INVITRO ACTIVITY OF SPARFLOXACIN (CI-978, AT-4140) FOR CLINICAL LEGIONELLA ISOLATES, PHARMACOKINETICS IN GUINEA-PIGS, AND USE TO TREAT GUINEA-PIGS WITH L-PNEUMOPHILA PNEUMONIA

The activities of sparfloxacin, ciprofloxacin, and erythromycin for 21 clinical Legionella isolates were determined by agar and broth dilution susceptibility testing and by growth inhibition assays in guinea pig alveolar macrophages (sparfloxacin and ciprofloxacin). All three antimicrobial agents had roughly equivalent activities when buffered charcoal yeast extract agar medium supplemented with 0.1% α-ketoglutarate was used as the test medium; the MICs for 90% of strains were 1.0 μg/ml for erythromycin and sparfloxacin and 0.5 μg/ml for ciprofloxacin. Buffered charcoal yeast extract medium supplemented with 0.1% α-ketoglutarate inhibited the activities of all the antimicrobial agents tested, as judged by the susceptibility of a control Staphylococcus aureus strain. Broth macrodilution MICs for two L. pneumophila strains in buffered yeast extract supplemented with 0.1% α-ketoglutarate were ≤ 0.03 μg/ml for sparfloxacin, 0.06 μg/ml for ciprofloxacin, and 0.25 μg/ml for erythromycin only erythromycin was inhibited by this medium. Ciprofloxacin and sparfloxacin (both 0.25 μg/ml) reduced bacterial counts of two L. pneumophila strains grown in guinea pig alveolar macrophages by 2 log10 CFU/ml, but regrowth occurred over a 3-day period. Sparfloxacin, but not ciprofloxacin (both 1 μg/ml), caused a 3- to 4-day postantibiotic effect. Pharmacokinetic and therapy studies of sparfloxacin were performed in guinea pigs with L. pneumophila pneumonia. For the pharmacokinetic study, sparfloxacin was given (10 mg/kg of body weight) to infected guinea pigs by the intraperitoneal route; peak levels in serum and lung were 2.6 μg/ml and 1.6 μg/g, respectively, at 1 h, with a terminal-phase half-life of elimination from serum of 5 h. All 15 infected guinea pigs treated with sparfloxacin (10 mg/kg/day) for 5 days survived for 11 days post-antimicrobial therapy, whereas 14 of 15 guinea pigs treated with erythromycin (60 mg/kg/day) survived for 11 days and 2 of 14 guinea pigs treated with saline survived for 11 days. Sparfloxacin was effective against L. pneumophila in vitro and in a guinea pig model of Legionnaires disease and may have been more effective than erythromycin. Sparfloxacin should be evaluated as a treatment of human Legionnaires disease.