PD-138312

PD 138312 and PD 140248 are novel broad-spectrum 7-pyrrolidinyl fluoronaphthyridines with a cyclopropyl or a difluorophenyl substitution at the 1 positions, respectively. They have been demonstrated to have excellent in vitro activity against gram-positive organisms. These compounds were evaluated for their in vivo potencies against acute systemic infections in mice and in a mouse pneumococcal pneumonia model. They were very effective by both the oral and subcutaneous routes of administration. Most remarkable were their comparative median protective values against methicillin-resistant Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes. In general, these compounds were 28- to 100-fold more active than ciprofloxacin against these clinically significant organisms when the drugs were given orally and 10- to 38-fold more active when the drugs were given parenterally. Average ratios of drug concentrations in mice after drug administration by the oral route to that after administration by the subcutaneous route indicate 34 to 44% greater bioavailabilities of PD 138312 and PD 140248 compared with that of ciprofloxacin. In a multidose pneumococcal mouse pneumonia model these new quinolones were extremely effective, with median curative doses of 2 to 2.8 mg/kg of body weight per dose. Ciprofloxacin was ineffective (median curative dose, >100 mg/kg per dose) in this model. Comparative pharmacokinetic studies in mice revealed a relative 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 longer half-life. These results indicate that PD 138312 and PD 140248 have excellent therapeutic potential against clinically important gram-positive pathogens when the drugs are administered both orally and parenterally.

Certain new fluoroquinolones have high activity against enterococci. Against Enterococcus faecalis (n = 18), MICs at which 90% of the isolates were inhibited were as follows (in micrograms per milliliter): clinafloxacin, 0.125; CI-990, 0.5; and PD 138312, 0.25 (compared with 1 microgram/ml for ciprofloxacin and 2 micrograms/ml for ofloxacin). Strains producing beta-lactamase or that were vancomycin resistant or resistant to high-level gentamicin were not quinolone cross-resistant. The drugs were bactericidal and were unaffected by 50% human serum. Oral efficacies (in milligrams per kilogram of body weight for 50% protective doses) in lethal mouse infections with quinolone-susceptible strains were 4.3 to 24 for clinafloxacin, 7.2 to 39 for CI-990, 7.2 to 76 for PD 138312, and 41 to > 100 for ciprofloxacin; when the drugs were given subcutaneously, the order was similar and values ranged from 1.1 to 12.5. Clinafloxacin, CI-990, and PD 138312 may have therapeutic potential in systemic enterococcal infections in humans.