Potential interaction between clorsulon and ivermectin for malaria vector control

Mass ivermectin (IVM) treatment of livestock (MITL) is under consideration as a malaria control tool as IVM-treated livestock are lethal to blood-feeding Anopheles mosquitoes. MITL is routinely used as a prophylaxis in livestock to reduce the burden and transmission of helminth infections. Recently, there has been a shift in the veterinary IVM market in Southeast Asia wherein nearly all standard IVM formulations are now co-formulated with clorsulon (CLO). CLO is used to treat the trematode liver fluke, Fasciola hepatica. Thus, the co-administration of IVM and CLO simultaneously targets multiple livestock infections. Additionally, F. hepatica frequently afflicts human populations in endemic areas, making control of F. hepatica in livestock beneficial for One Health. CLO interrupts glycolysis in F. hepatica, but its potential effect against Anopheles mosquitoes has never been evaluated. Anopheles dirus mosquitoes were blood-fed CLO across a range of concentrations (1-10,000 nM; 0.38-3807 ng/mL), and mosquito survival was monitored for 10 days. Co-feeding experiments were also performed with An. dirus blood-fed on IVM at two concentrations (4 and 6 ng/mL) without and with CLO corresponding to peak concentration in cattle (C_max) (2700 ng/mL) and five times the C_max (13,500 ng/mL), and mosquito survival was monitored for 10 days. CLO had no mosquito-lethal effect on An. dirus. The IVM and CLO co-feed experiment did not indicate any altered effect of IVM on mosquito survival when co-fed with CLO. IVM-CLO livestock co-formulations would not likely alter the Anopheles mosquito-lethal effect of MITL. The use of MITL-CLO for malaria control would have health benefits for livestock, treating helminth and liver fluke infections, and additional One Health benefits by reducing transmission risk of liver flukes to humans.