IN-VIVO THERAPEUTIC EFFICACIES OF PD-138312 AND PD-140248, 2 NOVEL FLUORONAPHTHYRIDINES WITH OUTSTANDING GRAM-POSITIVE POTENCY

PD 133312 and PD 140248 are novel broad-spectrum 7-pyrrolidinyl fluoro naphthyridines with a cyclopropyl or a difluorophenyl substitution at the 1 positions, respectively, They have been demonstrated to have exc ellent in vitro activity against gram-positive organisms, These compou nds were evaluated for their in vivo potencies against acute systemic infections in mice and in a mouse pneumococcal pneumonia model. They w ere very effective by both the oral and subcutaneous routes of adminis tration, Most remarkable were their comparative median protective valu es against methicillin-resistant Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes, In general, these compounds we re 28- to 100-fold more active than ciprofloxacin against these clinic ally significant organisms when the drugs were given orally and 10- to 38-fold more active when the drugs were given parenterally. Average r atios of drug concentrations in mice after drug administration by the oral route to that after administration by the subcutaneous route indi cate 34 to 44% greater bioavailabilities of PD 138312 and PD 140248 co mpared with that of ciprofloxacin. In a multidose pneumococcal mouse p neumonia model these new quinolones were extremely effective, with med ian curative doses of 2 to 2.8 mg/kg of body weight per dose, Ciproflo xacin was ineffective (median curative dose, >100 mg/kg per dose) in t his model. Comparative pharmacokinetic studies in mice revealed a rela tive superiority of PD 140248. Peak levels of PD 140248 in blood after the administration of a single oral 50-mg/kg dose were twice those of PD 138312 and ciprofloxacin, with PD 140248 having a substantially lo nger half-life, These results indicate that PD 138312 and PD 140248 ha ve excellent therapeutic potential against clinically important gram-p ositive pathogens when the drugs are administered both orally and pare nterally.