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Antimicrobial Agents and Chemotherapy, August 2005, p. 3147-3152, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3147-3152.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Countrywide Survey Shows Very High Prevalence of Plasmodium falciparum Multilocus Resistance Genotypes in Cambodia

Laboratoire d'Epidémiologie Moléculaire, Institut Pasteur du Cambodge, 5 bd Monivong, P.O. Box 983, Phnom Penh, Cambodia,¹ Pasteur Genopole Ile de France, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris cedex 15, France,² Unité d'Immunologie Moléculaire des Parasites, CNRS URA 2581, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris cedex 15, France,³ National Reference Center on Plasmodium Chemoresistance in the French West Indies and French Guiana, Institut Pasteur de Guyane, Cayenne, French Guiana,⁴ Unité d'Immunologie, Institut Pasteur de Dakar, BP 220, Dakar, Sénégal,⁵ National Malaria Center, Ministry of Health, 372 Monivong Boulevard, Phnom Penh, Cambodia⁶

Received 26 January 2005/ Returned for modification 16 March 2005/ Accepted 4 May 2005

Cambodia is located in an area of resistance to multiple antimalarials and has been the first country to implement the systematic use of an artesunate-mefloquine combination as first-line treatment for Plasmodium falciparum malaria. Little is known, however, about the prevalence of resistance mutations within the natural parasite populations, impeding rational drug policy in this context. Using direct sequencing of PCR products, we have analyzed sequence polymorphism of the dihydrofolate reductase-thymidylate synthase, dihydropteroate synthetase, and multidrug resistance 1 genes in a large number of clinical P. falciparum isolates collected in various areas of Cambodia. This highlighted a 100% prevalence of haplotypes with multiple mutations in the target genes of antifolates after more than a decade without use of antifolates for malaria therapy. A high prevalence of mutations in Pfmdr1, including mutations associated with decreased in vitro susceptibility to mefloquine and quinine, was also observed. In addition, novel, low-frequency mutations were detected in Pfmdr1. Our findings show an alarming rate of multilocus resistance genotypes in Cambodia, requiring diligent surveillance and imposing limitations on possible future drug combinations.