The articular toxicity of garenoxacin (formerly T-3811 or BMS-284756) was experimentally examined utilizing juvenile beagle dogs. Garenoxacin and two other reference quinolones were administered at intravenous dosages of 30 and 60 mg/kg. Each group consisted of 3 male dogs (Experiment I). Oral dosages of 50 mg/kg of 3 compounds were also given daily to male only and female only groups (Experiment II) over a period of 7 days. We evaluated the articular toxicity of garenoxacin compared to ciprofloxacin and norfloxacin. In Experiment I, no articular toxicity was detected in the 30 mg/kg garenoxacin group. One animal from the 60 mg/kg garenoxacin group developed detectable histopathological lesions in the articular cartilages of the shoulder, elbow and knee joints. In the 30 mg/kg ciprofloxacin group and the 30 and 60 mg/kg norfloxacin groups, histopathological articular cartilage lesions of the shoulder, elbow, carpus, hip, knee and tarsus joints were observed in all of the dogs. The area under the plasma concentration-time curve (AUC0-->infinity) values, after the first dose was administered, for the 30 mg/kg groups given garenoxacin, ciprofloxacin and norfloxacin were 164, 68.1 and 65.7 micrograms.hr/mL, respectively. In Experiment II, the degree of histopathological change was most significant in the ciprofloxacin group, followed by the norfloxacin group, and with comparatively the least changes in the garenoxacin group. The AUC0-->infinity values, obtained after the 6th day of antimicrobial administration, were 202 and 173 micrograms.hr/mL for male and female dogs, respectively, from the 50 mg/kg garenoxacin group. The AUC0-->infinity values for the garenoxacin group after the 6th daily administration were 7.8 to 17.0 times greater for male dogs and 3.8 to 13.2 times greater for female dogs than those obtained from the ciprofloxacin and norfloxacin groups. The concentrations of garenoxacin in the synovia, articular cartilage and the synovialis 4 hr following the last garenoxacin administration were 2.0 to 6.5 times higher for male dogs and 1.5 to 3.3 times higher for female dogs than the antimicrobial levels measured in the ciprofloxacin and norfloxacin groups. As discussed above, although the garenoxacin concentrations in plasma and joint tissue were higher than those for ciprofloxacin and norfloxacin, however, the articular toxicity of garenoxacin was much less than that of the other two antimicrobials.

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 g/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 g · 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.