What is the recommended treatment regimen for uncomplicated brucellosis in adults?

Treatment for Brucellosis

For uncomplicated brucellosis in adults, treat with doxycycline 100 mg twice daily for 6 weeks combined with either streptomycin 15 mg/kg daily intramuscularly for 2-3 weeks OR rifampicin 600-900 mg daily for 6 weeks. These two regimens are considered equally effective first-line options with the highest level of evidence (AI recommendation) 1.

First-Line Treatment Regimens

The Ioannina Recommendations, published in PLoS Medicine and representing international expert consensus, establish two gold-standard regimens 1:

Option 1: Doxycycline + Streptomycin (DOX-STR)

• Doxycycline: 100 mg orally twice daily for 6 weeks
• Streptomycin: 15 mg/kg intramuscularly daily for 2-3 weeks
• Strength: AI recommendation (highest evidence level)

Option 2: Doxycycline + Rifampicin (DOX-RIF)

• Doxycycline: 100 mg orally twice daily for 6 weeks
• Rifampicin: 600-900 mg orally once daily (morning dose) for 6 weeks
• Strength: AI recommendation (highest evidence level)

Both regimens have comparable relapse rates of 5-15% in uncomplicated cases 1, 2. The choice between them depends primarily on practical considerations rather than efficacy differences.

Preferred Alternative: Doxycycline + Gentamicin

Doxycycline + Gentamicin (DOX-GENT) is an acceptable alternative regimen 1:

• Doxycycline: 100 mg orally twice daily for 6 weeks
• Gentamicin: 5 mg/kg parenterally once daily for 7 days
• Strength: BI recommendation

This combination offers advantages over DOX-STR including wider gentamicin availability and preservation of streptomycin for tuberculosis treatment 1. Relapse rates are comparable to WHO-recommended regimens, though the optimal duration of gentamicin (5-14 days) requires further study 1.

Emerging Evidence: Sitafloxacin Monotherapy

Recent high-quality evidence from 2026 demonstrates that sitafloxacin 100 mg once daily for 6 weeks as monotherapy was non-inferior to doxycycline-rifampicin in a multicenter randomized trial 3. The clinical response rate was 89.9% (intention-to-treat) and 97.3% (per-protocol) with only 2.7% relapse rate. Notably, sitafloxacin showed numerically lower adverse events (10.9% vs 19.3%) and treatment discontinuation (2.5% vs 6.7%), though not statistically significant. This represents a potential paradigm shift, as monotherapy has historically been considered inadequate.

Second-Line Options

When first-line regimens cannot be used 1:

• TMP-SMX-containing regimens: Trimethoprim-sulfamethoxazole 800/160 mg twice daily for 6 weeks (CII recommendation) - historically associated with high relapse rates up to 46% when used alone 1
• Quinolone combinations: Ofloxacin 400 mg or ciprofloxacin 500 mg twice daily for 6 weeks in combination with doxycycline (CII recommendation) - not recommended as first-line due to cost and fluoroquinolone resistance concerns 1

Triple-Drug Regimens

A 2025 network meta-analysis found that DOX + STR + hydroxychloroquine ranked highest in comparative effectiveness (RR: 1.25,95% CI: 1.07-1.45) 4. However, this finding requires validation in prospective trials before routine adoption, as the Ioannina guidelines do not include triple therapy as standard for uncomplicated cases.

Critical Treatment Principles

Duration matters: Six weeks of doxycycline is essential. Shorter courses increase relapse risk significantly 1, 2. Patients who interrupt therapy or receive inadequate treatment duration are at highest risk for relapse 2.

Combination therapy is mandatory: Monotherapy (except potentially sitafloxacin based on emerging data) results in unacceptably high relapse rates. Even doxycycline alone, despite one well-designed trial showing similar relapse rates to DOX-RIF, is not recommended due to resistance concerns 1.

Relapse rates remain 5-15% even with optimal treatment 1. Relapses are usually mild and respond to the same regimens, but represent significant morbidity.

Common Pitfalls to Avoid

1. Premature treatment discontinuation: Patients often stop antibiotics early when symptoms improve, leading to relapse 2
2. Inadequate follow-up: Patients who miss follow-up appointments have higher relapse rates 2
3. Using rifampicin in TB-endemic areas without careful consideration: This can promote mycobacterial resistance with broader public health implications 1
4. Monotherapy with traditional agents: Except for sitafloxacin (based on recent evidence), monotherapy is inadequate 1
5. Osteoarticular involvement: These patients require longer treatment and have higher relapse risk - ensure adequate aminoglycoside duration 2

Special Populations

Pregnant women: Rifampicin + trimethoprim-sulfamethoxazole is most commonly used, though adverse obstetric outcomes occur in approximately 16% of cases 5. Ceftriaxone has been used in neurobrucellosis during pregnancy 2. Tetracyclines and fluoroquinolones are contraindicated.

Practical Algorithm

1. Confirm diagnosis through serology (tube agglutination test) and/or blood culture
2. Assess for complications: osteoarticular involvement, neurobrucellosis, endocarditis, pregnancy
3. For uncomplicated cases, choose:
   • DOX-STR if streptomycin available and patient can tolerate IM injections
   • DOX-RIF if all-oral regimen preferred or streptomycin unavailable
   • DOX-GENT as alternative if gentamicin more accessible
   • Consider sitafloxacin monotherapy based on emerging evidence if available
4. Ensure 6-week duration with close monitoring for adherence
5. Follow for 12 months to detect relapses