Division of Allergy, Immunology and Infectious Diseases, Palo Alto Medical Research Foundation, Division of Infectious Diseases, Department of Medicine, Stanford University School of Medicine, Palo Alto, California 94301
Trimethoprim (TMP) and sulfamethoxazole (SMZ) were studied alone and in combination to determine their effect in vitro on intracellular Toxoplasma gondii and in vivo against murine toxoplasmosis. In the in vitro experiments, whereas 1 and 2 µg/ml TMP had no demonstrable effect on intracellular T. gondii, 10–20 µg/ml TMP resulted in death of the intracellular organisms; concentrations as high as 100 µg/ml SMZ had no demonstrable effect against the intracellular organisms. When used in combination, a significant synergistic effect was noted with 2 µg/ml TMP-50 µg/ml SMZ. Studies on the kinetics of inhibition and/or killing of Toxoplasma revealed that 18 hours of treatment with 2 µg/ml TMP-50 µg/ml SMZ resulted in irreversible inhibition of the intracellular organisms. When used in vivo against a 50,000 LD100 dose of Toxoplasma, TMP fed by gavage or mixed in the diet had no effect in murine toxoplasmosis at doses as high as 200 mg/kg a day. SMZ administered by gavage had no effect at doses up to 200 mg/kg a day; but at 300 and 400 mg/kg SMZ, protection was 47% and 83%, respectively. Treatment of infected mice was continued for 14 consecutive days, whether the drugs were administered alone or in combination. The combination 200 mg/kg TMP-200 mg/kg SMZ, when administered by gavage, protected 87% of mice. Survival after 14 days of SMZ mixed in the diet was 0% at 100 mg/kg, 47% at 200 mg/kg, and 100% at 300 mg/kg. Survival with the combination was 40% for 200 mg/kg TMP-100 mg/kg SMZ and 100% for 100 mg/kg TMP-200 mg/kg SMZ. The half-life of TMP in serum of Swiss Webster mice was calculated to be 24 min. The results obtained in vivo were inferior to those obtainable with the combination of pyrimethamine plus sulfadiazine. The problems of interpretation of results obtained in the murine model using TMP-SMZ and in their extrapolation to the treatment of the infection in man are discussed.