Anti-toxoplasma effect of pyrimethamine, trimethoprim and sulphonamides alone and in combination: implications for therapy

The aim of the present study was to determine the in-vitro susceptibility of Toxoplasma gondii to dihydrofolate reductase inhibitors and sulphonamides alone, and in combination. It was found that pyrimethamine had the most potent anti-Toxoplasma activity, while sulphadiazine, sulphamethoxazole and sulphametrole were approximately equally effective, but only at a high concentration. The 50% inhibitory concentration of sulphamethoxazole was determined using different fixed concentrations of pyrimethamine or trimethoprim. It was found that a ten-fold increment of the concentration of pyrimethamine, reduced the IC50 of sulphamethoxazole 1000 times. The influence of trimethoprim on the IC50 of sulphamethoxazole was less concentration dependent. Addition of dihydrofolate or tetrahydrofolate did not influence the IC50 of pyrimethamine. In conclusion, the present dose recommendations for sulphonamides, when combined with pyrimethamine, may be unnecessarily high. There may be a justification for dose reduction of sulphonamides in order to prevent side effects.