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Antimicrobial Agents and Chemotherapy, December 2009, p. 5069-5073, Vol. 53, No. 12
0066-4804/09/$08.00+0     doi:10.1128/AAC.00638-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

In Vitro Activities of Piperaquine, Lumefantrine, and Dihydroartemisinin in Kenyan Plasmodium falciparum Isolates and Polymorphisms in pfcrt and pfmdr1{triangledown}

Leah Mwai,1,2 Steven M. Kiara,1 Abdi Abdirahman,1 Lewa Pole,1 Anja Rippert,3 Abdi Diriye,1 Pete Bull,1 Kevin Marsh,1,2 Steffen Borrmann,1,3 and Alexis Nzila1,2*

Kenya Medical Research Institute (KEMRI)/Wellcome Trust Collaborative Research Program, P.O. Box 230, 80108, Kilifi, Kenya,1 University of Oxford, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, United Kingdom,2 Institute of Hygiene, University of Heidelberg School of Medicine, Heidelberg, Germany3

Received 12 May 2009/ Returned for modification 9 August 2009/ Accepted 9 September 2009

We have analyzed the in vitro chemosensitivity profiles of 115 Kenyan isolates for chloroquine (CQ), piperaquine, lumefantrine (LM), and dihydroartemisinin in association with polymorphisms in pfcrt at codon 76 and pfmdr1 at codon 86, as well as with variations of the copy number of pfmdr1. The median drug concentrations that inhibit 50% of parasite growth (IC50s) were 41 nM (interquartile range [IQR], 18 to 73 nM), 50 nM (IQR, 29 to 96 nM), 32 nM (IQR, 17 to 46 nM), and 2 nM (IQR, 1 to 3 nM) for CQ, LM, piperaquine, and dihydroartemisinin, respectively. The activity of CQ correlated inversely with that of LM (r2 = –0.26; P = 0.02). Interestingly, parasites for which LM IC50s were higher were wild type for pfcrt-76 and pfmdr1-86. All isolates had one pfmdr1 copy. Thus, the decrease in LM activity is associated with the selection of wild-type pfcrt-76 and pfmdr1-86 parasites, a feature that accounts for the inverse relationship between CQ and LM. Therefore, the use of LM-artemether is likely to lead to the selection of more CQ-susceptible parasites.

* Corresponding author. Mailing address: KEMRI/Wellcome Trust, P.O. Box 230-80108, Kilifi, Kenya. Phone: 254-41-522535. Fax: 254-41-522390. E-mail: anzila{at}kilifi.kemri-wellcome.org

{triangledown} Published ahead of print on 21 September 2009.

Antimicrobial Agents and Chemotherapy, December 2009, p. 5069-5073, Vol. 53, No. 12
0066-4804/09/$08.00+0     doi:10.1128/AAC.00638-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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