Failure of atovaquone-proguanil malaria chemoprophylaxis in a traveler to Ghana

Boggild, Andrea K.; Lau, Rachel; Reynaud, Dénis; Kain, Kevin C.; Gerson, Marvin

doi:10.1016/j.tmaid.2014.12.010

Cited by 15 publications

(3 citation statements)

References 19 publications

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“…Several factors mitigate against this, including the fact that drug is present before any parasites are introduced, and that the number of liver stage parasites from which to select a mutant is relatively small (by orders of magnitude, a recognized "bottle neck" in the lifecycle). This analysis is supported by the absence of reported resistance in people prophylaxed with atovaquone + proguanil 36 , despite its being the most widely prescribed agent for this indication 37 , and the tens of millions who travel to malarious areas every year 38 .…”

Section: Discussionmentioning

confidence: 87%

Clinically relevant atovaquone-resistant human malaria parasites fail to transmit by mosquito

Balta,

Stiffler,

Sayeed

et al. 2023

Nat Commun

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Long-acting injectable medications, such as atovaquone, offer the prospect of a “chemical vaccine” for malaria, combining drug efficacy with vaccine durability. However, selection and transmission of drug-resistant parasites is of concern. Laboratory studies have indicated that atovaquone resistance disadvantages parasites in mosquitoes, but lack of data on clinically relevant Plasmodium falciparum has hampered integration of these variable findings into drug development decisions. Here we generate atovaquone-resistant parasites that differ from wild type parent by only a Y268S mutation in cytochrome b, a modification associated with atovaquone treatment failure in humans. Relative to wild type, Y268S parasites evidence multiple defects, most marked in their development in mosquitoes, whether from Southeast Asia (Anopheles stephensi) or Africa (An. gambiae). Growth of asexual Y268S P. falciparum in human red cells is impaired, but parasite loss in the mosquito is progressive, from reduced gametocyte exflagellation, to smaller number and size of oocysts, and finally to absence of sporozoites. The Y268S mutant fails to transmit from mosquitoes to mice engrafted with human liver cells and erythrocytes. The severe-to-lethal fitness cost of clinically relevant atovaquone resistance to P. falciparum in the mosquito substantially lessens the likelihood of its transmission in the field.

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Section: Discussionmentioning

confidence: 87%

Clinically relevant atovaquone-resistant human malaria parasites fail to transmit by mosquito

Balta,

Stiffler,

Sayeed

et al. 2023

Nat Commun

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show abstract

“…Several factors mitigate against this, including the fact that drug is present before any parasites are introduced, and that the number of liver stage parasites from which to select a mutant is relatively small (by orders of magnitude, a recognized "bottle neck" in the lifecycle). This analysis is supported by the absence of reported resistance in people prophylaxed with atovaquone + proguanil (36), despite its being the most widely prescribed agent for this indication (37), and the tens of millions who travel to malarious areas every year (38). Second is the concern that mutants occurring in a person dosed with long-acting atovaquone will be transmitted by mosquito to others.…”

Section: Discussionmentioning

confidence: 93%

Transmissibility of clinically relevant atovaquone-resistantPlasmodium falciparumby anopheline mosquitoes

Balta

Stiffler

Sayeed

et al. 2023

Preprint

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Rising numbers of malaria cases and deaths underscore the need for new interventions. Long-acting injectable medications, such as those now in use for HIV prophylaxis, offer the prospect of a malaria chemical vaccine, combining the efficacy of a drug (like atovaquone) with the durability of a biological vaccine. Of concern, however, is the possible selection and transmission of drug-resistant parasites. We addressed this question by generating clinically relevant, highly atovaquone-resistant, Plasmodium falciparum mutants competent to infect mosquitoes. Isogenic paired strains, that differ only by a single Y268S mutation in cytochrome b, were evaluated in parallel in southeast Asian (Anopheles stephensi) or African (Anopheles gambiae) mosquitoes, and thence in humanized mice. Fitness costs of the mutation were evident along the lifecycle, in asexual parasite growth in vitro and in a progressive loss of parasites in the mosquito. In numerous independent experiments, microscopic exam of salivary glands from hundreds of mosquitoes failed to detect even one Y268S sporozoite, a defect not rescued by coinfection with wild type parasites. Furthermore, despite uniformly successful transmission of wild type parasites from An. stephensi to FRG NOD huHep mice bearing human hepatocytes and erythrocytes, multiple attempts with Y268S-fed mosquitoes failed: there was no evidence of parasites in mouse tissues by microscopy, in vitro culture, or PCR. These studies confirm a severe-to-lethal fitness cost of clinically relevant atovaquone-resistant P. falciparum in the mosquito, and they significantly lessen the likelihood of their transmission in the field.

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“…However, IPT with MQAS did not reduce the burden of severe disease that required hospitalization . While daily proguanil has been a long time standard of therapy, the antimicrobial has recently fallen into disrepute due to questionable efficacy, poor compliance, or a combination of these two factors . Consequently, new approaches with the use of IPT have been evaluated and found to have very promising results, although the underrecognition of the contribution of malaria to SCD morbidity has led to poor uptake and implementation of this approach in most settings.…”

Section: Meningococcal Diseasementioning

confidence: 99%

Preventing Infections in Sickle Cell Disease: The Unfinished Business

Obaro

Tam

2016

Pediatr Blood Cancer

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While encapsulated bacterial agents, particularly Streptococcus pneumoniae, are recognized as important microbes that are associated with serious illness in hosts with sickle cell disease (SCD), multiple pathogens are implicated in infectious manifestations of SCD. Variations in clinical practice have been an obstacle to the universal implementation of infection preventive management through active, targeted vaccination of these individuals and routine usage of antibiotic prophylaxis. Paradoxically, in low-income settings, there is evidence that SCD also increases the risk for several other infections that warrant additional infection preventive measures. The infection preventive care among patients with SCD in developed countries does not easily translate to the adoption of these recommendations globally, which must take into account the local epidemiology of infections, available vaccines and population-specific vaccine efficacy, environment, health care behaviors, and cultural beliefs, as these are all factors that play a complex role in the manifestation of SCD and the prevention of infectious disease morbidity.

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Failure of atovaquone-proguanil malaria chemoprophylaxis in a traveler to Ghana

Cited by 15 publications

References 19 publications

Clinically relevant atovaquone-resistant human malaria parasites fail to transmit by mosquito

Clinically relevant atovaquone-resistant human malaria parasites fail to transmit by mosquito

Transmissibility of clinically relevant atovaquone-resistantPlasmodium falciparumby anopheline mosquitoes

Preventing Infections in Sickle Cell Disease: The Unfinished Business

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