THE KETOLIDE ANTIBIOTICS HMR-3647 AND HMR-3004 ARE ACTIVE AGAINST TOXOPLASMA-GONDII IN-VITRO AND IN MURINE MODELS OF INFECTION

Ketolides are a new class of macrolide antibiotics that have been show n to be active against a variety of bacteria including macrolide-resis tant bacteria and mycobacteria, We examined two ketolides, HMR 3647 an d HMR 3004, for their in vitro and in vivo activities against the prot ozoan parasite Toxoplasma gondii. In vitro, both ketolides at concentr ations as low as 0.05 mu g/ml markedly inhibited replication of tachyz oites of the RH strain within human foreskin fibroblasts. HMR 3004 dem onstrated some toxicity for host cells after they were exposed to 5 mu g of the drug per ml for 72 h, In contrast, HMR 3647 did not show any significant toxicity even at concentrations as high as 25 mu g/ml. In vivo, both ketolides provided remarkable protection against death in mice lethally infected intraperitoneally with tachyzoites of the RH st rain or orally with tissue cysts of the C56 strain of T, gondii, A dos age of 100 mg of HMR 3647 per kg of body weight per day administered f or 10 days protected 50% of mice infected with tachyzoites. The same d osage of HMR 3004 protected 100% of the mice. In mice infected with cy sts, a dosage of 30 mg of HMR 3647 per kg per day protected 100% of th e mice, whereas a dosage of 40 mg of HMR 3004 per kg per day protected 75% of the mice, These results demonstrate that HMR 3647 and HMR 3004 possess excellent activities against two different strains of T. gond ii and may be useful for the treatment of toxoplasmosis in humans.