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

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.

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.

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.

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.