INTRAVENOUS DOXYCYCLINE OR AZITHROMYCIN OR A COMBINATION OF THE TWO FOR TREATMENT OF SEVERE SCRUB TYPHUS: A RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL

Abstract

Intro: Scrub typhus, a life-threatening zoonotic bacterial infection caused by Orientia tsutsugamushi, transmitted by trombiculid mite larvae, is a public health challenge even beyond the ‘tsutsugamushi triangle’, its traditional endemic region in South and Southeast Asia. A billion people are estimated to be at risk in endemic regions, with an estimated one million cases and 150,000 deaths annually. The optimal antibiotic treatment for severe scrub typhus is unclear. Methods: This multi-centre, double-blind, randomised controlled trial compared the efficacy of intravenous azithromycin, doxycycline, or a combination of both in treating severe scrub typhus. Patients older than 15-years with severe scrub typhus with at least one organ involvement were enrolled. Participants underwent block randomization to be assigned in a 1:1:1 ratio to receive 7-day courses of intravenous doxycycline, azithromycin, or both. The primary outcome was a composite of all-cause mortality at day 28, persisting complications on day-7, and persisting fever on day-5. Secondary outcomes included all-cause mortality at 28 days, measures of recovery, treatment safety, and rate of bacterial clearance. Findings: Among 794 participants (median age 48-years), respiratory, hepatic, cardiovascular, renal, and neurological involvement was observed in 62%, 54%, 42%, 30%, and 20%, respectively. In the intention-to-treat analysis, combination therapy resulted in a lower composite outcome than doxycycline (risk difference (RD): -13.3%; 95% CI: -21.6%, -5.1%; P=0.002) or azithromycin (RD: -14.8%; 95% CI: -23.1%, -6.5%; P<0.001). The per-protocol analysis population showed a similar superiority. No significant difference was found between the azithromycin and doxycycline groups (RD: 1.5%; 95% CI: -7.0%, 10.0%; P=0.73). The between-group difference in the composite outcome was mainly due to persisting complications on day 7. Adverse events and 28-day mortality were similar between groups. Discussion: Reporting a practice-changing study Conclusion: Combination therapy with intravenous doxycycline and azithromycin is a better therapeutic option for the treatment of severe scrub typhus than monotherapies of either drug.