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 (Onchocer...
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Nature Portfolio
2017
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oai:doaj.org-article:5458446623e84d6f9b626f860c2cd9e32021-12-02T16:06:05ZShort-Course, High-Dose Rifampicin Achieves Wolbachia Depletion Predictive of Curative Outcomes in Preclinical Models of Lymphatic Filariasis and Onchocerciasis10.1038/s41598-017-00322-52045-2322https://doaj.org/article/5458446623e84d6f9b626f860c2cd9e32017-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00322-5https://doaj.org/toc/2045-2322Abstract 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.Ghaith AljayyoussiHayley E. TyrerLouise FordHanna SjobergNicolas PionnierDavid WaterhouseJill DaviesJoanne GambleHaelly MetugeDarren A. N. CookAndrew StevenRaman SharmaAna F. GuimaraesRachel H. ClareAndrew CassidyKelly L. JohnstonLaura MyhillLaura HaywardSamuel WanjiJoseph D. TurnerMark J. TaylorStephen A. WardNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017) |
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Medicine R Science Q Ghaith Aljayyoussi Hayley E. Tyrer Louise Ford Hanna Sjoberg Nicolas Pionnier David Waterhouse Jill Davies Joanne Gamble Haelly Metuge Darren A. N. Cook Andrew Steven Raman Sharma Ana F. Guimaraes Rachel H. Clare Andrew Cassidy Kelly L. Johnston Laura Myhill Laura Hayward Samuel Wanji Joseph D. Turner Mark J. Taylor Stephen A. Ward Short-Course, High-Dose Rifampicin Achieves Wolbachia Depletion Predictive of Curative Outcomes in Preclinical Models of Lymphatic Filariasis and Onchocerciasis |
| description |
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. |
| format |
article |
| author |
Ghaith Aljayyoussi Hayley E. Tyrer Louise Ford Hanna Sjoberg Nicolas Pionnier David Waterhouse Jill Davies Joanne Gamble Haelly Metuge Darren A. N. Cook Andrew Steven Raman Sharma Ana F. Guimaraes Rachel H. Clare Andrew Cassidy Kelly L. Johnston Laura Myhill Laura Hayward Samuel Wanji Joseph D. Turner Mark J. Taylor Stephen A. Ward |
| author_facet |
Ghaith Aljayyoussi Hayley E. Tyrer Louise Ford Hanna Sjoberg Nicolas Pionnier David Waterhouse Jill Davies Joanne Gamble Haelly Metuge Darren A. N. Cook Andrew Steven Raman Sharma Ana F. Guimaraes Rachel H. Clare Andrew Cassidy Kelly L. Johnston Laura Myhill Laura Hayward Samuel Wanji Joseph D. Turner Mark J. Taylor Stephen A. Ward |
| author_sort |
Ghaith Aljayyoussi |
| title |
Short-Course, High-Dose Rifampicin Achieves Wolbachia Depletion Predictive of Curative Outcomes in Preclinical Models of Lymphatic Filariasis and Onchocerciasis |
| title_short |
Short-Course, High-Dose Rifampicin Achieves Wolbachia Depletion Predictive of Curative Outcomes in Preclinical Models of Lymphatic Filariasis and Onchocerciasis |
| title_full |
Short-Course, High-Dose Rifampicin Achieves Wolbachia Depletion Predictive of Curative Outcomes in Preclinical Models of Lymphatic Filariasis and Onchocerciasis |
| title_fullStr |
Short-Course, High-Dose Rifampicin Achieves Wolbachia Depletion Predictive of Curative Outcomes in Preclinical Models of Lymphatic Filariasis and Onchocerciasis |
| title_full_unstemmed |
Short-Course, High-Dose Rifampicin Achieves Wolbachia Depletion Predictive of Curative Outcomes in Preclinical Models of Lymphatic Filariasis and Onchocerciasis |
| title_sort |
short-course, high-dose rifampicin achieves wolbachia depletion predictive of curative outcomes in preclinical models of lymphatic filariasis and onchocerciasis |
| publisher |
Nature Portfolio |
| publishDate |
2017 |
| url |
https://doaj.org/article/5458446623e84d6f9b626f860c2cd9e3 |
| work_keys_str_mv |
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