Delayed Onset of Symptoms and Atovaquone-Proguanil Chemoprophylaxis Breakthrough by Plasmodium malariae in the Absence of Mutation at Codon 268 of pmcytb
نویسندگان
چکیده
Plasmodium malariae is widely distributed across the tropics, causing symptomatic malaria in humans with a 72-hour fever periodicity, and may present after latency periods lasting up to many decades. Delayed occurrence of symptoms is observed in humans using chemoprophylaxis, or patients having received therapies targeting P. falciparum intraerythrocytic asexual stages, but few investigators have addressed the biological basis of the ability of P. malariae to persist in the human host. To investigate these interesting features of P. malariae epidemiology, we assembled, here, an extensive case series of P. malariae malaria patients presenting in non-endemic China, Sweden, and the UK who returned from travel in endemic countries, mainly in Africa. Out of 378 evaluable P. malariae cases, 100 (26.2%) reported using at least partial chemoprophylaxis, resembling the pattern seen with the relapsing parasites P. ovale spp. and P. vivax. In contrast, for only 7.5% of imported UK cases of non-relapsing P. falciparum was any chemoprophylaxis use reported. Genotyping of parasites from six patients reporting use of atovaquone-proguanil chemoprophylaxis did not reveal mutations at codon 268 of the cytb locus of the P. malariae mitochondrial genome. While travellers with P. malariae malaria are significantly more likely to report prophylaxis use during endemic country travel than are those with P. falciparum infections, atovaquone-proguanil prophylaxis breakthrough was not associated with pmcytb mutations. These preliminary studies, together with consistent observations of the remarkable longevity of P. malariae, lead us to propose re-examination of the dogma that this species is not a relapsing parasite. Further studies are needed to investigate our favoured hypothesis, namely that P. malariae can initiate a latent hypnozoite developmental programme in the human hepatocyte: if validated this will explain the consistent observations of remarkable longevity of parasitism, even in the presence of antimalarial prophylaxis or treatment.
منابع مشابه
Failure of atovaquone-proguanil malaria chemoprophylaxis in a traveler to Ghana.
Clinical failure of Malarone™ chemoprophylaxis is extremely rare. We report a case of Plasmodium falciparum malaria in a returned traveler to Ghana who fully adhered to atovaquone-proguanil (Malarone™) chemoprophylaxis daily dosing, yet took the pills on an empty stomach. Screening of the P. falciparum isolate revealed triple codon mutation of Dhfr at positions 51, 59, and 108. Plasma drug leve...
متن کاملParallel evolution of adaptive mutations in Plasmodium falciparum mitochondrial DNA during atovaquone-proguanil treatment.
Here we provide direct evidence that two adaptive nucleotide changes in the same codon (268) of the cytochrome b gene (pfcytb) each occurred repeatedly in independent Plasmodium falciparum lineages exposed to the antimalarial drug atovaquone-proguanil (AP). We analyzed the history of 7 AP resistance alleles from clinical isolates by sequencing the mitochondrial (mt) genome that encodes the pfcy...
متن کاملSevere atovaquone-resistant Plasmodium falciparum malaria in a Canadian traveller returned from the Indian subcontinent
BACKGROUND We report the first case of atovaquone/proguanil treatment failure in severe Plasmodium falciparum malaria acquired by a non-immune traveller to the Indian subcontinent. Recrudescent infection was complicated by neurological involvement 14 days after directly observed therapy with atovaquone/proguanil. Sequence analysis of the plasmodial cytochrome b gene confirmed a contribution of ...
متن کاملMolecular characterization of the cytochrome b gene and in vitro atovaquone susceptibility of Plasmodium falciparum isolates from Kenya.
The prevalence of a genetic polymorphism(s) at codon 268 in the cytochrome b gene, which is associated with failure of atovaquone-proguanil treatment, was analyzed in 227 Plasmodium falciparum parasites from western Kenya. The prevalence of the wild-type allele was 63%, and that of the Y268S (denoting a Y-to-S change at position 268) mutant allele was 2%. There were no pure Y268C or Y268N mutan...
متن کاملFailure of atovaquone/proguanil to prevent Plasmodium ovale malaria in traveler returning from Cameroon.
We report a case of a patient returning from Cameroon who developed Plasmodium ovale malaria, despite atovaquone/proguanil (AP, Malarone) prophylaxis, which is widely used for the prevention of chloroquine-resistant malaria. AP is indeed active only on schizont blood forms of P. ovale but not against liver-stage hypnozoites and does not realize effective prophylaxis against delayed onset of P. ...
متن کامل