Research Summary

Improving treatment outcomes in severe scrub typhus: a multicentre randomized controlled trial with pharmacokinetic/pharmacodynamic assessment and molecular characterisation of Orientia tsutsugamushi

Scrub typhus is a life-threatening acute febrile illness endemic in Asia which accounts for a million cases resulting in 150,000 deaths annually. The optimal treatment for severe scrub typhus remains unclear and has never been evaluated in a randomized clinical trial. The current mainstay of therapy for scrub typhus is doxycycline, but the optimal therapy for severe disease remains unclear as there is a complete absence of evidence. Intravenous doxycycline is unavailable in many countries, and intravenous azithromycin is used as an alternative but its use is not supported by robust evidence. Doxycycline resistant scrub typhus infections were reported in Northern Thailand in the 1990s, but further studies have not been carried out to confirm this or to assess whether this is present elsewhere. In this study, we aim to provide conclusive evidence for the optimal treatment of severe scrub typhus by demonstrating a reduction in mortality and improved outcomes in a multicentre randomized controlled trial. At the core of the project will be a multicentre, prospective, three arm RCT comparing i) 7 days IV azithromycin, ii) 7 days IV doxycycline, and iii) 7 days of combination of IV doxycycline and IV azithromycin. The study is designed to demonstrate differences in mortality and improved outcomes in this multicentre RCT. We will evaluate clinical and surrogate markers associated with severe disease, perform pharmacological investigations and characterize the isolates/strains involved.

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