Two-drug therapy for scrub typhus more effective than monotherapy
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A combination therapy of IV doxycycline and azithromycin was more effective for the treatment of severe scrub typhus than using either drug alone, according to findings published Wednesday in The New England Journal of Medicine.
A randomized controlled trial found that the two-drug combination was superior at reducing persistent complications by day 7 of treatment than monotherapy with either drug.
Complications from severe scrub typhus — which is caused by the bacteria Orientia tsutsugamushi and spread through the bite of infected chiggers — can be substantial and cause death. Although the mean case fatality rate is about 6%, researchers estimate it can reach 70% in severe disease, according to the authors of the new study.
Roughly 1 billion people are estimated to be at risk for scrub typhus in endemic areas, with about 1 million new cases per year and 150,000 deaths linked to the infection, according to the authors.
“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 is a matter of speculation,” George M. Varghese, MD, a professor and head of the department of infectious diseases at Christian Medical College in Vellore, India, and colleagues wrote.
“Better bacterial control during the critical first week of infection may result in prevention and faster resolution of severe manifestations of the illness,” they said.
Varghese and colleagues screened 1,684 patients for eligibility from Sept. 27, 2018, through Feb. 11, 2022, and randomly assigned 794 of them into three groups — 265 in the doxycycline group, 263 in the azithromycin group and 266 in the combination therapy group.
Participants in all three groups had similar demographic and clinical characteristics at baseline and ranged in age from 15 to 95 years; 54% were male. Nearly all patients presented with fever that had lasted for about 7 days, with the most common complications determined to be respiratory (62%), hepatic (54%), cardiovascular (42%), renal (42%) and neurologic (20%), the researchers reported. Treatment adherence was high in all three groups, ranging between 97% and 98%.
The use of combination therapy resulted in lower incidence of death than doxycycline monotherapy, 33% vs. 47%, for a risk difference of –13.3 percentage points (95% CI, –21.6 to –5.1). Incidence of death was also lower among the combination therapy group than the azithromycin group, in which it was 48%, leading to a risk difference of –14.8 percentage points (95% CI, –23.1 to 10).
“This important scientific progress in the treatment of scrub typhus emphasizes the need for rapid early diagnosis and effective prevention,” David H. Walker, MD, and Lucas S. Blanton, MD, said in an accompanying editorial.
In the editorial, Walker, who is executive director of the University of Texas Medical Branch’s (UTMB) Center for Biodefense and Emerging Infectious Disease, and Blanton, an infectious disease physician and professor at UTMB, point out that the disease has spread from already endemic areas to new ones.
The new findings on combination therapy for scrub typhus, they said, may offer significant benefits in underdeveloped areas where the infection is endemic but availability of advanced supportive care is limited.
“Patients often present for care before diagnostic antibodies have developed, and molecular diagnostics are unlikely to be available in primary community clinics,” they said. “Development of an easy-to-use, sensitive, diagnostic test could foster earlier appropriate treatment and alert the clinic staff to the local prevalence of scrub typhus, which would lead to earlier antimicrobial treatment of many patients with this difficult-to-diagnose, acute, undifferentiated febrile illness.”
References:
- Li Z, et al. Emerg Infect Dis. 2020;doi:10.3201/eid2606.191168.
- Varghese G M, et al. N Engl J Med. 2023;doi:10.1056/NEJMoa2208449.
- Walker DH, Blanton LS. N Engl J Med. 2023;doi:10.1056/NEJMe2200113.
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