Late clinical failure associated with cytochrome b codon 268 mutation during treatment of falciparum malaria with atovaquone–proguanil in traveller returning from Congo

Abstract

Background: The drug combination atovaquone-proguanil, is recommended for treatment of uncomplicated falciparum malaria in France. Despite high efficacy, atovaquone-proguanil treatment failures have been reported. Resistance to cycloguanil, the active metabolite of proguanil, is conferred by multiple mutations in the Plasmodium falciparum dihydrofolate reductase (pfdhfr) and resistance to atovaquone by single mutation on codon 268 of the cytochrome b gene (pfcytb). Case presentation: A 47-year-old female, native from Congo and resident in France, was admitted in hospital for uncomplicated falciparum malaria with parasitaemia of 0.5%, after travelling in Congo (Brazzaville and Pointe Noire). She was treated with atovaquone-proguanil (250 mg/100 mg) 4 tablets daily for 3 consecutive days. On day 5 after admission she was released home. However, many weeks after this episode, without having left France, she again experienced fever and intense weakness. On day 39 after the beginning of treatment, she consulted for fever, arthralgia, myalgia, photophobia, and blurred vision. She was hospitalized for uncomplicated falciparum malaria with a parasitaemia of 0.375% and treated effectively by piperaquine-artenimol (320 mg/40 mg) 3 tablets daily for 3 consecutive days. Resistance to atovaquone-proguanil was suspected. The Y268C mutation was detected in all of the isolates tested (D39, D42, D47). The genotyping of the pfdhfr gene showed a triple mutation (N51I, C59R, S108N) involved in cycloguanil resistance. Conclusion: This is the first observation of a late clinical failure of atovaquone-proguanil treatment of P. falciparum uncomplicated malaria associated with pfcytb 268 mutation in a traveller returning from Congo. These data confirm that the Y268C mutation is associated with delayed recrudescence 4 weeks or more after initial treatment. Although atovaquone-proguanil treatment failures remain rare, an increased surveillance is required. It is essential to declare

Morphological and molecular characteristics of Plasmodium juxtanucleare in layer chicken from three districts of Yogyakarta, Indonesia

“…The change in one nucleotide base in WA 10 and WA 24 influenced its protein sequence, which differed between L and S. Changes or mutations in protein sequences affect protein function [ 15 ]. A single mutation in codon 268 cytb of P. falciparum can cause resistance to atovaquone [ 16 ]. The nucleotide and protein sequences of WA 10 and WA 24 may be influenced by drug exposure targeting the mitochondrial electron transport chain (ETC).…”

Molecular Profiles of Multiple Antimalarial Drug Resistance Markers in Plasmodium falciparum and Plasmodium vivax in the Mandalay Region, Myanmar

“…Mutations in pfcytb of P. falciparum can induce treatment failures of atovaquone against P. falciparum by inhibiting parasite mitochondria electron transport mechanism [ 64 ]. A previous study has suggested that Y268N/S/C in pfcytb is related to resistance of atovaquone-proguanil (Malarone) in P. falciparum [ 65 ]. This mutation was not detected in P. falciparum isolates analyzed in this study, coinciding with a previous study on Myanmar P. falciparum isolates [ 66 ].…”

Atovaquone/Proguanil Resistance in an Imported Malaria Case in Chile

“…5 Previous case reports and studies have shown that resistance to atovaquone is associated with point mutations of the P. falciparum mitochondrial cytochrome b gene (Pfcytb) (most commonly Tyr268Ser) and resistance to proguanil is associated with point mutations in the P. falciparum dihydrofolate reductase gene (Pfdhfr-also relevant for antifolate resistance) such as N51I, C59R, and S108N. [6][7][8] A high rate of antifolate resistance is currently found in P. falciparum parasites across major areas of endemicity 2,7,9 ; however, the Tyr268Ser mutation in Pfcytb has been uncommonly reported in samples collected before therapy. 10,11 Interestingly, a report of results from a rodent model suggested that mutations in cytb may not be able to naturally spread within a Plasmodium population because of an associated fitness cost.…”