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Antimicrobial Agents and Chemotherapy, April 2000, p. 991-996, Vol. 44, No. 4
Kenya Medical Research Institute/Wellcome
Trust Collaborative Research Program, Wellcome Trust Research
Laboratories, Nairobi,1 and Center for
Geographic Medicine Research, Coast, Kenya Medical Research Institute,
Kilifi,4 Department of Pharmacology and
Therapeutics, University of Liverpool, Liverpool L69 3BX, United
Kingdom2; and Department of Genetics,
University of Washington, Seattle, Washington
98195-73603
Received 21 June 1999/Returned for modification 25 October
1999/Accepted 18 January 2000
The antifolate combination of pyrimethamine (PM) and sulfadoxine
(SD) is the last affordable drug combination available for wide-scale
treatment of falciparum malaria in Africa. Wherever this combination
has been used, drug-resistant parasites have been selected rapidly. A
study of PM-SD effectiveness carried out between 1997 and 1999 at
Kilifi on the Kenyan coast has shown the emergence of RI and RII
resistance to PM-SD (residual parasitemia 7 days after treatment) in 39 out of 240 (16.25%) patients. To understand the mechanism that
underlies resistance to PM-SD, we have analyzed the dihydrofolate
reductase (DHFR) and dihydropteroate synthase (DHPS) genotypes of 81 patients. Fifty-one samples were obtained, before treatment, from
patients who remained parasite free for at least 7 days after
treatment. For a further 20 patients, samples were obtained before
treatment and again when they returned to the clinic with parasites 7 days after PM-SD treatment. Ten additional isolates were obtained from
patients who were parasitemic 7 days after treatment but who were not
sampled before treatment. More than 65% of the isolates (30 of 46) in
the initial group had wild-type or double mutant DHFR alleles, and all
but 7 of the 47 (85%) had wild-type DHPS alleles. In the paired
(before and after treatment) samples, the predominant combinations of DHFR and DHPS alleles before treatment were of triple mutant DHFR and
double mutant DHPS (41% [7 of 17]) and of double mutant DHFR and
double mutant DHPS (29% [5 of 17]). All except one of the posttreatment isolates had triple mutations in DHFR, and most of these
were "pure" triple mutants. In these isolates, the combination of a
triple mutant DHFR and wild-type DHPS was detected in 6 of 29 cases
(20.7%), the combination of a triple mutant DHFR and a single mutant
(A437G) DHPS was detected in 4 of 29 cases (13.8%), and the
combination of a triple mutant DHFR and a double mutant (A437G, L540E)
DHPS was detected in 16 of 29 cases (55.2%). These results demonstrate
that the triply mutated allele of DHFR with or without mutant DHPS
alleles is associated with RI and RII resistance to PM-SD. The
prevalence of the triple mutant DHFR-double mutant DHPS combination may
be an operationally useful marker for predicting the effectiveness of
PM-SD as a new malaria treatment.
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Towards an Understanding of the Mechanism of
Pyrimethamine-Sulfadoxine Resistance in Plasmodium
falciparum: Genotyping of Dihydrofolate Reductase and
Dihydropteroate Synthase of Kenyan Parasites
*
Corresponding author. Mailing address: Wellcome Trust
Research Laboratories, P.O. Box 43640, Nairobi, Kenya. Phone: 2542 725 390. Fax: 254 2 711 673. E-mail: anzila{at}WTRL.OR.KE.
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