The increasing prevalence in Southeast Asia of Plasmodium falciparum
infections with delayed parasite clearance rates, following treatment of
malaria patients with the
artemisinin derivative
artesunate, highlights an urgent need to identify which of the currently available
artemisinin-based combination
therapies (ACTs) are most suitable to treat populations with emerging
artemisinin resistance. Here, we demonstrate that the rodent Plasmodium berghei
SANA strain has acquired
artemisinin resistance following
drug pressure, as defined by reduced parasite clearance and early recrudescence following daily exposure to high doses of
artesunate or the active metabolite
dihydroartemisinin. Using the
SANA strain and the parental
drug-sensitive N strain, we have interrogated the
antimalarial activity of five ACTs, namely,
artemether-lumefantrine,
artesunate-
amodiaquine, artesunate-
mefloquine,
dihydroartemisinin-
piperaquine, and the newest combination
artesunate-
pyronaridine. By monitoring
parasitemia and outcome for 30 days following initiation of treatment, we found that
infections with
artemisinin-resistant P. berghei
SANA parasites can be successfully treated with
artesunate-
pyronaridine used at doses that are curative for the parental
drug-sensitive N strain. No other partner
drug combination was as effective in resolving
SANA infections. Of the five partner drugs tested,
pyronaridine was also the most effective at suppressing the recrudescence of
SANA parasites. These data support the potential benefit of implementing ACTs with
pyronaridine in regions affected by
artemisinin-resistant
malaria.