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-PNEUMOPHILAPNEUMONIA

The activity of trovafloxacin against 22 clinical Legionella isolates was determined by broth microdilution susceptibility testing, The trov afloxacin 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 concentratio n, which was similar to the levels obtained with erythromycin. Trovafl oxacin (0.25 mu g/ml) reduced bacterial counts of two L. pneumophila s trains grown in guinea pig alveolar macrophages by >2 log(10) CFU/ml, without regrowth, under drug-free conditions over a 3-day period: trov afloxacin 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-1 16,517-27 per kg of body weight given intraperitoneally [i.p.], equiva lent to 7.5 mg of trovafloxacin per kg) pharmacokinetic studies perfor med in guinea pigs with L. pneumophila pneumonia revealed peak serum a nd lung trovafloxacin levels to be 3.8 mu g/ml and 5.0 mu g/g, respect ively, 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 equiva lent 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 hal f-lives of elimination from serum and lung were 0.8 and 1.1 h, respect ively, 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 trovafloxaci n 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 animal s treated with saline died, Trovafloxacin is an effective antimicrobia l agent against Legionellla in vitro and in vivo, with the ability to concentrate in macrophages and kill intracellular organisms.