Advance 1: Improvements in the treatment of severe malaria
In the two largest randomized controlled trials conducted in patients hospitalised with severe falciparum malaria artesunate was shown to reduce mortality substantially. The mortality reduction (95% confidence interval) was 34.7% (18·5 to 47·6%) in Southeast Asian adults and children and 22.5% (8·1 to 36·9%) in African children (3,4) (Figure 1). In African children it can be difficult to distinguish severe malaria from bacterial sepsis with incidental parasitaemia. In those children with a high likelihood of having severe malaria based on parasite biomass estimation the reduction in mortality was the same (i.e. one third) as observed in the Asian series (5). Artesunate was also better tolerated (less hypoglycaemia) and easier to administer (intravenous injection rather than controlled rate infusion, and no pain and local toxicity following intramuscular injection) than the previous “gold-standard” treatment quinine. Importantly there were also less neurological sequelae in the survivors so lives were not saved at the expense of neurological deficits. Artemether is nearly as active as artesunate in-vitro against P. falciparum but, being an oil-based intramuscular injection, is slowly and erratically absorbed from the intramuscular injection site in-vivo (particularly in shocked patients) (6). In contrast the water soluble artesunate is rapidly and reliably absorbed. This probably explains why the severe malaria mortality following artemether is higher than that following artesunate treatment (7,8). Community based pre-referral rectal artesunate was also shown to reduce malaria attributable mortality by 25% in children unable to take oral antimalarial medications (9) Since these trials reported artesunate has become the generally recommended first line treatment for severe malaria (1) and usage has increased substantially, although unfortunately quinine is still the only available parenteral antimalarial in some malaria endemic areas.
Following drug administration the DHA derivatives are rapidly and reliably converted back to DHA in-vivo which is then very rapidly eliminated (t1/2 < 1 hour) mainly by glucuronidation (10), yet they are highly efficacious when given once daily (11). The main pathological process in severe falciparum malaria is the sequestration of erythrocytes containing mature forms of the parasite in the vascular beds of vital organs (5,12). This reduces microcirculatory blood flow and probably markedly disturbs endothelial function. The key pharmacodynamic effect of the artemisinin derivatives, which mediates the life-saving advantage over quinine, is their action in killing the younger circulating stages of P. falciparum before they sequester (12). Unfortunately, this property is reduced markedly in artemisinin resistance.
Apart from the prompt initiation of renal replacement therapies (preferably haemofiltration) in acute kidney injury (12,13), no adjuvant therapies have proved beneficial and many (including aspirin, corticosteroids, heparin, mannitol, high dose phenobarbitone, anti-TNF antibody and rapid fluid loading) were found to be harmful in severe malaria (12,14).