Epidemic typhus: Combination therapy could save more lives

Epidemic typhus — a life-threatening infection caused by Orientia tsutsugamushi Bacteria — A major public health threat in South and Southeast Asia. An estimated 1 million cases have been reported from South and Southeast Asia, with a mortality rate of 10%. India is one of the hotspots with at least 25% of the disease burden. At CMC Vellore alone, 500-1,000 patients are treated each year, 250-300 of whom are severely ill.

A seroprevalence study conducted in Vellore, Tamil Nadu by researchers from CMC Vellore about five years ago showed more than 30% antibody positivity against bacteria in the community and exposure to the pathogen was shown.

Epidemic typhus poses a major public health threat due to the extremely high mortality rate in critically ill patients despite diagnosis and treatment. In a study published by researchers at CMC Vellore in 2014, he found that the mortality rate in patients with severe typhus disease with multiple organ failure was 24%.

Monotherapy with either doxycycline or azithromycin has been commonly used to date. In an ongoing trial in seven centers in India, patients were randomly assigned to receive both doxycycline and azithromycin combination therapy, and two other patients received either doxycycline or azithromycin alone. showed earlier resolution of complications compared to the two groups. The trial enrolled approximately 800 patients (265 in the doxycycline group, 263 in the azithromycin group and 266 in the combination therapy group). Result is, New England Journal of Medicine.

“The 28-day mortality rate was the same for all three groups (12.1%). It can save lives,” said CMC Vellore, professor of infectious diseases and principal investigator and corresponding author of the paper.

Respiratory, renal, hepatic, and central nervous system complications were less frequent in the combination therapy group than in the monotherapy group. More patients will need to be enrolled in the trial to conclusively prove that it will be effective, but the trial is now continuing as the benefits of combination therapy over monotherapy have already been established. is unethical,” said Dr. Varghese.

Of the patients who died in this study, 50% died within 48 hours of arrival. This indicates that patients who arrive late with multiple organ failure may be at higher risk of death as their condition may be too advanced for effective treatment.

“This trial shows that combination therapy using both doxycycline and azithromycin is much more effective in treating severe typhus than either drug alone.

“Although mortality was similar in the combination and monotherapy groups, the reduction in the number of complications at day 7 in the combination group represents an important benefit in undeveloped areas where typhus is endemic. are limited,” said an accompanying editorial in the journal.

treatment guidelines

Until the results of this trial were published, there were no clear treatment guidelines for severe typhus fever. Oral doxycycline was routinely used as monotherapy, but must be given intravenously in severe cases. This has made treatment with azithromycin attractive because of the wide availability of intravenous formulations of the drug. But even the largest trial to date comparing doxycycline and azithromycin included fewer than 100 of her mildly ill patients.

In contrast, the superiority of combination therapy for severe typhus is demonstrated by clinical evidence from the largest randomized controlled trial to date. Second, the combination therapy was able to achieve faster clearance of bacteria compared to monotherapy. The faster clearance in the combination therapy group may be due to complementary effects of the drugs.

The concentration of azithromycin in cells where bacteria grow can be 100 times higher than in plasma, while doxycycline has a higher concentration in plasma. The different sites at which the two agents block bacteria from producing proteins by different but complementary mechanisms may be the reason why combination therapy is able to eliminate pathogens faster.

No typical symptoms

Epidemic typhus is transmitted to humans through bites from small infected tick larvae. Mites breed from July to March. Only the larval stage of ticks requires blood meal, usually from rodents.

“The larvae are invisible to the naked eye and don’t hurt when they bite, so people don’t realize they’ve been bitten and possibly infected,” says Dr. Varghese. Infections do not cause typical symptoms, making accurate and early diagnosis difficult. Awareness of infection and disease is also very low despite the high burden of disease and mortality. Raising awareness can clearly lower mortality, as researchers at CMC Vellore have demonstrated.

“From 2005 to 2006, the mortality rate among patients presenting to our hospital was 15%. With increased awareness and early diagnosis, even monotherapy reduced the mortality rate from 15% to 6% in about 10 years.” ,” he recalls.