Folate Deficiency Associated with Drug Therapy for Tuberculosis

Two patients have been described who were found to have a megaloblastic anemia due to folate deficiency while receiving treatment for pulmonary tuberculosis with isoniazid and cycloserine. In an additional 120 patients studied with tuberculosis, serum folate concentrations were subnormal in 7 of 12 inadequately nourished and in 5 of 24 well-nourished patients with untreated tuberculosis, in 15 of 29 patients taking isoniazid and cycloserine, but in only 2 of 55 patients receiving other combinations of drugs for tuberculosis. In vitro studies showed that isoniazid had a depressant effect on the growth of L. casei but only when added in a concentration that greatly exceeded the pharmacologic dose; cycloserine had a similar effect at a concentration that was only threefold greater than that usually found in patients receiving therapeutic doses of this drug.

Serum concentrations of vitamin B₁₂ were normal in both patients described with megaloblastic anemia as well as in all 36 patients with untreated tuberculosis and were in the indeterminate range in 14 and subnormal in 3 patients who were receiving drug therapy. The addition to medium in vitro of cycloserine, but not of isoniazid or pyrazinamide depressed the growth of L. leichmannii.

These results confirm previously reported observations by others which indicate that folate deficiency is a frequent occurrence in patients with untreated tuberculosis. They suggest that abnormal folate determinations in these patients are due principally to inadequate dietary intake. In addition, the significantly greater incidence of abnormal folate determinations that was observed in adequately nourished patients taking cycloserine and the results of the in vitro studies suggest that this drug can be responsible for folate deficiency in some instances. The mechanism for this is unknown.