Molecular Markers for Failure of Sulfadoxine‐Pyrimethamine and Chlorproguanil‐Dapsone Treatment ofPlasmodium falciparumMalaria

Abstract

Molecular assays for monitoring sulfadoxine-pyrimethamine-resistant Plasmodium falciparum have not been implemented because of the genetic and statistical complexity of the parasite mutations that confer resistance and their relation to treatment outcomes. This study analyzed pretreatment dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) genotypes and treatment outcomes in a double-blind, placebo-controlled trial of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment for uncomplicated P. falciparum malaria. Multiple logistic regression was used to identify mutations that were predictive of treatment failure and to identify interactions and confounding factors. Infections caused by parasites with 3 DHFR mutations and 2 DHPS mutations (the "quintuple mutant") were associated with sulfadoxine-pyrimethamine treatment failure but not with chlorproguanil-dapsone treatment failure. The presence of a single DHFR mutation (Arg-59) with a single DHPS mutation (Glu-540) accurately predicted the presence of the quintuple mutant. If this model is validated in other populations, it will finally be possible to use molecular markers for surveillance of antifolate-resistant P. falciparum malaria in Africa.

Dhfr and dhps mutations in <i>Plasmodium falciparum</i> isolates in Mlandizi, Kibaha,

“…Similar findings have been reported in northern (Pearce et al, 2003) and southeastern Tanzania (Mshinda, 2000) and in Malawi (Kublin et al, 2002;Bwijo et al, 2003). On the Thai-Myanmar border, Thailand, where high levels of resistance to SP have been reported, the Ile 51/ Arg 59/ Asn 108/ Leu 164 alleles of dhfr were very common (Nair et al, 2002).…”

“…This resistance emerges as a result of mutations on the dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) enzyme systems of P. falciparum. In Africa, resistance to SP is associated with three mutations in the dhfr gene (Ile 51, Arg 59, Asn 108 ) and two mutations in the dhps gene (Gly 437, Glu 540 ) (Kublin et al, 2002).…”

Expression of Plasmodium falciparum G6PD‐6PGL in laboratory parasites and in patient isolates in G6PD‐deficient and normal Nigerian children

“…It will be important to confirm our findings in a larger study, to take into account the considerable genetic variation in both the host and the parasite: particularly because, as a rule, natural P. falciparum infections are known to involve multiple strains (Basco & Ringwald 2001;Beck et al, 2001;Kublin et al, 2002). Furthermore, parasites which cause severe (cerebral) malaria may be different from parasites causing milder forms of malaria.…”

Mutaciones puntuales en los genes dhfr y dhps de Plasmodium falciparum de tres regiones endémicas

“…Lo anterior sugiere que el codón 59 no es afectado por la presión ejercida con la sulfadoxinapirimetamina y que el mecanismo de selección de mutaciones puede ser distinto en parásitos de Suramérica comparado con el de parásitos de África (28,29), pero esto debe ser corroborado con estudios de parásitos provenientes de diferentes regiones del país y de otros países, así como con muestras tomadas en diferentes periodos.…”