Abstract
BackgroundChloroquine (CQ), a cost effective antimalarial drug with a relatively good safety profile and therapeutic index, is no longer used by itself to treat patients with Plasmodium falciparum due to CQ-resistant strains. P. vivax, representing over 90% of malaria cases in Brazil, despite reported resistance, is treated with CQ as well as with primaquine to block malaria transmission and avoid late P. vivax malaria relapses. Resistance to CQ and other antimalarial drugs influences malaria control, thus monitoring resistance phenotype by parasite genotyping is helpful in endemic areas.MethodsA total of 47 P. vivax and nine P. falciparum fresh isolates were genetically characterized and tested for CQ, mefloquine (MQ) and artesunate (ART) susceptibility in vitro. The genes mdr1 and pfcrt, likely related to CQ resistance, were analyzed in all isolates. Drug susceptibility was determined using short-term parasite cultures of ring stages for 48 to 72 hour and thick blood smears counts. Each parasite isolate was tested with the antimalarials to measure the geometric mean of 50% inhibitory concentration.ResultsThe low numbers of P. falciparum isolates reflect the species prevalence in Brazil; most displayed low sensitivity to CQ (IC50 70 nM). However, CQ resistance was rare among P. vivax isolates (IC50 of 32 nM). The majority of P. vivax and P. falciparum isolates were sensitive to ART and MQ. One hundred percent of P. falciparum isolates carried non-synonymous mutations in the pfmdr1 gene in codons 184, 1042 and 1246, 84% in codons 1034 and none in codon 86, a well-known resistance mutation. For the pfcrt gene, mutations were observed in codons 72 and 76 in all P. falciparum isolates. One P. falciparum isolate from Angola, Africa, showing sensitivity to the antimalarials, presented no mutations. In P. vivax, mutations of pvmdr1 and the multidrug resistance gene 1 marker at codon F976 were absent.ConclusionAll P. falciparum Brazilian isolates showed CQ resistance and presented non-synonymous mutations in pfmdr1 and pfcrt. CQ resistant genotypes were not present among P. vivax isolates and the IC50 values were low in all samples of the Brazilian West Amazon.
Highlights
Chloroquine (CQ), a cost effective antimalarial drug with a relatively good safety profile and therapeutic index, is no longer used by itself to treat patients with Plasmodium falciparum due to CQ-resistant strains
The present study aimed to examine the phenotypic and genotypic chemoresistance profile of P. falciparum and P. vivax to commonly used anti-malarial drugs in a Brazilian malaria-endemic area in the Amazon Region
Anti-malarial susceptibility Ex-vivo drug susceptibility was assessed in field isolates from all 56 patients with a single species infection, either P. vivax (n = 47) or P. falciparum (n = 9); eight of the latter were Brazilian isolates freshly collected in the state of Rondônia, in the Brazilian Western Amazon (Figure 1) and one was from an individual returning from Angola, Africa, diagnosed and studied in Belo Horizonte, Brazil, outside the endemic malaria region
Summary
Chloroquine (CQ), a cost effective antimalarial drug with a relatively good safety profile and therapeutic index, is no longer used by itself to treat patients with Plasmodium falciparum due to CQ-resistant strains. P. vivax, representing over 90% of malaria cases in Brazil, despite reported resistance, is treated with CQ as well as with primaquine to block malaria transmission and avoid late P. vivax malaria relapses. One of the most prevalent parasitic diseases in the world, still causes high morbidity and death, mainly in Plasmodium falciparum-infected, non-treated patients [1]. CQ is the drug of choice to treat vivax malaria in endemic areas of Brazil and primaquine (PQ) is used to avoid late malaria relapses [3]. In Brazil, the first option for falciparum malaria treatment is the combination of artemether (480 mg daily for four days) and lumefantrine (2880 mg daily for four days). PQ (45 mg) is administrated on day one to avoid malaria transmission These doses are recommended for adults with 50 Kg weight or more [4]. A reduced susceptibility to artemisinin derivatives has been described in P. falciparum-treated patients [14,15]
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