In vitro studies have shown that
trimetrexate, a
lipid-soluble analogue of
methotrexate, is 1500 times more potent than
trimethoprim as an inhibitor of
dihydrofolate reductase from Pneumocystis carinii. Furthermore,
trimetrexate is readily taken up by P carinii, while performed folates such as
leucovorin are not. These observations suggest that the combination of
trimetrexate plus
leucovorin, which can specifically protect mammalian host tissues from the toxic effects of the
antifolate, may be useful in the treatment of
pneumocystis pneumonia. This concept was tested in a clinical study of 49 patients with
acquired immunodeficiency syndrome (
AIDS) and
P carinii pneumonia who were treated for 21 days with
trimetrexate and
leucovorin. Patients were divided into three groups: 16 patients who were unable to tolerate or had failed both
pentamidine isethionate and
trimethoprim-sulfamethoxazole therapy were treated with
trimetrexate plus
leucovorin (Group I); 16 patients who were unable to tolerate
sulfonamide therapy were treated with
trimetrexate with
leucovorin as initial therapy (Group II); and 17 patients in whom
trimetrexate with
leucovorin plus
sulfadiazine was used as initial therapy (Group III). Response and survival rates were 69% and 69% in Group I; 63% and 88%, respectively, in Group II; and 71% and 76%, respectively, in Group III. Toxicity was minimal. The results indicate that
trimetrexate with
leucovorin is safe and effective for initial
therapy in
AIDS patients with
P carinii pneumonia and in those intolerant or unresponsive to standard
therapies.