Disease relevance of T-3811MEa

• The objective of this study was to define the pharmacodynamic profile of BMS-284756 against Streptococcus pneumoniae [1].
• The purpose of this study was to evaluate the pharmacodynamic profile and effectiveness of BMS-284756 for therapy of experimental meningitis caused by penicillin- and cephalosporin-resistant S. pneumoniae (CRSP) [2].
• Staphylococcus aureus mutants selected by BMS-284756 [3].
• BMS-284756 inhibited approximately 60 to approximately 70% of the Enterococcus faecium (including vancomycin-resistant) strains and 90 to 100% of the Enterobacteriaceae strains and gastroenteric bacillary pathogens at the anticipated MIC susceptible breakpoint (</=4 microg/ml) [4].
• The 50% protective doses of BMS-284756 against wild-type and mutant strains were 2.2 and 1.6 mg/kg of body weight/day, respectively, compared to the levofloxacin values of 16 and 71 mg/kg/day and moxifloxacin values of 4.7 and 61.6 mg/kg/day [5].

High impact information on T-3811MEa

• Garenoxacin (T-3811ME, BMS-284756) is a novel, broad-spectrum des-F(6) quinolone currently under study for the treatment of community-acquired respiratory tract infections [6].
• In vitro activities of garenoxacin (BMS-284756) against Haemophilus influenzae isolates with different fluoroquinolone susceptibilities [7].
• Garenoxacin (BMS-284756) and moxifloxacin in experimental meningitis caused by vancomycin-tolerant pneumococci [8].
• Both the wild-type strain MT5 and grlA mutant MT5224c4 should be considered susceptible to both BMS-284756 and levofloxacin, and both quinolones are predicted to have clinical efficacy [5].
• The in vivo efficacy of BMS-284756, levofloxacin, and moxifloxacin against S. aureus strain ISP794 and its single mutant 2C6(1)-1 directly reflected the in vitro activity: increased MICs correlated with decreased in vivo efficacy [5].

Chemical compound and disease context of T-3811MEa

• Garenoxacin (BMS 284756) was active against 105 of 108 (97%) recent clinical Gardnerella vaginalis isolates at < or =2 micro g/ml by using the reference agar dilution method for anaerobes [9].
• BMS-284756 is a novel des-fluoro(6) quinolone with a broad antimicrobial activity, including Streptococcus pneumoniae [2].
• We did not observe signs of chondrotoxicity in immature rats treated orally with garenoxacin (BMS-284756) at doses up to five times 600 mg/kg of body weight or with ciprofloxacin, whereas ofloxacin induced typical cartilage lesions [10].
• BMS-284756 in experimental cephalosporin-resistant pneumococcal meningitis [2].
• Against Streptococcus pneumoniae, BMS-284756 and gemifloxacin were more active than other quinolones [11].

Biological context of T-3811MEa

• Single-dose pharmacokinetics and penetration of BMS 284756 into an inflammatory exudate [12].
• 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 [13].
• Comparative killing kinetics of the novel des-fluoro(6) quinolone BMS-284756, fluoroquinolones, vancomycin and beta-lactams [14].

Anatomical context of T-3811MEa

• 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 [13].
• BMS 284756 penetrated well into inflamed meninges (44% +/- 11%) and produced good bactericidal activity (-0.82 +/- 0.22 Delta log(10) CFU/ml. h) in the treatment of experimental meningitis in rabbits due to a penicillin-sensitive strain [15].

Associations of T-3811MEa with other chemical compounds

• The in vitro and in vivo activities of T-3811ME, a novel des-F(6)-quinolone, were evaluated in comparison with those of some fluoroquinolones, including a newly developed one, trovafloxacin [16].
• Gemifloxacin and BMS 284756 exhibited the best in vitro activity against all 14 isolates tested [17].
• Efficacy studies of BMS-284756, levofloxacin and azithromycin were performed in guinea pigs with L. pneumophila pneumonia [18].
• MEASUREMENTS AND MAIN RESULTS: Serial blood samples were collected, and plasma samples were analyzed for BMS-284756 using a validated liquid chromatography with tandem mass spectrometry detection method [19].

Gene context of T-3811MEa

• Although all quinolones selected, to a greater or lesser degree, for resistant clones with mutations usually in parC or gyrA, BMS-284756 tended to select for resistant clones at a lower rate than other quinolones studied [20].
• Even against a penicillin- and quinolone-resistant strain, BMS 284756 showed good bactericidal activity (-0.52 +/- 0.12 Delta log(10) CFU/ml. h) [15].
• In vitro susceptibility testing of BMS-284756 by the BSAC standardized disc testing method [21].

Analytical, diagnostic and therapeutic context of T-3811MEa

• The pharmacokinetics of a single dose of BMS 284756 were determined following oral administration of a 600-mg dose to eight healthy male volunteers [12].
• A sensitive, simple, and accurate method for determination of BMS-284756, a novel des-F(6)-quinolone antimicrobial agent in mouse serum was developed by HPLC with fluorescence detection [22].

References