Accession Number:

ADA528213

Title:

Effects of Point Mutations in Plasmodium falciparum Dihydrofolate Reductase and Dihydropterate Synthase Genes on Clinical Outcomes and In Vitro Susceptibility to Sulfadoxine and Pyrimethamine

Descriptive Note:

Journal article

Corporate Author:

UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD DEPT OF PREVENTIVE MEDICINE AND BIOMETRICS

Report Date:

2009-08-01

Pagination or Media Count:

11.0

Abstract:

Sulfadoxine-pyrimethamine was a common first line drug therapy to treat uncomplicated falciparum malaria but increasing therapeutic failures associated with the development of significant levels of resistance worldwide has prompted change to alternative treatment regimes in many national malaria control programs. Methodology and Finding We conducted an in vivo therapeutic efficacy trial of sulfadoxine-pyrimethamine at two locations in the Peruvian Amazon enrolling 99 patients of which, 86 patients completed the protocol specified 28 day follow up. Our objective was to correlate the presence of polymorphisms in P. falciparum dihydrofolate reductase and dihydropteroate synthase to in vitro parasite susceptibility to sulfadoxine and pyrimethamine and to in vivo treatment outcomes. Inhibitory concentration 50 values of isolates increased with numbers of mutations single 108N, sextuplet BR 51I108N164L and 437G581G and septuplet BR51I108N164L and 437G540E581G with geometric means of 76 nM 35166 nM, 582 nM 49-6890- nM and 4909 35756741 nM nM for sulfadoxine and 33 nM 2251 nM, 81 nM 19 345 nM, and 215 nM 176262 nM for pyrimethamine. A single mutation present in the isolate obtained at the time of enrollment from either dihydrofolate reductase 164L or dihydropteroate synthase 540E predicted treatment failure as well as any other single gene alone or in combination. Patients with the dihydrofolate reductase 164L mutation were 3.6 times as likely to be treatment failures failures 85.4 164L vs 23.7 I164 relative risk 3.61 95 CI 2.14 6.64 while patients with the dihydropteroate synthase 540E were 2.6 times as likely to fail treatment 96.7 540E vs 37.5 K540 relative risk 2.58 95 CI 1.88 3.73. Patients with both dihydrofolate reductase 164L and dihydropteroate synthase 540E mutations were 4.1

Subject Categories:

  • Genetic Engineering and Molecular Biology
  • Medicine and Medical Research
  • Microbiology

Distribution Statement:

APPROVED FOR PUBLIC RELEASE