INVITRO AND INVIVO ACTIVITIES OF A NEW QUINOLONE, WIN-57273, POSSESSING POTENT ACTIVITY AGAINST GRAM-POSITIVE BACTERIA

The antibacterial activity of a new 7-dimethylpyridinyl quinolone, WIN 57273, was assessed by using in vitro and in vivo models. Agar inclusion and broth dilution in vitro tests revealed broad-spectrum activity against gram-positive and selected gram-negative organisms, with the greatest potency observed against the staphylococci. The MIC for 90% of coagulase-positive strains tested (MIC90) was ≤ 0.002 μg/ml; for the coagulase-negative strains the MIC90 was 0.008 μg/ml. Against enterococci the MIC90 was 0.06 μg/ml, with comparable activity observed against group A and group B streptococci as well as against the pneumococci. In general, the MIC90s for the gram-negative bacteria were ≤ 1 μg/ml. Exceptions were Serratia marcescens (MIC90, 16 μg/ml), Citrobacter freundii (MIC90, 4 μg/ml), and Pseudomonas aeruginosa (MIC90, 8 μg/ml). The greatest potency was observed against Haemophilus spp. and Neisseria spp., with MIC90s of 0.06 and 0.016 μg/ml, respectively. Broad-spectrum activity was also observed against anaerobes, with MIC90s ranging from 0.125 to 0.5 μg/ml among the species tested. The in vivo efficacy was determined by using a murine model by calculating the 50% protective doses against a lethal bacterial infection caused by strains of Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The staphylococci were most susceptible, with 50% protective doses for all strains ranging from 0.1 to 0.7 mg/kg. With the exception of the Pseudomonas infection, which was refractory to treatment, animals that were part of the other infection models responded to less than 10 mg/kg. Equivalent activity was seen with the subcutaneous or the oral route of drug administration. WIN 57273 was significantly more potent than ciprofloxacin in treating gram-positive bacterial infections (2- to 20-fold) but was significantly less effective at treating gram-negative bacterial infections (30- to 300-fold).