756) may be expected to be evaluated for the management of meningitis caused by highly penicillin-resistant pneumococci.
authors.affiliation: Research Laboratories, Toyama Chemical Co., Ltd., Toyama, Japan. MASAHIRO_TAKAHATA@toyama-chemical.co.jp
authors.forename: Masahiro
authors.initials: M
authors.lastname: Takahata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamada
authors.forename: Teiichi
authors.initials: T
authors.lastname: Morita
authors.forename: Shinichi
authors.initials: S
authors.lastname: Furubou
authors.forename: Shinzaburo
authors.initials: S
authors.lastname: Minami
authors.forename: Yozo
authors.initials: Y
authors.lastname: Todo
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Narita
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000134:cerebrospinal fluid / Q000627:therapeutic use*; D001921:Brain / Q000473:pathology; D002443:Ceftriaxone / Q000627:therapeutic use; D002511:Cephalosporins / Q000627:therapeutic use; D024841:Fluoroquinolones; D007211:Indoles / Q000134:cerebrospinal fluid / Q000627:therapeutic use*; D007275:Injections, Intravenous; D054833:Isoindoles; D008297:Male; D008586:Meningitis, Pneumococcal / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000382:microbiology; D010403:Penicillin Resistance; D015363:Quinolones / Q000134:cerebrospinal fluid / Q000627:therapeutic use*; D011817:Rabbits; D013296:Streptococcus pneumoniae / Q000187:drug effects*
chemical_list: D000890:Anti-Infective Agents; D002511:Cephalosporins; D024841:Fluoroquinolones; D007211:Indoles; D054833:Isoindoles; D015363:Quinolones; C118960:T 3811ME; D002443:Ceftriaxone