Novel biaryl oxazolidinones: in vitro and in vivo activities with pharmacokinetics in an animal model

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 (MIC 90) values of RBx 1000075, RBx 1000276 and linezolid against the isolates tested were, respectively: methicillin-sensitive Staphylococcus aureus, 0.25, 1 and 4 μg/mL; methicillin-resistant S. aureus (MRSA), 0.5, 2 and 4 μg/mL; methicillin-sensitive Staphylococcus epidermidis, 0.25, 1 and 2 μg/mL; methicillin-resistant S. epidermidis, 0.5, 1 and 2 μg/mL; and enterococci, 0.25, 1 and 4 μg/mL. Against respiratory pathogens, MIC 90 values were: Streptococcus pneumoniae, 0.125, 0.5 and 2 μg/mL; Streptococcus pyogenes, 1, 0.5 and 2 μg/mL; and Moraxella catarrhalis, 0.5, 2 and 4 μg/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 (ED 50) of 6.25 and 9.92 mg/kg body weight for once-daily administration and 4.96 and 5.56 mg/kg body weight for twice-daily administration, respectively, whereas for linezolid the corresponding ED 50 values were 9.9 and 5.56 mg/kg body weight. In pulmonary infection with S. pneumoniae ATCC 6303, 50% survival was observed with RBx 1000075 at 50 mg/kg once daily, whereas 60% survival was observed with RBx 1000276 at 50 mg/kg thrice daily. The absolute oral bioavailabilities of RBx 1000075 and RBx 1000276 were 48% and 73%, with half-lives of 13.5 and 3.2 h, respectively. RBx 1000075 and RBx 1000276 are promising investigational oxazolidinones against Gram-positive pathogens.