Indian researchers have found a 'combination antibiotic treatment' for severe scrub typhus, a major public health threat in India and other South Asian countries. The researchers claim that this treatment is more effective for treating severe scrub typhus than single-drug therapies.
What is scrub typhus?
Scrub typhus, also known as bush typhus, is a disease caused by a bacteria called Orientia tsutsugamushi, and is spread to people through the bites of infected chiggers or larval mites. Scrub typhus commonly causes symptoms such as fever, chills, headache, body aches, muscle pain, cough, results in mental changes, which range from confusion to coma, and leads to the formation of rashes, enlarged lymph nodes, and dark, scab-like regions at the site of the chigger bite. These regions are called eschars. Scrub typhus also leads to an altered sensorium, which is an umbrella term referring to intellectual and cognitive functions.
What is the fatality of scrub typhus?
The median case fatality of scrub typhus when infection is left untreated is approximately six per cent. In the case of severe disease, the median fatality can reach 70 per cent. Approximately one-third of hospitalised patients develop severe scrub typhus, which includes multiorgan dysfunction and shock, and can lead to death in approximately a quarter of cases despite therapy.
Where is scrub typhus endemic?
Regions where cases of scrub typhus occur include rural areas of Southeast Asia, China, India, Indonesia, Japan and northern Australia, according to the Centers for Disease Control and Prevention (CDC).
Scrub typhus, a potentially life-threatening condition, primarily infects rodents, and is transmitted to humans through the larvae of trombiculid mites, or berry mites, which, in their larval form, often bite their human or animal host, and embed their mouthparts into the skin, causing intense irritation to the host.
About a billion people in South Asian countries, where scrub typhus is endemic, are estimated to be at risk of contracting the infection. Every year, a million people get infected with scrub typhus, and about 1.5 lakh people succumb to the infection.
As part of the new study, researchers have conducted the largest ever randomised controlled trial on the treatment of severe scrub typhus. The study was recently published in The New England Journal of Medicine.
The study was conducted by researchers from the Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Puducherry, Christian Medical College, Vellore, Indira Gandhi Medical College & Hospital (IGMC), Shimla, SVIMS Tirupati, Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak, and KMC Manipal.
How has scrub typhus been treated historically?
While scrub typhus has historically been treated with doxycycline or chloramphenicol, data from randomised, controlled trials are lacking, particularly for severe scrub typhus, the study said.
Chloramphenicol has been used less frequently in recent years because of its toxicity profile. Oral azithromycin is increasingly used for mild scrub typhus.
How the study was conducted
As part of the new study, the researchers conducted a randomised, controlled trial in which they compared the efficacy of intravenous doxycycline, azithromycin, or a combination of both in treating severe scrub typhus. The researchers enrolled 794 patients who were 15 years of age or older with severe scrub typhus, and had at least one organ involved.
The median age of the patients was 48 years. They were assigned a seven-day course of intravenous doxycycline, azithromycin, or both, referred to as a combination therapy.
What was the primary outcome?
According to the study, the primary outcome was a composite of death from any cause on day 28, persistent complications on day 7, and persistent fever on day 5.
The complications included respiratory, hepatic, cardiovascular, renal and neurologic problems.
Incidence of composite primary outcome lower in combination therapy group
The patients who received combination therapy showed a lower incidence of the composite primary outcome than those who received only doxycycline. The incidence of composite primary outcome in patients who received combination therapy was 33 per cent, while that in the patients who received doxycycline was 47 per cent.
The incidence of composite primary outcome for patients administered with combination therapy was also lower than that of patients who received azithromycin. The incidence for the patients administered with azithromycin was 48 per cent.
Overall, the study found that patients who received combination therapy had fewer complications due to the disease on day 7.
The study said that no significant difference was observed between the azithromycin and doxycycline groups.
For all the three groups, adverse events and 28-day mortality were similar. The overall mortality rate of the participants was 12 per cent.
Since Orientia tsutsugamushi is an intracellular organism that proliferates and survives in endothelial cells (thin layer of cells lining blood vessels and lymphatic nodes) and macrophages (a type of white blood cells), adequate intracellular antibiotic concentrations are important.
What characteristics make doxycycline and azithromycin favourable for scrub typhus treatment?
Both doxycycline and azithromycin have excellent tissue penetration, and azithromycin accumulates intracellularly to concentrations that are 100 times as high as those in plasma. Combination therapy cleared away bacteria quicker and made patients improve faster.
Complications requiring organ support lower in combination therapy group
When the researchers analysed the trial, they found that complications requiring organ support such as ventilatory assistance, supplementary oxygen or dialysis were fewer by day 7 in the group that was administered combination therapy, than in the monotherapy group. Also, the resolution of hepatic and renal involvement was more frequent.
Combination therapy results has greater effect against the bacterium
According to the study, the combination of the two drugs may result in a more complete blockade of protein synthesis with a consequently greater effect against Orientia tsutsugamushi.
Together, doxycycline and azithromycin resulted in better bacterial control during the critical first week of infection. This is how combination therapy may result in prevention and faster resolution of severe manifestations of illness.
The authors conducted that combination therapy with intravenous doxycycline and azithromycin was a better therapeutic option for the treatment of severe scrub typhus than monotherapy with either drug alone.