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Antimicrobial Agents and Chemotherapy, October 2004, p. 3940-3943, Vol. 48, No. 10
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.10.3940-3943.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Combination Therapy Counteracts the Enhanced Transmission of Drug-Resistant Malaria Parasites to Mosquitoes

Rachel L. Hallett,1,{dagger} Colin J. Sutherland,1,{dagger}* Neal Alexander,1 Rosalynn Ord,1 Musa Jawara,2 Chris J. Drakeley,3 Margaret Pinder,2 Gijs Walraven,2,{ddagger} Geoffrey A. T. Targett,1 and Ali Alloueche1,§

Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom,1 Medical Research Council Laboratories, Banjul, The Gambia,2 Joint Malaria Programme, Moshi, Tanzania3

Received 12 March 2004/ Returned for modification 20 May 2004/ Accepted 31 May 2004

Malaria parasites carrying genes conferring resistance to antimalarials are thought to have a selective advantage which leads to higher rates of transmissibility from the drug-treated host. This is a likely mechanism for the increasing prevalence of parasites with resistance to chloroquine (CQ) and sulfadoxine-pyrimethamine in sub-Saharan Africa. Combination therapy is the key strategy being implemented to reduce the impact of resistance, but its effect on the transmission of genetically resistant parasites from treated patients to mosquito vectors has not been measured directly. In a trial comparing CQ monotherapy to the combination CQ plus artesunate (AS) in Gambian children with uncomplicated falciparum malaria, we measured transmissibility by feeding Anopheles gambiae mosquitoes with blood from 43 gametocyte-positive patients through a membrane. In the CQ-treated group, gametocytes from patients carrying parasites with the CQ resistance-associated allele pfcrt-76T prior to treatment produced infected mosquitoes with 38 times higher Plasmodium falciparum oocyst burdens than mosquitoes fed on gametocytes from patients infected with sensitive parasites (P < 0.001). Gametocytes from parasites carrying the resistance-associated allele pfmdr1-86Y produced 14-fold higher oocyst burdens than gametocytes from patients infected with sensitive parasites (P = 0.011). However, parasites carrying either of these resistance-associated alleles pretreatment were not associated with higher mosquito oocyst burdens in the CQ-AS-treated group. Thus, combination therapy overcomes the transmission advantage enjoyed by drug-resistant parasites.

* Corresponding author. Mailing address: Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel St., London WC1E 7HT, United Kingdom. Phone: 44 (0)20 7927 2338. Fax: 44 (0)20 7636 8739. E-mail: colin.sutherland{at}lshtm.ac.uk.

{dagger} R.L.H. and C.J.S. made equivalent contributions to the work.

{ddagger} Present address: Community Health, Aga Khan Health Services, Secrétariat de Son Altesse l’Aga Khan Aiglemont, 60270 Gouvieux, France.

{ddagger} Present address: Community Health, Aga Khan Health Services, Secrétariat de Son Altesse l’Aga Khan Aiglemont, 60270 Gouvieux, France.

§ Present address: IRIS Research Center, Chiron Vaccines, 53100 Siena, Italy.

Antimicrobial Agents and Chemotherapy, October 2004, p. 3940-3943, Vol. 48, No. 10
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.10.3940-3943.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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