In vitro evaluations of antimalarial drugs and their relevance to clinical outcomes

Abstract

Plasmodium falciparum resistance to the former first-line antimalarials chloroquine and sulfadoxine/pyrimethamine has reached critically high levels in many malaria-endemic regions. This has spurred the introduction of several new artemisinin-based combination therapies (ACTs) that display excellent potency in treating drug-resistant malaria. Monitoring for the emergence of drug resistant P. falciparum is important for maximising the clinically effective lifespan of ACTs. Here, we provide a commentary on the article by Kaddouri et al., published in this issue of the International Journal of Parasitology, which documents the levels of susceptibility to ACT drugs and chloroquine in P. falciparum isolates from Mali. These authors report that some isolates approached a proposed in vitro threshold of resistance to monodesethyl-amodiaquine (the principal effective metabolite of amodiaquine, an important ACT partner drug), and establish baseline levels of susceptibility to the ACT drugs dihydroartemisinin and lumefantrine. The majority of clinical isolates manifested in vitro resistance to chloroquine. The authors also show good concordance between field-based assays employing a non-radioactive lactate dehydrogenase-based method of determining in vitro drug IC(50) values and the well-established [(3)H]hypoxanthine-based radioactive method. This work illustrates a good example of drug resistance surveillance, whose global coordination is being championed by the World Antimalarial Resistance Network. Our current opinion also more generally discusses the complexities inherent to conducting in vitro investigations with P. falciparum patient isolates and correlating these findings with treatment outcome data.

Fig. 1

Emergence of resistance to the principal antimalarials. Each colored bar represents an antimalarial monotherapy or combination. Years to the left of each bar represent the date the drug was introduced and the first reported instance of resistance. Ovals below the time line denote the approximate periods when resistance spread though different geographical regions. Quinine, chlororoquine and sulfadoxine/pyrimethamine remained effective for considerable periods after the first reported instances of resistance. Halofantrine has had limited usage since about 1998 due to cardiotoxicity concerns. Amodiaquine was removed from the list of approved antimalarials in 1990 due to concerns over serious side effects, but was reinstated in 1996 because the perceived benefits outweighed the risks (dashed border). Chemically pure artemisinin (Qinghaosu) and its derivatives were first used in field trials in China in the early 1970s. Artemisinin has a low radical cure rate when used alone in a short course, presumably due to its very short half-life in vivo. Since 1994, artemisinin and its derivatives have been used in combination therapies (ACTs). No clinical resistance to ACTs has yet been demonstrated. Timelines were derived from (Wongsrichanalai et al., 2002; Hyde, 2005; Tinto et al., 2008) and references therein. ACTs: Artemisinin-based Combination Therapies, AQ, amodiaquine; Ato/Pg: Atovaquone/Proguanil, CQ: Chloroquine, Halo: Halofantrine, MQ, mefloquine; Q: Quinine, R: Resistance, S/P: Sulfadoxine/Pyrimethamine.