Activity of trovafloxacin (CP-99,219) against Legionella isolates: In vitro activity, intracellular accumulation and killing in macrophages, and pharmacokinetics and treatment of guinea pig with L pneumophila pneumonia

The activity of trovafloxacin against 22 clinical Legionella isolates was determined by broth microdilution susceptibility testing, The trovafloxacin concentration required to inhibit 90% of strains tested was less than or equal to 0.004 mu g/ml, in contrast to 0.032 mu g/ml for ofloxacin, In guinea pig alveolar macrophages, trovafloxacin achieved intracellular levels up to 28-fold over the extracellular concentration, which was similar to the levels obtained with erythromycin. Trovafloxacin (0.25 mu g/ml) reduced bacterial counts of two L. pneumophila strains grown in guinea pig alveolar macrophages by >2 log(10) CFU/ml, without regrowth, under drug-free conditions over a 3-day period: trovafloxacin was significantly more active than ofloxacin or erythromycin (0.25 to 1 mu g/ml) in this assay, Single-dose (10 mg of prodrug CP-116,517-27 per kg of body weight given intraperitoneally [i.p.], equivalent to 7.5 mg of trovafloxacin per kg) pharmacokinetic studies performed in guinea pigs with L. pneumophila pneumonia revealed peak serum and lung trovafloxacin levels to be 3.8 mu g/ml and 5.0 mu g/g, respectively, at 0.5 h and 4.2 mu g/ml and 2.9 mu g/g, respectively, at 1 h, Administration of a lower prodrug dose (1.4 mg of trovafloxacin equivalent per kg i.p.) gave levels in lung and serum of 0.4 mu g/g and 0.4 mu g/ml, respectively, 1 h after drug administration, The terminal half-lives of elimination from serum and lung were 0.8 and 1.1 h, respectively, All 15 infected guinea pigs treated for 5 days with CP-116,517-27 once daily (10 mg/kg/day i.p., equivalent to 7.5 mg of trovafloxacin per kg/day) survived for 10 days after antimicrobial therapy, as did all 15 guinea pigs treated with ofloxacin once daily (10 mg/kg/day i.p.) for 5 days, None of 13 animals treated with saline survived, In a second experiment with animals, trovafloxacin (1.4 mg/kg/day i.p. for 5 days) protected all 16 guinea pigs from death, whereas all 15 animals treated with saline died, Trovafloxacin is an effective antimicrobial agent against Legionellla in vitro and in vivo, with the ability to concentrate in macrophages and kill intracellular organisms.