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

Aljayyoussi, Ghaith, Tyrer, Hayley, Ford, Louise, Sjoberg, Hanna, Pionnier, Nicolas ORCID: https://orcid.org/0000-0002-2379-4945, Waterhouse, David, Davies, Jill, Gamble, Jo, Metugene, Haelly, Cook, Darren, Steven, Andrew, Sharma, Raman, Guimaraes, Ana, Clare, Rachel ORCID: https://orcid.org/0000-0002-3945-0530, Cassidy, Andrew, Johnston, Kelly, Myhill, Laura, Hayward, Laura, Wanji, Samuel, Turner, Joseph ORCID: https://orcid.org/0000-0002-2185-5476, Taylor, Mark ORCID: https://orcid.org/0000-0003-3396-9275 and Ward, Steve ORCID: https://orcid.org/0000-0003-2331-3192 (2017) 'Short Course, High Dose Rifampicin Achieves Wolbachia Depletion Predictive of Curative Outcomes in Preclinical Models of Lymphatic Filariasis and Onchocerciasis'. Scientific Reports, Vol 7, Issue 210.

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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.

Item Type:	Article
Subjects:	QX Parasitology > Helminths. Annelida > QX 203 Nematoda WC Communicable Diseases > Tropical and Parasitic Diseases > WC 695 Parasitic diseases (General) WC Communicable Diseases > Tropical and Parasitic Diseases > WC 880 Filariasis and related conditions (General) WC Communicable Diseases > Tropical and Parasitic Diseases > WC 885 Onchocerciasis
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI):	https://doi.org/10.1038/s41598-017-00322-5
Depositing User:	Elly Wallis
Date Deposited:	30 Mar 2017 12:53
Last Modified:	17 Jul 2020 10:58
URI:	https://archive.lstmed.ac.uk/id/eprint/6918

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