Studies of the effects of trimethoprim and sulfamethoxazole on human granulopoiesis

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 micrograms/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 micrograms/ml) had no discernible effect on granulopoiesis. The combination of 8 micrograms/ml of trimethoprim and 40 micrograms/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.

Drug-Induced Hematological Cytopenia in Kidney Transplantation and the Challenges It Poses for Kidney Transplant Physicians

“…The effects are reversed with folinic acid supplementation. Similar effects were demonstrated on folate depleted granulocyte precursors in another study done in vitro setting [ 213 ]. It is proposed that the effect of large doses of trimethoprim on the hematopoietic system is probably the result of interference with the methylation of deoxyuridine arising from inhibition of dihydrofolate reductase, specifically in presence of folate deficiency.…”

Hematopoiesis and the bacterial microbiome

“…[46][47][48] Trimethoprim has been shown to exert an antifolate activity on granulocyte progenitors, an effect that can be reversed by folinic acid administration. 49 However, cytopenias related to other antibiotics have not been related to folate deficiency, and their vastly different incidence suggests that the mechanisms of action differ as well.…”

Drug‐induced neutropenia due to direct effects on CFU‐C — Ten years of culture experience

“…Four of the 17 cases in this report have already been published, P8, P17, P7 and P1 (3,4,8,9). The patients with sensitivity to sulphamethoxazole P2, chlorpromazine P4, methimazole P 10, and carbamazepine P11 and P12 have not previously been reported, although other workers have studied the effects of these drugs on CFU-C (12)(13)(14)(15)(16). In the remaining 6 patients for whom marrow growth was obtained no conclusive sensitivity to the putative agent was demonstrated.…”