title: In-vitro and in-vivo activities of roxithromycin in combination with pyrimethamine or sulphadiazine against Toxoplasma gondii.
abstract: The efficacy of roxithromycin alone or in combination with pyrimethamine or sulphadiazine was examined in vitro and in a murine model of acute toxoplasmosis. In-vitro studies were performed with MRC5 fibroblast tissue cultures, with quantification of toxoplasma growth by an enzyme-linked immunosorbent assay. For in-vivo studies, mice were infected with 10(4) tachyzoites of the virulent RH strain and then treated perorally for 10 days from day 1 after infection. The efficacy of each drug regimen was assessed by determination of survival rates and sequential titration of parasites in blood, brain and lungs, using a tissue culture method. In vitro, roxithromycin inhibited toxoplasma growth at a concentration of > or = 0.02 mg/L; the 50% inhibitory concentration was estimated to be 1.34 mg/L. No synergistic effect was observed when it was combined with pyrimethamine or sulphadiazine. In vivo, roxithromycin alone at 50 or 200 mg/kg/day slightly prolonged survival compared with untreated mice, but a striking synergistic effect was observed when roxithromycin was administered in combination with pyrimethamine or sulphadiazine at subtherapeutic doses, i.e., 12.5 and 100 mg/kg/day, respectively. Combination regimens consistently resulted in a marked reduction fo the parasite burdens in blood and tissue, compared with those in mice treated with any of the agents alone. These results suggest that in-vivo activities of either pyrimethamine or sulphadiazine against T. gondii are reinforced by roxithromycin and such combinations should be considered in development of alternative treatments for human toxoplasmosis.
authors.affiliation: Laboratoire de Parasitologie-Mycologie, Hôpital Saint-Louis, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Romand
authors.forename: A
authors.initials: A
authors.lastname: Bryskier
authors.forename: M
authors.initials: M
authors.lastname: Moutot
authors.forename: F
authors.initials: F
authors.lastname: Derouin
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D000890:Anti-Infective Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D002478:Cells, Cultured; D004338:Drug Combinations; D005260:Female; D005347:Fibroblasts; D051379:Mice; D011739:Pyrimethamine / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D015575:Roxithromycin / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D013411:Sulfadiazine / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D014122:Toxoplasma / Q000187:drug effects*; D014124:Toxoplasmosis, Animal / Q000188:drug therapy* / Q000469:parasitology
chemical_list: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D004338:Drug Combinations; D013411:Sulfadiazine; D015575:Roxithromycin; D011739:Pyrimethamine