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Antimicrobial Agents and Chemotherapy, November 2001, p. 3122-3127, Vol. 45, No. 11
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.11.3122-3127.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Association of Genetic Mutations in Plasmodium vivax dhfr with Resistance to Sulfadoxine-Pyrimethamine: Geographical and Clinical Correlates

Mallika Imwong,1 Sasithon Pukrittakayamee,1 Sornchai Looareesuwan,1 Geoffrey Pasvol,2 Jean Poirreiz,3 Nicholas J. White,1,4,* and Georges Snounou5

Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand1; Department of Infection and Tropical Medicine, Imperial College School of Medicine, Northwick Park Hospital, Harrow,2 and Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford,4 United Kingdom; and Laboratoire de Biologie, Centre Hospitalier, Dunkerque,3 and Unité de Parasitologie Bio-Médicale, Institut Pasteur, 75724 Paris Cedex 15,5 France

Received 30 April 2001/Returned for modification 19 July 2001/Accepted 15 August 2001

Mutations in the Plasmodium falciparum gene (dhfr) encoding dihydrofolate reductase are associated with resistance to antifols. Plasmodium vivax, the more prevalent malaria parasite in Asia and the Americas, is considered antifol resistant. Functional polymorphisms in the dhfr gene of P. vivax (pvdhfr) were assessed by PCR-restriction fragment length polymorphism using blood samples taken from 125 patients with acute vivax malaria from three widely separated locations, Thailand (n = 100), India (n = 16), and Madagascar and the Comoros Islands (n = 9). Upon evaluation of the three important codons (encoding residues 57, 58, and 117) of P. vivax dhfr (pvdhfr), double- or triple-mutation genotypes were found in all but one case from Thailand (99%), in only three cases from India (19%) and in no cases from Madagascar or the Comoros Islands (P < 0.0001). The dhfr PCR products of P. vivax from 32 Thai patients treated with the antifolate sulfadoxine-pyrimethamine (S-P) were investigated. All samples showed either double (53%) or triple (47%) mutations. Following treatment, 34% of the patients had early treatment failures and only 10 (31%) of the patients cleared their parasitemias for 28 days. There were no significant differences in cure rates, but parasite reduction ratios at 48 h were significantly lower for patients whose samples showed triple mutations than for those whose samples showed double mutations (P = 0.01). The three mutations at the pvdhfr codons for residues 57, 58, and 117 are associated with high levels of S-P resistance in P. vivax. These mutations presumably arose from selection pressure.

* Corresponding author. Mailing address: Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Rd., Bangkok 10400, Thailand. Phone: 66-2-246-0832. Fax: 66-2-246-7795. E-mail: fnnjw{at}diamond.mahidol.ac.th.

Antimicrobial Agents and Chemotherapy, November 2001, p. 3122-3127, Vol. 45, No. 11
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.11.3122-3127.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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