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Treating patients ill with severe scrub typhus – a life-threatening infection that kills tens of thousands of people a year - with a combination of intravenous antibiotics doxycycline and azithromycin is significantly more effective than the current monotherapy of using either drug alone, say researchers in a study published in the New England Journal of Medicine (NEJM).

LOMWRU field researchers searching for field rats In Laos, vectors of mites infected with the bacteria Orientia tsutsugamushi. © MORU 2023
LOMWRU field researchers in Laos searching for field rats, vectors of mites infected with the bacteria Orientia tsutsugamushi, which causes scrub typhus.

1 March 2023, Bangkok Thailand

Using data from the double-blind, randomized, controlled Intravenous Treatment for Scrub Typhus (INTREST) clinical trial, researchers from several Indian health institutes compared the efficacy and safety of three 7-day intravenous antibiotic treatments (doxycycline, azithromycin, or a combination of both) in patients with severe scrub typhus.

They found that combination therapy was superior to therapy with intravenous doxycycline or azithromycin alone. Patients who were treated with combination antibiotics had fewer complications from the infection on day 7. Poor outcome, defined as a composite of death, persistent complications or prolonged fever was reduced by nearly one-third, to 33% for combination therapy versus 47% for doxycycline and 48% for azithromycin.

“Combination therapy with intravenous doxycycline and azithromycin is a better, more effective way to treat severe scrub typhus than monotherapies of either drug by itself. This new evidence will change treatment guidelines, leading to swifter recovery and potentially saving thousands of lives of people with scrub typhus in the future,” said INTREST study lead author Prof George M Varghese, Department of Infectious Diseases, Christian Medical College in Vellore, India.

A life-threatening infection caused by the bacteria Orientia tsutsugamushi, scrub typhus is transmitted to humans by bites from tiny infected mites. Scrub typhus is a major public health threat in India, other South Asian countries and around the tropics that kills an estimated 10% of the approximately 1 million people infected by it every year.

INTREST is the largest ever randomised controlled trial on the treatment of scrub typhus, and the only one on the treatment of severe scrub typhus. Funded by the Wellcome Trust/DBT India Alliance, the study was led by Prof Varghese and the INTREST trial investigators in India in collaboration with University of Oxford Prof Nicholas Day and colleagues at Mahidol Oxford Tropical Medicine Research Unit (MORU) in Bangkok. PGI Chandigarh, IGMC Shimla, PGIMS Rohtak, JIPMER Pondicherry, CMC Vellore, SVIMS Tirupati and KMC Manipal were the seven participating centres across India.

“The INTREST study highlights the need for similar large randomised controlled clinical trials for other neglected tropical diseases, so that their treatment can be improved. This will benefit the millions of people affected by these under-studied diseases each year,” said Prof Day.

Scrub typhus typically presents as fever that may be associated with headache, cough, shortness of breath, and brain symptoms, like confusion and disorientation. One-third of patients develop severe disease that affects multiple organs in the body and leads to lethally low blood pressures. Death rates in severe disease can reach up to 70% without treatment and 24% with treatment.

In the past scrub typhus has been treated with doxycycline or chloramphenicol, though in recent years the use of chloramphenicol has reduced because of its toxicity. Meanwhile, the use of oral azithromycin for mild scrub typhus has increased. Small trials conducted in Thailand and South Korea among patients with mild scrub typhus showed that both azithromycin and doxycycline have similar efficacy. However, systematic reviews of available trials reveal that there is no uniformity in the doses of drugs used or in the outcomes of patients within the studies conducted so far. Hence, it is not clear which drug or how much of it should be used.

Researchers do not know for certain why a combination of doxycycline and azithromycin should be more clinically effective in the treatment of severe scrub typhus than either of the drugs alone. The study found that when both azithromycin and doxycycline were administered together to patients with severe scrub typhus, the bacteria were cleared away quicker and patients improved faster. This could be because doxycycline and azithromycin stop the bacteria from producing proteins through different, but complimentary, mechanisms. As a consequence the combination of the two drugs may have reduced bacterial growth and multiplication, leading to quicker control of bacterial growth and more rapid resolution of symptoms.


Intravenous Doxycycline, Azithromycin or Both for Severe Scrub Typhus. Varghese GM, Dayanand D, Gunasekaran K, Kundu D, Wyawahare M, Sharma N, Chaudhry D, Mahajan SK, Saravu K, Aruldhas BW, Mathew BS, Nair RG, Newbigging N, Mathew A, Abhilash KPP, Biswal M, Prasad AH, Saxhariah A, Iyadurai R, Hansdak SG, Sathyendra S, Sudarsanam TD, Prakash JAJ, Manesh A, Mohan A, Traning J, Blacksell SD, Peerawaranun P, Waithira N, Mukaka M, Cheah PY, Peter JV, Abraham OC, and Day NPJ for the INTREST Trial Investigators. NEJM 2023; 388:792-803. doi: 10-1056/NEJMoa2208449.