Drug-resistant malaria

Abstract

In the past 21 years, a modest increase in the range of antimalarial drugs approved for clinical use has been complemented by a more impressive expansion in the analysis and understanding of the molecular mechanisms underlying resistance to these agents. Such resistance is a major factor in the increasing difficulty in controlling malaria, and important developments during this period are recounted here.

Figure 1

Approximate dates of introduction of antimalarial drugs as clinical agents, and observations of treatment failure. Quinine (Q) has been used in Europe since the 17th century and resistance to it was observed sporadically from the early 20th century. By 1965, consistent reports of treatment failure were appearing, mainly from Southeast Asia. Quinine is now reserved for use as a drug of last resort. CQR had spread to essentially all of sub-Saharan Africa by 1988. Despite a rapid spread of pyrimethamine (Pyr)-sulfadoxine (SDX) resistance in Southeast Asia from the mid-to-late 1960s onwards, this combination has been used widely and successfully, albeit with diminishing efficacy, to combat chloroquine (CQ)-resistant parasites in Africa since the early 1990s. Artemisinin was used in Chinese field trials as monotherapy in the 1970s. High rates of recrudescence were observed because of the very short half-life of the drug in human plasma (~4 h), although there are also reports of parasites from clinical cases with reduced sensitivity to artemisinins in vitro. Artemisinin derivatives are now used clinically only in combinations with other antimalarial drugs – no clinical resistance to these has yet been observed. Mefloquine (Mef) resistance had been reported in some field trials in the early 1980s. Atovaquone (Ato) is now used clinically only as atovaquone– proguanil (PG) combination (Malarone). LapDap (chlorproguanil–dapsone) can overcome many Pyr–SDX-resistant infections but it targets the same enzymes as this combination and is not 100% efficacious. Other abbreviations: Art, artemisinin and derivatives; comb, combinations; Hal, halofantrine; LD, LapDap; R, resistance.