Reduction of the Efficacy of Antifolate Antimalarial Therapy by Folic Acid Supplementation

Abstract

Malaria and anemia are common conditions in patients presenting to outpatient clinics in Kenya. Anemia is usually due to malaria infection with underlying micronutrient deficiency. Iron therapy has been shown to enhance recovery from anemia in children with malaria, without affecting malaria treatment. Iron and folic acid are often prescribed together for anemic individuals. Until recently in Kenya, the drug of first choice for non-severe malaria was sulfadoxine-pyrimethamine (SP), an antifolate antimalarial drug. In this study, 303 patients of all ages with anemia and uncomplicated Plasmodium falciparum malaria attending an outpatient clinic in an area of seasonal malaria were treated with SP and iron, and were randomized to receive folic acid. Parasite clearance rates were measured using a survival analysis plot for both parasitologic and clinical failure. There was a significant reduction in the efficacy of SP in patients taking standard therapeutic doses of folic acid using the survival curve for parasitologic failure (P < 0.0001), but no difference for clinical failure (P = 0.7008). Folic acid supplementation did not enhance recovery from anemia.

Safety and benefits of interventions to increase folate status in malaria‐endemic areas

“…In Kenyan patients treated for falciparum malaria with sulfadoxine‐pyrimethamine, daily supplementation with folic acid (2·5 or 5 mg for those aged <2 and ≥2 years, respectively) reduced the time to treatment failure as assessed by parasitological examination of blood slides collected at various points of follow‐up (Carter et al , 2005). There was no evidence of an effect on recovery from anaemia.…”

Current Status of Folic Acid Supplementation on Colorectal Cancer Prevention

“…These include masking of vitamin B 12 deficiency primarily in elderly [58]; decreased natural killer cell cytotoxicity [56]; resistance to antifolate drugs used against arthritis [59][60][61], malaria [62], and cancer [63,64]; an increased risk of insulin resistance and obesity and asthma in children born to folic acid-supplemented mothers [65]; accelerated progression of diabetic nephropathy [66]; an increased risk of cognitive impairment in elderly with suboptimal vitamin B 12 status [67,68]; aberrant patterns and dysregulation of DNA methylation [69]; and the promotion of progression of existing precancerous lesions or cancer [1,2,15,16].…”

Folate Biosynthesis - Reappraisal of Old and Novel Targets in the Search for New Antimicrobials

“…Gene amplification was demonstrated as a potential sulfonamide drug resistance mechanism in model systems [22,23] and recently shown to be a clinically valid resistance mechanism following chromosomal amplification of genetic elements encoding DHPS in S. agalactieae [24]. The competing effect of increased levels of the DHPS substrate pABA was shown to confound the effects of sulfonamides [2] both clinically and in model systems [25] as was the acquisition of environmental folates [26,27]. Drug resistance mutations have long been known to confer a fitness compromise.…”

“…It has been demonstrated that antimalarial therapy using antifolates can be significantly compromised by the concomitant dietary supplementation of folic acid [26,27]. In addition, increased expression levels of DHPS increase or decrease sulfa drug resistance depending on whether pABA is high or low, respectively [22,28].…”