With the growing acquired immunodeficiency syndrome (AIDS) epidemic, the use of pyrimethamine and sulfadiazine in the treatment of central nervous system toxoplasmosis has increased. Pyrimethamine exerts its antiparasitic effect by inhibiting the enzyme dihydrofolate reductase, which the parasite requires for DNA synthesis. By the same mechanism, pyrimethamine can also potentially cause megaloblastic anemia by depleting folic acid stores ([1]). At the dosages regularly used in humans, pyrimethamine alone does not commonly cause substantial megaloblastic anemia. The ability of pyrimethamine to inhibit the dihydrofolate reductase enzyme has been shown to be relatively selective to the parasite ([2]).

We evaluated a patient who developed life-threatening megaloblastic anemia after prolonged treatment with pyrimethamine and sulfadiazine. The patient presented with profound pancytopenia and bleeding that were rapidly corrected with folinic acid. This 35-year-old man was positive for human immunodeficiency virus (HIV) infection and was diagnosed with central nervous system toxoplasmosis in April 1992. He was treated with pyrimethamine, 25 mg orally per day, and sulfadiazine, 2 g orally each day, during the next 16 months. In August 1993, persistent oral mucosal bleeding developed. A physical examination showed oral purpura and petechiae in the extremities. Laboratory findings included the following: a platelet count of 3 x 10⁹/L (normal range, 150 to 450 x 10⁹/L), leukocyte count of 0.6 x 10⁹/L (normal, 4.0 to 10.0 x 10⁹/L), a hematocrit of 0.25 (normal, 0.40 to 0.48), and a mean corpuscular volume of 106. Bone marrow aspirates showed marked megaloblastic changes in all cell lines. Serum erythrocyte folate levels were 56 ng/mL (normal, 200 to 700 ng/mL), lactate dehydrogenase levels were 1175 U/L (normal, 300 to 618 U/L), and vitamin B₁₂ levels were 4700 pg/mL (normal, 250 to 1000 pg/mL). Results of all other laboratory studies, including that for antiplatelet antibodies, were negative.

Pyrimethamine therapy was discontinued, and the patient was given folinic acid at 10 mg orally each day and a single platelet transfusion. Twelve hours after the first dose of folinic acid, the platelet count was 21 x 10⁹/L and the bleeding had ceased. By day 7, the platelet count was 100 x 10⁹/L and the leukocyte count was 6.7 x 10⁹/L. On day 13, the platelet count was 456 x 10⁹/L and the leukocyte count was 10.4 x 10⁹/L. Pyrimethamine was restarted on day 10, and the patient continued to receive folinic acid thereafter. Six months later, his platelet count remained at 157 x 10⁹/L.

Although pyrimethamine and sulfadiazine are commonly used to treat patients with central nervous system toxoplasmosis, the hematologic toxicity of this combination has not been studied in detail ([3], [4]). One recently completed prospective study of patients positive for HIV suggested that the use of pyrimethamine prophylaxis without folinic acid replacement might adversely affect survival ([5]). Our experience shows the severe hematologic toxicity that can occur in patients requiring pyrimethamine-sulfadiazine therapy. This toxicity can be rapidly overcome with the addition of folinic acid, which restores DNA synthesis even in the presence of a dihydrofolate reductase inhibitor (pyrimethamine). Folinic acid supplementation should be considered for prophylaxis in any patient receiving prolonged pyrimethamine and sulfadiazine.