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Antimicrobial Agents and Chemotherapy, March 2007, p. 991-997, Vol. 51, No. 3
0066-4804/07/$08.00+0     doi:10.1128/AAC.00875-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Amodiaquine and Artemether-Lumefantrine Select Distinct Alleles of the Plasmodium falciparum mdr1 Gene in Tanzanian Children Treated for Uncomplicated Malaria{triangledown}

G. S. Humphreys,1 I. Merinopoulos,1 J. Ahmed,1 C. J. M. Whitty,1 T. K. Mutabingwa,1,2 C. J. Sutherland,1 and R. L. Hallett1*

London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, United Kingdom,1 National Institute for Medical Research, Dar-es-Salaam, Tanzania2

Received 15 July 2006/ Returned for modification 11 September 2006/ Accepted 13 December 2006

The artemisinin-based combination therapies artemether-lumefantrine (AL) and amodiaquine (AQ) plus artesunate have been adopted for treatment of Plasmodium falciparum malaria in many African countries. Molecular markers of parasite resistance suitable for surveillance have not been established for any of the component drugs in either of these combinations. We assessed P. falciparum mdr1 (Pfmdr1) alleles present in 300 Tanzanian children presenting with uncomplicated falciparum malaria, who were enrolled in a clinical trial of antimalarial therapy. Pfmdr1 genotype analysis was also performed with isolates from 182 children who failed AQ monotherapy and 54 children who failed AL treatment. Pfmdr1 alleles 86Y, 184Y, and 1246Y were more common among treatment failures in the AQ group than among pretreatment infections. The converse was found in the AL-treated group. Children presenting with the 86Y/184Y/1246Y Pfmdr1 haplotype and treated with AQ were significantly more likely to retain this haplotype if they were parasite positive during posttreatment follow-up than were children treated with AL (odds ratio, 33.25; 95% confidence interval, 4.17 to 1441; P, <0.001). We conclude that AL and AQ exert opposite within-host selective effects on the Pfmdr1 gene of P. falciparum.

* Corresponding author. Mailing address: Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom. Phone: 44 20 7927 2338. Fax: 44 20 7636 8739. E-mail: Rachel.Hallett{at}lshtm.ac.uk.

{triangledown} Published ahead of print on 28 December 2006.

Antimicrobial Agents and Chemotherapy, March 2007, p. 991-997, Vol. 51, No. 3
0066-4804/07/$08.00+0     doi:10.1128/AAC.00875-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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