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: Masahiro Takahata, Hiroshi Yamada, Teiichi Morita, Shinichi Furubou, Shinzaburo Minami, Yozo Todo, Yasuo Watanabe, Hirokazu Narita
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 46 Issue 6 Pg. 1760-5 (Jun 2002) ISSN: 0066-4804 [Print] United States
• PMID: 12019087 (Publication Type: Journal Article)

Chemical References

• Anti-Infective Agents
• Cephalosporins
• Fluoroquinolones
• Indoles
• Isoindoles
• Quinolones
• T 3811ME
• Ceftriaxone

Topics

• Animals
• Anti-Infective Agents (cerebrospinal fluid, therapeutic use)
• Brain (pathology)
• Ceftriaxone (therapeutic use)
• Cephalosporins (therapeutic use)
• Fluoroquinolones
• Indoles (cerebrospinal fluid, therapeutic use)
• Injections, Intravenous
• Isoindoles
• Male
• Meningitis, Pneumococcal (cerebrospinal fluid, drug therapy, microbiology)
• Penicillin Resistance
• Quinolones (cerebrospinal fluid, therapeutic use)
• Rabbits
• Streptococcus pneumoniae (drug effects)