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Abstract
BackgroundThe emergence of Plasmodium falciparum resistant to most currently used antimalarial drugs is the major problem in malaria control along the Thai-Myanmar and Thai-Cambodia borders. Although artemisinin-based combination therapy has been recommended for the treatment of multidrug-resistant falciparum malaria, these combinations are not available for some people, such as travelers from North America. A fixed-dose combination of atovaquone and proguanil (Malarone) has been proved to be effective for the treatment and prophylaxis of malaria which is already approved by countries in North America and Europe. Determination of the phenotypes and genotypes related to atovaquone/proguanil response in Thai isolates of P. falciparum will be useful for rationale drug use. The main purpose of this study was to explore the in vitro atovaquone/proguanil susceptibility of recently adapted Thai isolates of P. falciparum. Genotypic characterization of the cytb gene of these isolates was also determined since it has been reported that point mutations, particularly codon 268 in the cytochrome b gene (cytb) have been linked to atovaquone/proguanil treatment failure.MethodsEighty three P. falciparum isolates collected during 1998 to 2005 from four different multidrug resistance areas of Thailand were determined for the in vitro atovaquone/proguanil susceptibilities using radioisotopic assay. Mutations in the cytb gene were determined by PCR-RFLP and sequence analysis.ResultsThe mean atovaquone and proguanil IC50 was 3.4 nM and 36.5 μM, respectively. All 83 Thai isolates were atovaquone sensitive. None of the 83 isolates contained the mutations at codon 268 of the cytb gene. DNA sequencing of the cytb gene of 20 parasite isolates showed no other mutations.ConclusionIn agreement with a recent efficacy study of atovaquone/proguanil, the present information indicates that atovaquone/proguanil can be one of the drugs of choice for the treatment and prophylaxis of multidrug-resistant falciparum malaria in Thailand.
Highlights
The emergence of Plasmodium falciparum resistant to most currently used antimalarial drugs is the major problem in malaria control along the Thai-Myanmar and ThaiCambodia borders
Malarone® is a fixed-dose combination of atovaquone and proguanil
The atovaquone and proguanil IC50 values of P. falciparum isolates obtained in various years and from various endemic areas were shown in Figure 1 and 2, respectively
Summary
The emergence of Plasmodium falciparum resistant to most currently used antimalarial drugs is the major problem in malaria control along the Thai-Myanmar and ThaiCambodia borders. A fixed-dose combination of atovaquone and proguanil (Malarone) has been proved to be effective for the treatment and prophylaxis of malaria which is already approved by countries in North America and Europe. Malarone® is a fixed-dose combination of atovaquone and proguanil It is highly effective for the treatment and prophylaxis of multidrug-resistant falciparum malaria [2,3]. Atovaquone exerts its action via inhibiting plasmodial mitochondria electron transport at the level of the cytochrome bc complex and collapsing mitochondrial membrane potential [4,5]. It inhibits dihydroorotate dehydrogenase (DHOD) enzyme which catalyses the reaction from dihydroorotate to orotate [6]. Proguanil was added for the synergistic effect which is probably due to enhancing atovaquone to collapse mitochondrial membrane potential [7]
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