Evaluation of Oral Doxycycline, Azithromycin, or Sequential Doxycycline-Azithromycin Treatment for Scrub Typhus.

Background: Scrub typhus is a leading cause of febrile illness across the Asia-Pacific region. Doxycycline is the first-line therapy, with azithromycin as an alternative; sequential treatment (doxycycline followed by azithromycin) is used for nonresponders. However, comparative real-world effectiveness for sequential therapy remains uncertain. Methods: We conducted a single-center, non-interventional target-trial emulation at the 970th Hospital of the People's Liberation Army (January 2023 - June 2025). Consecutive patients ≥12 years receiving oral doxycycline, azithromycin, or sequential doxycycline/azithromycin treatment were included. The primary outcome was 48-hour defervescence sustained ≥24 h without antipyretics. Secondary outcomes were time to defervescence, Day 5 failure, complications, length of stay, 28-day mortality, and safety. Confounding was addressed using inverse probability weighting (generalized boosted models). The confirmatory comparison (doxycycline vs azithromycin) was limited to non-pregnant initiators (pregnancy excluded due to structural non-overlap) to satisfy positivity. The sequential pathway was explored descriptively with time-varying and 48-hour landmark analyses. Results: We analyzed 512 patients (doxycycline 206, azithromycin 208, and sequential 98). Crude 48-hour defervescence was 82.0%, 78.8%, and 66.3%, respectively. In the confirmatory inverse probability of treatment weighting (IPTW) analysis, doxycycline vs azithromycin showed no difference (adjusted RR 1.03, 95% CI 0.95-1.12; p=0.34). Weighted time-to-event analysis was concordant (aHR 1.08, 95% CI 0.96-1.21; p=0.20). Secondary outcomes were similar between monotherapies (Day-5 failure aRR 0.83, 95% CI 0.56-1.24; complications aRR 0.94, 95% CI 0.66- 1.33; median length of stay 5 [IQR 4-7] days in both; 28-day mortality 1.6% overall). The sequential switch group had lower crude 48-hour defervescence, consistent with escalation after early non-response. Pairwise causal contrasts involving the sequential pathway were not presented due to structural bias. Conclusions: Oral doxycycline and azithromycin demonstrated comparable effectiveness and safety for early defervescence in routine care. Inferior crude outcomes with sequential therapy likely reflect clinical escalation. Multi-center validation and randomized trials are warranted.