Selection of Antifolate-Resistant Plasmodium falciparum by Sulfadoxine-Pyrimethamine Treatment and Infectivity to Anopheles Mosquitoes

Abstract

Resistance-conferring mutations in dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) in Plasmodium falciparum are selected by treatment with sulfadoxine pyrimethamine (SP). We assessed the association between these mutations and transmission capacity of parasites to Anopheles mosquitoes on the Pacific coast of Colombia. Patients with uncomplicated P. falciparum malaria received SP treatment and were followed-up to compare the prevalence of DHFR and DHPS mutations before and after SP treatment. Membrane feeding assays were used to measure infectivity to mosquitoes of post-treatment gametocytes with and without these mutations. Per-protocol treatment efficacy was 95.0% (132 of 139). Gametocytes carrying resistance-conferring mutations were selected after SP treatment and were infective to mosquitoes. Seven days after treatment, infections with two DHFR mutations had a 10-fold higher probability of infecting mosquitoes than infections with no DHFR mutations (odds ratio = 10.23, P< 0.05). Low-level drug resistance mutations have the potential to enhance transmission of P. falciparum and spread resistant parasites.

Sub-microscopic gametocyte carriage in febrile children living in different areas of Gabon

“…However recent data suggest that submicroscopic gametocytes carriage could persist after anti-malarial treatment [14,15]. This duration of gametocytaemia is increased in case of drug resistant parasite carriage and maintains the spread of drug resistance [16,17]. Therefore, the presence of submicroscopic gametocytes following anti-malarial treatment could be a possible marker of resistant parasites, and a valuable indicator of drug efficacy, that could be assessed using molecular methods.…”

Epidemiology and Infectivity of Plasmodium falciparum and Plasmodium vivax Gametocytes in Relation to Malaria Control and Elimination

“…Given this relationship with resistance-associated mutations, gametocytes and posttreatment malaria transmission may serve as effective early parasitological indicators of reduced drug sensitivity (25,183,274). Two examples of the use of gametocyte carriage as a warning system for an increase in the prevalence of parasite resistance have been reported.…”

“…Similarly, mutations in the dhfr and dhps genes, encoding SP resistance, were related to increased gametocyte carriage following (30,275,288) or even prior to (288) treatment and to a longer duration of gametocyte carriage than that for wild-type parasites (25). A study by Méndez and colleagues showed that malaria transmission was enhanced 10-fold for parasites with low levels of resistance compared to fully sensitive parasites, despite high SP cure rates in Colombia (274). This may be explained partly by a longer parasite clearance time for dhfr/dhps mutant parasites allowing asexual parasites to differentiate into gametocytes (275), although other factors may also be important (25,275).…”

Directional Selection at the pfmdr1, pfcrt, pfubp1, and pfap2mu Loci of Plasmodium falciparum in Kenyan Children Treated With ACT

“…Thus, residual asexual parasitemia, if genetically determined, may provide an enhanced likelihood of infecting the vector population, and thus further human hosts. Such evolutionary success, where parasites harboring genetic markers of drug resistance exhibit a transmission advantage, has previously been implicated in the development of resistance to chloroquine and antifolate malaria drugs [10–12]. …”