1. In this randomized controlled trial, combination therapy with intravenous (IV) doxycycline and azithromycin was superior to monotherapy with either drug alone for severe scrub typhus.
2. Combination therapy with IV doxycycline and azithromycin resulted in lower complications of severe scrub typhus as compared to monotherapy.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Severe scrub typhus is a life-threatening zoonotic bacterial infection caused by Orientia tsutsugamushi and is endemic in Asia and Northern Australia. Scrub typhus typically presents as an acute febrile illness that may be associated with headache, cough, shortness of breath, and altered sensorium. An eschar at the site of the mite bite serves as a highly distinctive diagnostic clue. Historically, scrub typhus has been treated with doxycycline or chloramphenicol, though there is a gap in knowledge as to what the most appropriate treatment option is for severe scrub typhus. Overall, this study found that combination therapy with intravenous doxycycline and azithromycin is a better therapeutic option for the treatment of severe scrub typhus than monotherapy with either drug. This study was limited by not being generalizable to young children and pregnant women. Nevertheless, these study’s findings are significant, as they demonstrate that doxycycline and azithromycin combined will serve as the most appropriate treatment for severe scrub typhus, and this regimen is superior to monotherapy with either antibiotic alone.
Click to read the study in NEJM
Relevant Reading: Progress in Treating a Neglected Tropical Disease
In-Depth [randomized controlled trial]: This multicenter superiority trial was conducted at seven sites across India. Patients who were age 18 years of age or older, with severe scrub typhus as assessed by lateral flow assay of a whole blood sample or an eschar and with involvement of at least one organ that led to IV treatment, were eligible for the study. Patients who had received treatment with doxycycline, azithromycin, or chloramphenicol for more than 24 hours within three days before recruitment; pregnancy or breast-feeding; treatment with antitubercular therapy (because rifampicin has activity against O. tsutsugamushi); documentation of immune suppression; treatment with contraindicated concomitant drugs; or any previous adverse reaction to a trial drug were excluded from the study. The primary outcome measured was a composite measure of death from any cause on day 28, persistent complications on day seven, and persistent fever on day five. Based on the primary analysis, the use of combination therapy resulted in a lower incidence of the composite primary outcome than the use of doxycycline (33% and 47%, respectively), for a risk difference of −13.3% (95% Confidence Interval [CI], −21.6 to −5.1; P = 0.002). The incidence with combination therapy was also lower than that with azithromycin (48%), for a risk difference of −14.8% (95% CI, −23.1 to −6.5; p<0.001). No significant difference was seen between the azithromycin and doxycycline groups (risk difference, 1.5%; 95% CI, −7.0 to 10.0; p=0.73). Overall, this study demonstrates that combination therapy with IV doxycycline and azithromycin was a better option for treating severe scrub typhus than monotherapy with either azithromycin or doxycycline and will help guide management for scrub typhus in the future.
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