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

Abstract

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.

Preclinical development of an oral anti- Wolbachia macrolide drug for the treatment of lymphatic filariasis and onchocerciasis

“…Because of the high efficacy achieved in mouse and gerbil models of lymphatic filariasis infection, we next investigated whether A-1535469 and A-1574083 showed anti-Wolbachia activity in mouse and gerbil models of Onchocerca infection. Preclinical models of onchocerciasis were generated by implanting adult male O. ochengi parasites isolated from naturally infected cattle (11,16) into immunodeficient mice or outbred gerbils. Both A-1535469 (250 mg/kg) and A-1574083 (75 mg/kg) given for 14 days mediated a 99.4 and 98.8% median reduction in Wolbachia, respectively, in immunodeficient mice implanted with Onchocerca ( Fig.…”

The changing global landscape of health and disease: addressing challenges and opportunities for sustaining progress towards control and elimination of neglected tropical diseases (NTDs)

“…Having demonstrated the efficacy of doxycycline as a macrofilaricide, A·WOL have promising candidate alternatives which can shorten the duration of treatment needed to secure adult worm death or permanent sterilization of infection. Such alternatives include high-dose rifampicin (Aljayyoussi et al 2017) and a new entity TylAMac™ (Turner et al 2015).…”

High-dose rifamycins enable shorter oral treatment in a murine model of Mycobacterium ulcerans disease

“…Integrated approaches to control neglected tropical diseases are increasingly advocated. It is thus noteworthy that high-dose, short-course regimens with rifampicin are being investigated as potential therapeutic agents for lymphatic filariasis and onchocerciasis (38) in addition to TB, offering potential synergies in the research and implementation of new, more efficient regimens in co-endemic areas.…”