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Adaptation of a Thai Multidrug-Resistant C2A Clone of Plasmodium falciparum to Aotus Monkeys and Its Preliminary in vivo Antimalarial Drug Efficacy-Resistance Profile

A multidrug-resistant (MDR) clone of Plasmodium falciparum (C2A) from Thailand was adapted through serial passage to Aotus monkeys. During adaptation, the parasite showed resistance to a single 20 or 40 mg/kg oral dose of mefloquine (MQ). Infection was only cured when MQ was administered orally at 40 mg/kg once in combination with intravenous artesunic acid at 20 mg/kg for 3 days. Similarly, the parasite clone was found to be resistant to quinine, failing at 20 mg/kg orally for 5 days in combination with an experimental dihydrofolate reductase (DHFR) inhibitor (WR297608) at 10, 20, or 40 mg/kg orally for 3 days, and with atovaquone/proguanil at 25 mg/kg for 3 days. This new model will allow in vivo testing of new antimalarial compounds or their combinations against a currently circulating MDR P. falciparum strain.

Received September 2, 2008. Accepted for publication June 18, 2009.

Acknowledgments: We thank Tropical Medicine Research, Malaria Drug and Vaccine Evaluation Center/Gorgas Memorial Institute of Health Studies, in Panama City, Panama: William Otero and Jorge Aparicio for their microscopy, and technical assistance, Camilo Marin and the animal care takers for their assistance with animal handling and care, Maritza Brewer for secretarial assistance, Gladyz Calviño and Bertha de Gordon for administrative assistance, Bryan L. Smith for the critical review of the manuscript and Jorge Motta, ICGES former director general, and Gines Sanchez and Ceferino Sanchez for their constant encouragement and support.

Financial support: This work was supported by USAMRDC contracts no. DAMD-17-96-C-6051, DAMD17-01-C0039, and W81XWH-07-C-044.

Disclosure: The experiments reported here were conducted according to the principles set forth in the "Guide for the Care and Use of Laboratory Animals," Institute of Laboratory Animal Resources, National Research Council (Department of Health and Human Services, National Institutes of Health publication, 1996).

Disclaimer: The opinions and assertions contained herein are the private ones of the author and are not to be construed as official or reflecting the views of the U.S. Army.

^* Address correspondence to Nicanor Obaldía III, ICGES, Apdo 00816-02593, Panama, Republic of Panama. E-mail: nobaldia{at}gorgas.gob.pa

Authors’ addresses: Nicanor Obaldía III, Malaria Drug and Vaccine Evaluation Center, Tropical Medicine Research, Panama City, Republic of Panama, and Gorgas Memorial Institute of Health Studies (ICGES), Apdo 00816-02593, Panama City, Republic of Panama, Tel: 507-527-4811, Fax: 507-227-8330, E-mail: nobaldia{at}gorgas.gob.pa. Wilbur Milhous and Dennis Kyle, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Springs, MD 20910; present address: Department of Global Health, College of Public Health, University of South Florida, Tampa, FL 33612.