**1. Introduction**

The artemisinin group of antimalarials is considered to be highly and rapidly effective compared with other traditional malaria drugs. Resistance to artemisinins emerged in 2008 in parts of Southeast Asia and continues to spread [1]. Although there is more evidence to confirm drug resistance [2, 3], artemisinin and its derivatives are still widely used in current malaria therapy [2, 4]. Clinical artemisinin resistance is demonstrated as a delayed clearance phenotype; that is, infection finally resolves with treatment with artemisinin-based combination therapies (ACTs), but the time required for parasite clearance substantially increases [5].

High rates of recrudescence with daily monotherapy of artemisinins for 3–5 days are observed in humans. However, this shortfall is being overcome using oral ACTs and injectable artesunate (IV-AS) in combination with slow-acting antimalarial drugs. The rapid parasite killing of artemisinins in the treatment of early uncomplicated malaria with ACTs may prevent its progression to more severe disease with subsequent reduction in severe cases and associated mortality [6]. ACTs are currently the preferred treatment for malaria due to their enhanced efficacy and the potential to lower the emergence and spread of resistance [7].

The WHO has endorsed ACTs as the "policy standard" for all malaria infections in areas where *P. falciparum* is the predominant infecting species. Four ACTs recommended by a WHO Expert Consultative Group in 2001 are artemether (AM)-lumefantrine (Coartem), AS-mefloquine (Artequin), AS-amodiaquine, and AS-sulfadoxine/pyrimethamine [8]. Monotherapy with the artemisinins was significantly decreased after 2001 to prevent the emergence of resistance. However, IV-AS, as a monotherapy, is still in first line of treatment for both adults and children in Asian countries [9] for complicated and severe malaria, as well as some areas in Africa [10].

Recent trials have used IV-AS with its more favorable pharmacokinetic profile [11, 12]. The SEAQUAMAT trial, a large multicenter randomized trial carried out in Bangladesh, Thailand, Myanmar, Indonesia, India, and Vietnam, showed a 34.7% reduction in mortality from all causes associated with IV-AS as compared to intravenous quinine [13]. This remains the largest trial performed for severe malaria and was the first to conclusively demonstrate a benefit over standard quinine therapy. There is strong evidence that IV-AS will reduce the risk of death by one-third when compared to quinine therapy in cases of severe malaria. Consequently, IV-AS was immediately recommended for patients with severe malaria by The European Network on Imported Infections Disease Surveillance (TropNetEurop) after these trials [14].

The most recent development in antimalarial therapy is the use of artemisinin derivatives, especially IV-AS, which will potentially revolutionize the management of severe and complicated [15]. Therefore, there is a strong case for continued need for AS as a monotherapy, if only for this niche indication [16]. However, there is currently no useable formulation available that is produced under good manufacturing practice (GMP) conditions. The Walter Reed Army Institute of Research (WRAIR) continues to develop a novel cGMP injection of AS since 2004, which is in the process of US FDA approval [17, 18].
