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Antimicrobial Agents and Chemotherapy, June 2002, p. 1760-1765, Vol. 46, No. 6
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.6.1760-1765.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Evaluation of T-3811ME (BMS-284756), a New Des-F(6)-Quinolone, for Treatment of Meningitis Caused by Penicillin-Resistant Streptococcus pneumoniae in Rabbits

Masahiro Takahata,* Hiroshi Yamada, Teiichi Morita, Shinichi Furubou, Shinzaburo Minami, Yozo Todo, Yasuo Watanabe, and Hirokazu Narita

Research Laboratories, Toyama Chemical Co., Ltd., Toyama, Japan

Received 29 May 2001/ Returned for modification 14 November 2001/ Accepted 6 February 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 µg/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 µg · 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.

* Corresponding author. Mailing address: Research Laboratories, Toyama Chemical Co., Ltd., 4-1, Shimookui 2-chome, Toyama, 930-8508, Japan. Phone: 81-764-31-8268. Fax: 81-764-31-8208. E-mail: MASAHIRO_TAKAHATA{at}toyama-chemical.co.jp.

Antimicrobial Agents and Chemotherapy, June 2002, p. 1760-1765, Vol. 46, No. 6
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.6.1760-1765.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.





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