Susceptibility of human Plasmodium knowlesi infections to anti-malarials

Abstract

Background: Evidence suggests that Plasmodium knowlesi malaria in Sarawak, Malaysian Borneo remains zoonotic, meaning anti-malarial drug resistance is unlikely to have developed in the absence of drug selection pressure. Therefore, adequate response to available anti-malarial treatments is assumed.

Methods: Here the ex vivo sensitivity of human P. knowlesi isolates in Malaysian Borneo were studied, using a WHO schizont maturation assay modified to accommodate the quotidian life cycle of this parasite. The in vitro sensitivities of P. knowlesi H strain adapted from a primate infection to in vitro culture (by measuring the production of Plasmodium lactate dehydrogenase) were also examined together with some assays using Plasmodium falciparum and Plasmodium vivax.

Results: Plasmodium knowlesi is uniformly highly sensitive to artemisinins, variably and moderately sensitive to chloroquine, and less sensitive to mefloquine.

Conclusions: Taken together with reports of clinical failures when P. knowlesi is treated with mefloquine, the data suggest that caution is required if using mefloquine in prevention or treatment of P. knowlesi infections, until further studies are undertaken.

Figure 1

IC₅₀ values for anti-malarial drugs against Plasmodium isolates, using the schizont maturation assay. Data points represent mean IC₅₀ values (nM) derived from single experiments performed in triplicate. Plasmodium knowlesi (black symbols), P. vivax (red symbols) and P. falciparum (green symbols). Filled symbols indicate R² values ≥ 0.8, with unfilled symbols indicting R² values < 0.8. Mefloquine, MQ; Chloroquine, CQ; Artemisinin, AR; Artemether, AM; Artesunate, AS; Dihydroartemisinin, DHA. Note that there is only mefloquine data for one of the two P. vivax isolates.

Figure 2

Alignment of CRT, ATP6, and MDR1 homologues of P. knowlesi H strain and P. vivax Sal-1 strain, against P. falciparum 3D7 and strains with known point mutations associated with drug resistance. Amino acids are colour coded, with green representing the drug sensitive P. falciparum 3D7, and red representing amino acid changes found in P. falciparum isolates that have a change in drug sensitivity.