Takahata Masahiro, Yamada Hiroshi, Morita Teiichi, Furubou Shinichi, Minami Shinzaburo, Todo Yozo, Watanabe Yasuo, Narita Hirokazu
Research Laboratories, Toyama Chemical Co., Ltd., Toyama, Japan.
Antimicrob Agents Chemother. 2002 Jun;46(6):1760-5. doi: 10.1128/AAC.46.6.1760-1765.2002.
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.
T-3811ME（BMS-284756）是一种新型去F(6)-喹诺酮类药物，对革兰氏阳性菌具有高度活性，包括耐青霉素肺炎链球菌（PRSP）菌株。T-3811ME的游离碱T-3811对28株临床分离的PRSP菌株表现出强效活性（90%受试菌株被抑制时的最低抑菌浓度，0.0625微克/毫升）。给患有PRSP引起的脑膜炎的兔子静脉注射T-3811ME（以T-3811计，20毫克/千克体重）后，脑脊液（CSF）中T-3811的浓度-时间曲线下面积（AUC）为5.79微克·小时/毫升，比未患脑膜炎的兔子脑脊液中T-3811的AUC高4.5倍。此外，脑脊液中T-3811ME（以T-3811计，20毫克/千克）的AUC/MIC为185，比头孢曲松（静脉注射100毫克/千克）的AUC/MIC高4.3倍。给予任何剂量的T-3811ME（以T-3811计，5、10和20毫克/千克）后，脑脊液中的活菌数呈剂量依赖性下降。特别是，给予20毫克/千克（以T-3811计）后，脑脊液中的活菌数明显少于未治疗组（P<0.01）。通过组织病理学评估，给予T-3811ME（以T-3811计，20毫克/千克）6小时后，治疗组大脑脑膜增厚和中性粒细胞浸润到大脑脑膜的程度比未治疗组轻。T-3811ME（BMS-284756）有望用于评估治疗由高度耐青霉素肺炎球菌引起的脑膜炎。
