Treatment outcomes of oral doxycycline versus intravenous azithromycin in adults hospitalized with scrub typhus: A retrospective study using inverse probability treatment weighting (IPTW) propensity analysis

Objective: Only a few well-designed studies that have investigated the effectiveness of azithromycin in treating adult patients hospitalized with scrub typhus are currently available. The purpose of our study was to compare the effects of intravenous azithromycin administration with those of oral doxycycline, and to evaluate cardiovascular death associated with intravenous azithromycin in adult patients hospitalized with scrub typhus. Methods: This retrospective study investigated Korean National Infectious Disease Cohort Collaborative-registered scrub typhus-infected patients who were hospitalized between January 1, 2013, and December 31, 2021, and who were ≥18 years old. The primary outcome was time to fever clearance and the secondary outcomes were treatment failure, relapse, scrub typhus-related death, or azithromycin-related cardiovascular death. To address any indication bias, inverse probability of treatment weighting (IPTW) analysis was performed. Times to fever clearance between the doxycycline and azithromycin groups were compared using log-rank tests and Kaplan–Meier curves. Results: A total of 326 consecutive patients with laboratory-confirmed scrub typhus were included in this study of whom 109 were treated with azithromycin and 217 with doxycycline. Using IPTW, there were no statistically significant differences in the following end points between the azithromycin and doxycycline groups: median time to fever clearance (3 days vs. 3 days, P = 0.649), treatment failure (0.71% vs. 0.42%, P = 0.702), relapse (0.0% vs. 0.0%), and scrub typhus-related death (5.12% vs. 0.0%, P = 0.155). No azithromycin-related cardiovascular deaths occurred. In the sensitivity analyses, there were no significant changes in effect size. Conclusions: Our study showed that the therapeutic effects and safety of intravenous azithromycin are comparable to those of oral doxycycline administration in patients hospitalized with scrub typhus. A well-designed randomized controlled trial may help further evaluate the most adequate route of administration, dose and duration of treatment with azithromycin.