02348nas a2200301   4500000000100000008004100001260002800042653003900070653002500109653001900134653001500153653001400168100001800182700001200200700001100212700001400223700001500237700001700252700001300269700001300282700001500295700001200310245016600322856005400488300000800542490000600550520149000556       2017                            d  bNature Publishing Group10aNeglected tropical diseases (NTDs)10aLymphatic filariasis10aonchocerciasis10aRifampicin10aTreatment1 aAljayyoussi G1 aTyrer H1 aFord L1 aSjoberg H1 aPionnier N1 aWaterhouse D1 aDavies J1 aGamble J1 aMetugene H1 aCook DA00aShort-course, high-dose Rifampicin achieves Wolbachia depletion predictive of curative outcomes in preclinical models of lymphatic filariasis and onchocerciasis.  uhttp://www.nature.com/articles/s41598-017-00322-5  a2100 v73 a<p>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 &gt;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 &gt;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.</p>