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Antimicrobial Agents and Chemotherapy, June 2004, p. 2116-2123, Vol. 48, No. 6
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.6.2116-2123.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Evolution of Resistance to Sulfadoxine-Pyrimethamine in Plasmodium falciparum

Michelle L. Gatton,^1,2* Laura B Martin,^1,2, and Qin Cheng³

Malaria and Scabies Group, Queensland Institute of Medical Research, Royal Brisbane Hospital, Brisbane, Queensland 4029,¹ Australian Centre for International and Tropical Health and Nutrition, University of Queensland, Queensland 4072,² Department of Drug Resistance and Diagnostics, Australian Army Malaria Institute, Gallipoli Barracks, Enoggera, Queensland 4051, Australia³

Received 27 October 2003/ Returned for modification 22 December 2003/ Accepted 5 February 2004

The development of resistance to sulfadoxine-pyrimethamine by Plasmodium parasites is a major problem for the effective treatment of malaria, especially P. falciparum malaria. Although the molecular basis for parasite resistance is known, the factors promoting the development and transmission of these resistant parasites are less clear. This paper reports the results of a quantitative comparison of factors previously hypothesized as important for the development of drug resistance, drug dosage, time of treatment, and drug elimination half-life, with an in-host dynamics model of P. falciparum malaria in a malaria-naïve host. The results indicate that the development of drug resistance can be categorized into three stages. The first is the selection of existing parasites with genetic mutations in the dihydrofolate reductase or dihydropteroate synthetase gene. This selection is driven by the long half-life of the sulfadoxine-pyrimethamine combination. The second stage involves the selection of parasites with allelic types of higher resistance within the host during an infection. The timing of treatment relative to initiation of a specific anti-P. falciparum EMP1 immune response is an important factor during this stage, as is the treatment dosage. During the third stage, clinical treatment failure becomes prevalent as the parasites develop sufficient resistance mutations to survive therapeutic doses of the drug combination. Therefore, the model output reaffirms the importance of correct treatment of confirmed malaria cases in slowing the development of parasite resistance to sulfadoxine-pyrimethamine.

Present address: Malaria Vaccine Development Unit, NIAID, National Institutes of Health, Bethesda, Md.

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