title: 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.
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
authors.forename: Ghaith
authors.identifier: 0000-0002-5288-4501
authors.initials: G
authors.lastname: Aljayyoussi
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
authors.forename: Hayley E
authors.initials: HE
authors.lastname: Tyrer
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
authors.forename: Louise
authors.identifier: 0000-0001-7919-2866
authors.initials: L
authors.lastname: Ford
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
authors.forename: Hanna
authors.initials: H
authors.lastname: Sjoberg
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Pionnier
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
authors.forename: David
authors.initials: D
authors.lastname: Waterhouse
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
authors.forename: Jill
authors.initials: J
authors.lastname: Davies
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
authors.forename: Joanne
authors.initials: J
authors.lastname: Gamble
authors.affiliation: Research Foundation in Tropical Medicine and the Environment, Buea, Cameroon.|Department of Microbiology and Parasitology, University of Buea, Buea, Cameroon.
authors.forename: Haelly
authors.initials: H
authors.lastname: Metuge
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
authors.forename: Darren A N
authors.initials: DAN
authors.lastname: Cook
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Steven
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
authors.forename: Raman
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
authors.forename: Ana F
authors.initials: AF
authors.lastname: Guimaraes
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
authors.forename: Rachel H
authors.initials: RH
authors.lastname: Clare
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Cassidy
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Johnston
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Myhill
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Hayward
authors.affiliation: Research Foundation in Tropical Medicine and the Environment, Buea, Cameroon.|Department of Microbiology and Parasitology, University of Buea, Buea, Cameroon.
authors.forename: Samuel
authors.initials: S
authors.lastname: Wanji
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Turner
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK. Mark.Taylor@lstmed.ac.uk.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Taylor
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Ward
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000494:pharmacology; D017178:Brugia malayi / Q000187:drug effects / Q000382:microbiology / Q000502:physiology; D004269:DNA, Bacterial / Q000187:drug effects; D004195:Disease Models, Animal; D004605:Elephantiasis, Filarial / Q000188:drug therapy* / Q000469:parasitology; D047108:Embryonic Development / Q000187:drug effects; D005370:Filarioidea / Q000187:drug effects / Q000382:microbiology* / Q000502:physiology; D006801:Humans; D051379:Mice; D017181:Onchocerca volvulus / Q000187:drug effects / Q000382:microbiology / Q000502:physiology; D009855:Onchocerciasis / Q000188:drug therapy* / Q000469:parasitology; D012293:Rifampin / Q000008:administration & dosage* / Q000494:pharmacology; D016896:Treatment Outcome; D020577:Wolbachia / Q000187:drug effects* / Q000235:genetics; D014958:Wuchereria bancrofti / Q000187:drug effects / Q000382:microbiology / Q000502:physiology
chemical_list: D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D012293:Rifampin