Comparison of sitafloxacin monotherapy versus doxycycline plus rifampicin for acute uncomplicated human brucellosis: a multicenter, randomized, open-label, non-inferiority trial

Background Sitafloxacin has demonstrated superior in vitro activity against Brucella species. However, its potential for treating human brucellosis has not been investigated yet. Therefore, this study evaluated and compared the effects of definitive treatment with sitafloxacin monotherapy to those of doxycycline–rifampicin in patients with acute uncomplicated brucellosis. Methods This multicenter, open-label, randomized, non-inferiority clinical trial was conducted from August 2023 to July 2025 at three hospitals in China and included 238 adult patients with brucellosis symptoms for less than 3 months who met the study criteria. They were randomized in a 1:1 ratio to receive sitafloxacin monotherapy (100 mg once daily) or combined doxycycline (100 mg every 12 h) and rifampicin (10 mg/kg daily) for 6 weeks. Adherence, efficacy, and safety were evaluated over a 12-month follow-up period. The primary outcome was the clinical response rate at the end of 6 weeks, and the secondary outcomes were treatment failure rate, relapse during follow-up, and safety profiles. The non-inferiority margin was 12%. Findings In the intention-to-treat population, the clinical response rate was 89.9% in the sitafloxacin group and 83.2% in the doxycycline–rifampicin group (risk difference [RD] = 6.7%; 95% CI: −2.0 to 15.7). In the per-protocol population, the response rates were 97.3% and 96.1%, respectively (RD, 1.2%; 95% CI: −4.4 to 7.2). The symptom relapse rates were 2.7% and 1.9% in the sitafloxacin and doxycycline–rifampicin groups, respectively (RD, 0.8%; 95% CI: –4.4 to 6.0). The adverse event-related treatment discontinuation rate was numerically lower in the sitafloxacin group (2.5% vs. 6.7%, RD, –4.20%; 95% CI: –10.5 to 1.3), although the difference did not reach statistical significance. Similarly, the overall incidence of treatment-related adverse events was also numerically lower in the sitafloxacin group (10.9% vs. 19.3%; p = 0.07). These results met the prespecified criterion for non-inferiority. Interpretation Sitafloxacin monotherapy was non-inferior to doxycycline–rifampicin for treating acute uncomplicated brucellosis, and showed a favorable safety and tolerability profile. Thus, sitafloxacin monotherapy may have potential as an alternative regimen in this clinical setting. Funding This work was supported by the National Key Research and Development Program of China (2023YFC2308800)and the Natural Science Foundation of Shandong Province (ZR2023MH169). Trial registration ChiCTR2300072703.