Novel biaryl oxazolidinones: in vitro and in vivo activities with pharmacokinetics in an animal model
International Journal of Antimicrobial Agents(2009)
Abstract
RBx 1000075 and RBx 1000276, the new investigational oxazolidinones, have an extended spectrum of in vitro activity against Gram-positive pathogens and showed minimum inhibitory concentrations (MICs) lower than comparator drugs. MIC for 90% of the organisms (MIC90) values of RBx 1000075, RBx 1000276 and linezolid against the isolates tested were, respectively: methicillin-sensitive Staphylococcus aureus, 0.25, 1 and 4μg/mL; methicillin-resistant S. aureus (MRSA), 0.5, 2 and 4μg/mL; methicillin-sensitive Staphylococcus epidermidis, 0.25, 1 and 2μg/mL; methicillin-resistant S. epidermidis, 0.5, 1 and 2μg/mL; and enterococci, 0.25, 1 and 4μg/mL. Against respiratory pathogens, MIC90 values were: Streptococcus pneumoniae, 0.125, 0.5 and 2μg/mL; Streptococcus pyogenes, 1, 0.5 and 2μg/mL; and Moraxella catarrhalis, 0.5, 2 and 4μg/mL. In vivo efficacies of RBx 1000075 and RBx 1000276 were evaluated in murine systemic infection against S. aureus (MRSA 562) and in a pulmonary infection model against S. pneumoniae ATCC 6303. In murine systemic infection, RBx 1000075 and RBx 1000276 showed efficacy against MRSA 562, exhibiting a 50% effective dose (ED50) of 6.25 and 9.92mg/kg body weight for once-daily administration and 4.96 and 5.56mg/kg body weight for twice-daily administration, respectively, whereas for linezolid the corresponding ED50 values were 9.9 and 5.56mg/kg body weight. In pulmonary infection with S. pneumoniae ATCC 6303, 50% survival was observed with RBx 1000075 at 50mg/kg once daily, whereas 60% survival was observed with RBx 1000276 at 50mg/kg thrice daily. The absolute oral bioavailabilities of RBx 1000075 and RBx 1000276 were 48% and 73%, with half-lives of 13.5 and 3.2h, respectively. RBx 1000075 and RBx 1000276 are promising investigational oxazolidinones against Gram-positive pathogens.
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Key words
MRSA,Oxazolidinone,Linezolid-resistant,Animal model
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