CHENNAI, 2nd March 2023: An Indian multi-institute team of researchers have identified a better drug treatment for ‘Severe Scrub Typhus,’ a life-threatening infection caused by the bacteria, Orientia tsutsugamushi. This infection, which primarily affects rodents, is transmitted to humans (zoonoses) by the larvae of trombiculid mites.
The Researchers found that a ‘Combination antibiotic treatment’ (using a combination of drugs) is more effective for treating severe scrub typhus than single-drug therapies.
Scrub typhus is a major public health threat in India and other South Asian countries. It is estimated that in endemic regions, about a billion people are at risk of contracting the infection, while a million people get infected and 1.5 lakh people die from it every year.
Prof. George M Varghese, an infectious diseases physician and Researcher from Christian Medical College in Vellore, Tamil Nadu, and the INTREST trial investigators conducted a multi-centric, randomised controlled trial funded by the DBT/Wellcome India Alliance to identify the best treatment option for patients with severe scrub typhus. It demonstrated that treatment with intravenous doxycycline and azithromycin is more effective than using either drug on its own.
This new study, the largest ever randomised controlled trial on the treatment of severe scrub typhus, was published recently in The New England Journal of Medicine (DOI: 10.1056/NEJMoa2208449). The Research Paper can be accessed using the following link - https://www.nejm.org/doi/full/10.1056/NEJMoa2208449?query=featured_home
The collaborating institutions included the Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, Indira Gandhi Medical College & Hospital (IGMC) Shimla, Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Puducherry, Christian Medical College, Vellore, SVIMS Tirupati and KMC Manipal.
Explaining the significance of this research, Prof. George M Varghese, Department of Infectious Diseases, Christian Medical College, Vellore, Tamil Nadu, said, “The implication of this study is that when using a combination of azithromycin and doxycycline to treat severe scrub typhus, more patients can be discharged from the hospital by day 7 as they would have fewer persisting complications, such as respiratory distress syndrome (ARDS), hepatitis, hypotension/shock, meningoencephalitis, and kidney failure. This trial provides evidence that combination therapy with intravenous doxycycline and azithromycin is a better therapeutic option for the treatment of severe scrub typhus than monotherapies of either drug. This new evidence will change treatment guidelines and save the lives of thousands of people with scrub typhus in the future.”
Highlighting the need for such research, Prof. George M Varghese added, “Scrub typhus typically presents as a fever that may be associated with headaches, coughs, shortness of breath, and brain symptoms, like confusion and disorientation. About six per cent of patients infected with scrub typhus could die in spite of diagnosis and treatment. One-third of patients develop severe disease that affects multiple organs in the body and leads to lethally low blood pressure. Death rates in severe disease can reach up to 70 per cent without treatment and 24 per cent with treatment.”
RESEARCH TRIALS
Historically, scrub typhus was treated with doxycycline or chloramphenicol. However, 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 was not clear which drug or how much of it should be used.
In the current study, about 800 adult patients with severe scrub typhus were included. They were split in a 1:1:1 ratio into three groups through a randomisation process to receive intravenous doxycycline, intravenous azithromycin, or a combination of both intravenous doxycycline and azithromycin, respectively, for a duration of 7 days. The treating team, study management group, and participants were not told which patient was assigned to which group or treatment regimen.
The study assessed the efficacy of treatment using death from any cause on day 28, persisting complications on day 7, and persisting fever on day 5 as indicators. The side effects of treatment were also assessed.
The trial 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. In line with other studies, this study also found that there was no difference in the outcome between using doxycycline or azithromycin alone. The overall mortality rate in this study was 12%.
As Orientia tsutsugamushi is a bacterium which multiplies and survives inside host cells, it is important that the antibiotic reaches high concentrations within host cells as well. This 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. The combination of the two drugs may have result in a more complete blockade of protein synthesis and consequently reduced bacterial growth and multiplication. As combination therapy quickly controlled bacterial growth within the first week of infection, severe disease may have been prevented and resolution of symptoms might have quickened.
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