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Lymphatic filariasis (LF) and onchocerciasis are priority neglected tropical diseases targeted for elimination. The only safe drug treatment with substantial curative activity against the filarial nematodes responsible for LF ( Brugia malayi, Wuchereria bancrofti ) or onchocerciasis ( Onchocerca volvulus ) is doxycycline. The target of doxycycline is the essential endosymbiont,  Wolbachia.  Four to six weeks doxycycline therapy achieves >90% depletion of  Wolbachia  in worm tissues leading to blockade of embryogenesis, adult sterility and premature death 18–24 months post-treatment. Long treatment length and contraindications in children and pregnancy are obstacles to implementing doxycycline as a public health strategy. Here we determine, via preclinical infection models of  Brugia malayi  or  Onchocerca ochengi  that elevated exposures of orally-administered rifampicin can lead to  Wolbachia  depletions from filariae more rapidly than those achieved by doxycycline. Dose escalation of rifampicin achieves >90%  Wolbachia  depletion in time periods of 7 days in  B. malayi  and 14 days in  O. ochengi . Using pharmacokinetic-pharmacodynamic modelling and mouse-human bridging analysis, we conclude that clinically relevant dose elevations of rifampicin, which have recently been determined as safe in humans, could be administered as short courses to filariasis target populations with potential to reduce anti- Wolbachia  curative therapy times to between one and two weeks.

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Short-Course, High-Dose Rifampicin Achieves Wolbachia Depletion Predictive of Curative Outcomes in Preclinical Models of Lymphatic Filariasis and Onchocerciasis