In-vitro and in-vivo activities of roxithromycin in combination with pyrimethamine or sulphadiazine against Toxoplasma gondii.
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.
Romand
S
S
Laboratoire de Parasitologie-Mycologie, Hôpital Saint-Louis, Paris, France.
Bryskier
A
A
Moutot
M
M
Derouin
F
F
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
D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D004338:Drug Combinations; D013411:Sulfadiazine; D015575:Roxithromycin; D011739:Pyrimethamine