Mutations indhfrinPlasmodium falciparumInfections Selected by Chlorproguanil‐Dapsone Treatment

Abstract

Treatment with the novel antifolate drug combination chlorproguanil-dapsone effectively cleared asymptomatic Plasmodium falciparum infections in 246 (93.5%) of 263 children in the Usambara Mountains of Tanzania during the course of a 2-week follow-up. Samples from 71 recurrent infections, collected over a 9-week follow-up, showed selection for parasites with the triple mutant Ile(51)-Arg(59)-Asn(108) in dihydrofolate reductase. There was no selection for mutations in dihydropteroate synthetase, the target enzyme of dapsone. Search for complete identity in the highly polymorphic genes coding for merozoite surface proteins 1 and 2 in parasite samples collected before and after treatment indicated that the majority of recurrent parasitemias were new infections. These observations on selection in Tanzania and the lack of selection reported from a less endemic area suggest that the active metabolite of chlorproguanil, which has a short half-life in the blood, may persist in the liver, where it exerts selective pressure on growing preerythrocytic stages.

Analysis of sulphadoxine/pyrimethamine resistance-conferring mutations of Plasmodium falciparum from Mozambique reveals the absence of the dihydrofolate reductase 164L mutant

“…These reports may be interpreted as early warning signs for a potential introduction of this genotype in Africa and prompted us to survey Mozambican parasites for this mutation. Pfdhfr 164L mutants were not identified in the present investigation however (Table 1), corroborating previous findings indicating that this mutation has not yet established itself in Africa [18,19]. Although the number of isolates analysed in the current report may not be representative of the whole parasite population in this area, numerous other mutant alleles of pfdhfr and pfdhps , normally present in the region, were observed (Table 1).…”

Molecular Correlates of High-Level Antifolate Resistance in Rwandan Children with Plasmodium falciparum Malaria

“…MOLECULAR CORRELATES OF ANTIFOLATE RESISTANCE 481 this gene, irrespective of its effect on pfdhfr, as observed previously (3,4,22). In contrast, there was selection for the pfdhps triple-mutation genotype after treatment with AQϩSP in Rukara but not in Mashesha.…”

Mechanisms of Resistance of Malaria Parasites to Antifolates

“…Limited in vitro data does suggest that the development of resistance to chlorproguanil-dapsone is inherently more difficult than to sulfadoxine-pyrimethamine (Winstanley et al, 1995), but as yet, strong support from in vivo field data are lacking (Bukirwa et al, 2004). A study in Tanzania looked at mutations that developed in DHFR and DHPS during the 9 weeks following treatment with chlorproguanil-dapsone (Curtis et al, 2002). In this study, the triple DHFR mutant, S108N/N51I/C59R, was significantly more prevalent following treatment with chlorproguanil-dapsone than prior to treatment.…”