The control of malaria is challenged by resistance of Plasmodium falciparum to multiple drugs. New combination regimens are now advocated for the treatment of uncomplicated falciparum malaria, but the extent of resistance to newer agents is incompletely understood. We measured the in vitro sensitivity of P. falciparum parasites cultured from children enrolled in a drug efficacy trial in Kampala, Uganda, from 2006 to 2008. Sensitivities were measured by comparing levels of histidine-rich protein-2 in parasites incubated with different concentrations of drugs with those in untreated controls. The cultured parasites exhibited a wide range of sensitivities to chloroquine (CQ); monodesethylamodiaquine (MDAQ), the major active metabolite of amodiaquine; and quinine (QN). Mean 50% inhibitory concentration (IC 50 ) results were above standard cutoffs for resistance for CQ and MDAQ. Parasites were generally sensitive to dihydroartemisinin (DHA), lumefantrine (LM), and piperaquine (PQ). For CQ, MDAQ, and QN but not the other drugs, activities against individual strains were highly correlated. We also assessed known resistance-mediating polymorphisms in two putative transporters, pfcrt and pfmdr1. When parasites that were least and most sensitive to each drug were compared, the pfmdr1 86Y mutation was significantly more common in parasites that were most resistant to CQ and MDAQ, and the pfmdr1 D1246Y mutation was significantly more common in parasites that were most resistant to MDAQ and QN. In summary, we demonstrated in parasites from Kampala a range of sensitivities to older drugs; correlation of sensitivities to CQ, MDAQ, and QN; and good activity against nearly all strains for DHA, LM, and PQ.Resistance of Plasmodium falciparum to available drugs remains a major challenge to the control of malaria. Older drugs, including the aminoquinolines chloroquine (CQ) and amodiaquine (AQ) and the antifolate sulfadoxine/pyrimethamine (SP), are already seriously compromised, with unacceptable levels of treatment failure in most of Africa (61). In the setting of increasing drug resistance, the WHO has recommended artemisininbased combination therapy (ACT) for the treatment of uncomplicated falciparum malaria (42). The commonly used ACTs in Africa are artemether/lumefantrine (AM/LM), artesunate/ amodiaquine (AS/AQ), and dihydroartemisinin/piperaquine (DHA/PQ), each containing an artemisinin combined with a longer-acting drug. These ACTs have shown excellent efficacy for the treatment of malaria in Africa. However, there is concern that heavy use of ACTs will offer strong selective pressure for parasites with diminished sensitivity to the drugs. This development may seriously jeopardize the efficacy of ACTs.Multiple recent studies in Africa have demonstrated excellent efficacy of AM/LM, AS/AQ, and DHA/PQ for the treatment of falciparum malaria (8,18,29,30,34,46,63,64). Clinical trials provide our primary means of assessing antimalarial drug efficacy, but they offer only an indirect measure of the sensitivity of parasites to drugs be...
