Updated therapeutic options for human brucellosis: A systematic review and network meta-analysis of randomized controlled trials

Background: In clinical practice guidelines, there is no consensus about the medications that should be initially offered to patients with brucellosis. To provide informative evidence, we compared and ranked brucellosis medications based on their efficacy and safety. Methods: For this systematic review and network meta-analysis, we searched 4 English databases and 3 Chinese databases, from the date of database inception to December 13, 2023. We included randomized controlled trials (RCTs) involving children and adolescents with brucellosis, comparing different antibiotic regimens. We excluded studies explicitly targeting patients with spondylitis brucellosis, endocarditis brucellosis, and neuro-brucellosis. The primary outcomes were overall failure (efficacy) and side effects (safety). Secondary outcomes were relapse and therapeutic failure. Pairwise meta-analysis was first examined. Data were analyzed using random effects network meta-analysis, with subgroup and sensitivity analyses performed. The Confidence in Network Meta-Analysis (CINeMA) framework was used to assess the certainty of evidence. The protocol was preregistered in PROSPERO (CRD42023491331). Results: Of the 11,747 records identified through the database search, 43 RCTs were included in the network meta-analysis. Compared with standard therapy (Doxycycline + Rifampicin), Rifampicin + Tetracyclines (RR 4.96; 95% CI 1.47 to 16.70; very low certainty of evidence), Doxycycline + TMP/SMX (RR 0.18; 95% CI 0.06 to 0.52; low certainty of evidence), Doxycycline + Quinolones (RR 0.27; 95% CI 0.11 to 0.71; low certainty of evidence), Streptomycin + Tetracyclines (RR 0.04; 95% CI 0.01 to 0.16; low certainty of evidence), and Single (RR 0.05; 95% CI 0.02 to 0.16; moderate certainty of evidence) were less efficacious. Doxycycline + Gentamicin ranked the best in efficacy (SUCRA values: 0.94), the second is Triple (SUCRA values: 0.87), and the third is Doxycycline + Streptomycin (SUCRA values: 0.78). Conclusions: Brucellosis medications differ in efficacy and safety. Doxycycline + Gentamicin, Triple, and Doxycycline + Streptomycin have superior efficacy and safety. Treatment of brucellosis should strike a balance between efficacy, safety, and cost. Author summary: Brucellosis, with nearly 500,000 new cases outbreak in more than 170 countries or regions worldwide each year, is a zoonotic infectious disease caused by Brucella. Due to the lack of an effective human vaccine and the impracticality of eradicating brucellosis in animals globally, treatment remains the primary strategy for addressing human brucellosis. However, there is no consensus in clinical practice guidelines regarding the initial medications for brucellosis treatment. Therefore, we compared and ranked brucellosis medications based on their efficacy and safety to aid clinicians in matching risk/benefits of drugs to brucellosis treatment. In this systematic review and network meta-analysis of 43 randomized clinical trials with 4,283 patients, 6 weeks of doxycycline plus 1 to 2 weeks of gentamicin or plus 2 to 3 weeks of streptomycin is the best therapy for human brucellosis. Six weeks of rifampicin plus quinolones treatment is considered as an alternative therapy. If finances allow, consider triple therapy. Single, Streptomycin + Tetracyclines, Streptomycin + TMP/SMX, and Rifampicin + TMP/SMX therapies cannot currently be recommended.