Evaluation of trimethoprim and sulphamethoxazole as monotherapy or in combination in the management of toxoplasmosis in murine models

The combination of trimethoprim (TMP) and sulphamethoxazole (SMX) is common ly used for the prevention of cerebral toxoplasmosis although there is no f irm experimental basis to support this regimen. We used strain RH tachyzoit es for challenge in the acute murine model of toxoplasmosis and found that TMP administered as a single agent, failed to eradicate toxoplasma even at the highest dose (70 mg/kg per day). SMX alone at 600 mg/kg per day, protec ted ten out of ten mice, although inoculation of brain from surviving anima ls to naive mice resulted in the development of an encephalitis. When combi ned, TMP (60 mg/kg per day) and SMX (300 mg/kg per day) protected ten out o f ten mice and gave a 'cure' in four out of four mice. In the chronic cysto genic murine models, the combination TMP plus SMX administered from day 5 f or 15 days or from day 28 for 288 days, gave protection and even apparent t oxoplasmal eradication ('cure') at the highest dosing (60/300 mg/kg per day ). However, microscopic severe encephalitis was found in mice classified as 'cured' after reinoculation. This result makes the interpretation of 'cure ' very difficult. In conclusion TMP and SMX act synergistically, SMX being the more active arm of the combination. The combination was efficient in pr eventing the lethal development of chronic toxoplasma encephalitis, but did not guarantee complete recovery. (C) 1999 Elsevier Science B.V. and Intern ational Society of Chemotherapy. All rights reserved.