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Antimicrobial Agents and Chemotherapy, May 2002, p. 1510-1515, Vol. 46, No. 5
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.5.1510-1515.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

In Vitro Interactions of Artemisinin with Atovaquone, Quinine, and Mefloquine against Plasmodium falciparum

S. Gupta,1 M. M. Thapar,1 W. H. Wernsdorfer,2 and A. Björkman1*

Department of Infectious Diseases, Karolinska Hospital, Stockholm 17176, Sweden,1 Department of Specific Prophylaxis and Tropical Medicine, Institute of Pathophysiology, University of Vienna, A-1095 Vienna, Austria2

Received 16 January 2001/ Returned for modification 27 September 2001/ Accepted 30 January 2002

The interactions of artemisinin with atovaquone, quinine, and mefloquine were investigated in three Plasmodium falciparum strains (strains F-32, FCR-3, and K-1) by an in vitro culture assay. The parasites were cultured for 48 h in the presence of different concentrations and proportions of two drugs at a time in a checkerboard design. The response parameters were determined, and the sums of the fractional inhibitory concentrations ({Sigma}FICs) of the drug combinations were calculated for different degrees of inhibition (50% effective concentration [EC50], EC90, and EC99). Within therapeutically relevant molar ratios (19 to 200), the combination of quinine and artemisinin showed mean {Sigma}FICs of 1.71 at the EC50, 0.36 at the EC90, and 0.13 at the EC99, indicating increasing synergism. Within the range of molar ratios of 4.3 to 50, the combination of mefloquine and artemisinin yielded mean {Sigma}FCIs of 0.93, 0.44, and 0.31 at the EC50, EC90, and EC99, respectively, indicating synergism. The atovaquone combination showed additive activity to synergism at atovaquone/artemisinin proportions considered relevant to the in vivo situation, i.e., between 4.3 and 200, with the mean {Sigma}FICs decreasing from 1.34 at the EC50 to 0.85 and 0.23 at the EC90 and EC99, respectively. Interstrain differences in the degree of drug interaction were seen with the three strains for all combinations. Synergism was most consistent with quinine.

* Corresponding author. Mailing address: Department of Infectious Diseases, Karolinska Hospital, Stockholm 17176, Sweden. Phone 46 8 51771866. Fax: 46 8 51771806. E-mail: anders.bjorkman{at}ks.se.

Antimicrobial Agents and Chemotherapy, May 2002, p. 1510-1515, Vol. 46, No. 5
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.5.1510-1515.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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