Intravenous Doxycycline, Azithromycin, or Both for Severe Scrub Typhus

   This multicenter, double-blind, randomized trial (INTREST) compared intravenous doxycycline, azithromycin, and combination therapy for severe scrub typhus across 794 patients aged ≥15 years with organ involvement. Combination therapy significantly reduced the composite primary outcome (death at day 28, persistent complications at day 7, persistent fever at day 5) compared to doxycycline (33% vs. 47%; risk difference –13.3 percentage points; P = 0.002) and azithromycin (33% vs. 48%; –14.8 percentage points; P < 0.001). Monotherapies had comparable outcomes. While mortality, fever clearance, and ICU metrics were similar, PCR negativity for Orientia tsutsugamushi occurred faster with azithromycin-containing regimens. Safety profiles were comparable. Authors suggest intravenous doxycycline plus azithromycin as a preferred regimen for severe scrub typhus.

   This multicenter, double-blind, randomized trial (INTREST) compared intravenous doxycycline, azithromycin, and combination therapy for severe scrub typhus across 794 patients aged ≥15 years with organ involvement. Combination therapy significantly reduced the composite primary outcome (death at day 28, persistent complications at day 7, persistent fever at day 5) compared to doxycycline (33% vs. 47%; risk difference –13.3 percentage points; P = 0.002) and azithromycin (33% vs. 48%; –14.8 percentage points; P < 0.001). Monotherapies had comparable outcomes. While mortality, fever clearance, and ICU metrics were similar, PCR negativity for Orientia tsutsugamushi occurred faster with azithromycin-containing regimens. Safety profiles were comparable. Authors suggest intravenous doxycycline plus azithromycin as a preferred regimen for severe scrub typhus.