Kenyan Plasmodium falciparum field isolates: correlation between pyrimethamine and chlorcycloguanil activity in vitro and point mutations in the dihydrofolate reductase domain

Sixty-nine Kenyan Plasmodium falciparum field isolates were tested in vitro against pyrimethamine (PM), chlorcycloguanil (CCG), sulfadoxine (SD), and dapsone (DDS), and their dihydrofolate reductase (DHFR) genotypes were determined. The in vitro data show that CCG is more potent than PM and that DDS...

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Published in:Antimicrobial agents and chemotherapy Vol. 42; no. 1; p. 164
Main Authors: Nzila-Mounda, A, Mberu, E K, Sibley, C H, Plowe, C V, Winstanley, P A, Watkins, W M
Format: Journal Article
Language:English
Published: United States 01.01.1998
Subjects:
Animals
Antimalarials - pharmacology
Humans
Kenya
Malaria, Falciparum - drug therapy
Plasmodium falciparum - drug effects
Plasmodium falciparum - enzymology
Point Mutation
Proguanil - analogs & derivatives
Proguanil - pharmacology
Protozoan Proteins - drug effects
Protozoan Proteins - genetics
Pyrimethamine - pharmacology
Sensitivity and Specificity
Tetrahydrofolate Dehydrogenase - drug effects
Tetrahydrofolate Dehydrogenase - genetics
Triazines
Kenya
ISSN:0066-4804
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Summary:Sixty-nine Kenyan Plasmodium falciparum field isolates were tested in vitro against pyrimethamine (PM), chlorcycloguanil (CCG), sulfadoxine (SD), and dapsone (DDS), and their dihydrofolate reductase (DHFR) genotypes were determined. The in vitro data show that CCG is more potent than PM and that DDS is more potent than SD. DHFR genotype is correlated with PM and CCG drug response. Isolates can be classified into three distinct groups based on their 50% inhibitory concentrations (IC50s) for PM and CCG (P < 0.01) and their DHFR genotypes. The first group consists of wild-type isolates with mean PM and CCG IC50s of 3.71 +/- 6.94 and 0.24 +/- 0.21 nM, respectively. The second group includes parasites which all have mutations at codon 108 alone or also at codons 51 or 59 and represents one homogeneous group for which 25- and 6-fold increases in PM and CCG IC50s, respectively, are observed. Parasites with mutations at codons 108, 51, and 59 (triple mutants) form a third distinct group for which nine- and eightfold increases in IC50s, respectively, of PM and CCG compared to the second group are observed. Surprisingly, there is a significant decrease (P < 0.01) of SD and DDS susceptibility in these triple mutants. Our data show that more than 92% of Kenyan field isolates have undergone at least one point mutation associated with a decrease in PM activity. These findings are of great concern because they may indicate imminent PM-SD failure, and there is no affordable antimalarial drug to replace PM-SD (Fansidar).
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ISSN:0066-4804
DOI:10.1128/aac.42.1.164