Anopheles Mosquitoes Exposed to Long-Acting Antimalarials via Drug-Supplemented Bloodmeal Absorb Drug but Do Not Suffer Fitness Costs

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BACKGROUND: The World Health Organization's recommendations for antimalarial chemoprevention and mass treatment use in endemic areas have greatly expanded, allowing more flexibility in demographic groups and regions targeted. An overlooked aspect of expanding human population-level drug exposure is the downstream impact of drug on the vector. Anopheles mosquitoes re-feed often with ≥4 bloodmeals during their lifespan. This provides repeated opportunities for mosquitoes to ingest drug via bloodmeals taken from people with antimalarials in the bloodstream and raises questions as to drug impact on mosquitoes. METHODS: We supplemented bloodmeals with physiologic levels of long-acting antimalarials to assess drug exposure impact on Anopheles mosquito fitness and determine drug absorption extent. RESULTS: We did not observe any significant differences in mosquito feeding, behavior, fecundity, or viability after amodiaquine, desethylamodiaquine, piperaquine, and sulfadoxine-pyrimethamine ingestion in lab-reared An. gambiae or field-derived An. coluzzii mosquitoes. Interrogating drug distribution within mosquitoes utilizing LC-MS/MS, desethylamodiaquine, amodiaquine's longer-acting active metabolite, was fed at half and twice Cmax concentrations, with drug then dose-dependently detected in pooled whole mosquitoes, midguts, and hemolymph. This was significant for whole mosquitoes harvested at 24hrs and 120hrs, and midguts harvested at 24hrs. Between 24 to 120hrs, drug decreased in midguts but increased in hemolymph. CONCLUSIONS: We show sustained biochemical evidence of antimalarial absorption into Anopheles hemolymph following bloodmeal ingestion without fitness costs. These studies provide a foundation to next assess vector-stage antimalarial drug exposure impact on parasite development in infected mosquitoes, which could in turn have implications on transmission dynamics and drug resistance spread.

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