Trimetrexate for the Treatment of Pneumocystis carinii Pneumonia in Patients with the Acquired Immunodeficiency Syndrome

Preclinical studies have demonstrated that trimetrexate is a potent inhibitor of dihydrofolate reductase from Pneumocystis carinii . On the basis of this evidence, this lipid-soluble antifolate was used as an antipneumocystis agent in 49 patients with the acquired immunodeficiency syndrome (AIDS) and pneumocystis pneumonia. Simultaneous treatment with the reduced folate leucovorin was used as a specific antidote to protect host tissues from the toxic effects of the antifolate without affecting the antipneumocystis action of trimetrexate. Patients were assigned to three groups and treated for 21 days: in Group I, trimetrexate with leucovorin was used as salvage therapy in patients in whom standard treatments (both pentamidine isethionate and trimethoprim–sulfamethoxazole) could not be tolerated or had failed (16 patients); in Group II, trimetrexate with leucovorin was used as initial therapy in patients with a history of sulfonamide inefficacy or intolerance (16 patients); and in Group III, trimetrexate with leucovorin plus sulfadiazine was used as initial therapy (17 patients). The response and survival rates were, respectively, 69 percent and 69 percent in Group I; 63 percent and 88 percent in Group II; and 71 percent and 77 percent in Group III. Trimetrexate therapy had minimal toxicity; transient neutropenia or thrombocytopenia occurred in 12 patients and mild elevation of serum aminotransferases in 4. We conclude that the combination of trimetrexate and leucovorin is safe and effective for the initial treatment of pneumocystis pneumonia in patients with AIDS and for the treatment of patients with intolerance or lack of response to standard therapies. (N Engl J Med 1987; 317:978–85.) PNEUMOCYSTIS carinii pneumonia occurs as a complication of immunosuppression in patients who have received cancer chemotherapy or an organ transplant, and is now recognized as the most frequent pulmonary infection and the most common cause of death in patients with the acquired immunodeficiency syndrome (AIDS). At least 100,000 cases of pneumocystis pneumonia are expected to occur in patients with AIDS in the United States by 1991. 1 Initial therapy for P. carinii pneumonia commonly employs either pentamidine isethionate or a combination of trimethoprim, an inhibitor of dihydrofolate reductase, and sulfamethoxazole, an inhibitor of de novo biosynthesis of folic acid. The use . . .