Studies of the effects of trimethoprim and sulfamethoxazole on human granulopoiesis

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Abstract
Trimethoprim and sulfamethoxazole (Bactrim r) is a widely used antibiotic combination effective against a broad spectrum of microbial organisms. There are reports of neutropenia developing during even brief periods of oral therapy, particularly in individuals with either folate deficiency or increased folate requirements. We have investigated the effects of these drugs on circulating granulocyte precursors (CFU‐C) from normal donors and the mechanism of inhibition on granulopoiesis using an in vitro CFU‐C assay. In 12 healthy adults, the number of circulating granulocytes and granulocyte progenitors was not significantly altered by a 5‐day course of therapy. However, in experiments that simulated the in vivo condition of folate deficiency (folate‐free cultures were prepared with cells harvested from normal donors), trimethoprim (8 μg/ml) resulted in a 47% decrease in the total number of colonies; this inhibitory effect was prevented when 100 ng of folinic acid was also added to the culture. Sulfamethoxazole (40 μg/ml) had no discernible effect on granulopoiesis. The combination of 8 μg/ml of trimethoprim and 40 μg/ml of sulfamethoxazole resulted in a 52% decrease in the number of colonies generated and this inhibition was again prevented by folinic acid. Our results suggest that the neutropenia occasionally observed in patients treated with trimethoprim‐sulfamethoxazole is due to the inhibitory effects on granulopoiesis by trimethoprim, namely its antifolate action, which is reversed by folinic acid. Based on these studies, in patients with either folate deficiency or increased folate requirements, trimethoprim‐sulfamethoxazole should be used with caution.