What is the recommended treatment regimen for brucellosis, including options for resistant cases?

Brucellosis Investigation and Treatment

Diagnosis and Investigation

Blood cultures and serological testing (standard tube agglutination titer ≥1:160) are the primary diagnostic methods for brucellosis. 1

• Blood cultures should be obtained from all suspected cases, as isolation of Brucella species provides definitive diagnosis 2
• Standard tube agglutination testing with titers ≥1:160 combined with compatible clinical findings is diagnostic when cultures are negative 2
• MRI should be performed when spinal involvement (spondylitis) or neurological complications are suspected 3

First-Line Treatment for Uncomplicated Brucellosis

The optimal treatment is doxycycline 100 mg twice daily for 6 weeks combined with streptomycin 15 mg/kg daily intramuscularly for 2-3 weeks, which has the lowest relapse rates (5.3%) compared to other regimens. 1, 4, 2

Primary Regimen Options (in order of preference):

• Doxycycline-Streptomycin (DOX-STR): Doxycycline 100 mg twice daily orally for 6 weeks PLUS streptomycin 15 mg/kg daily IM for 2-3 weeks (AI recommendation) 5, 1, 4

  • This combination has demonstrated only 7.45% treatment failure/relapse rate versus 24% with doxycycline-rifampin 2
  • Considered the gold standard with superior efficacy 4

• Doxycycline-Gentamicin (DOX-GENT): Doxycycline 100 mg twice daily orally for 6 weeks PLUS gentamicin 5 mg/kg daily parenterally in single dose for 7 days (BI recommendation) 5, 1

  • Offers comparable efficacy to DOX-STR with the advantage of wider availability and shorter parenteral therapy duration 1
  • Relapse rates of 10-20% reported, approximately 5% higher than WHO-recommended regimens 1
  • Spares streptomycin for tuberculosis treatment 5

• Doxycycline-Rifampin (DOX-RIF): Doxycycline 100 mg twice daily orally for 6 weeks PLUS rifampin 600-900 mg daily as single morning dose for 6 weeks (AI recommendation) 5, 1, 4

  • Second-choice regimen due to higher relapse rates (16% vs 5.3% with DOX-STR) 4, 2
  • Avoid in regions where tuberculosis is endemic due to risk of mycobacterial resistance 1, 3, 4

Alternative Regimens (Second-Line)

• Trimethoprim-Sulfamethoxazole (TMP-SMX) combinations: TMP-SMX 800+160 mg twice daily for 6 weeks (CII recommendation) 5

  • Cost-effective alternative in resource-limited settings 1
  • Can be combined with doxycycline or rifampin 6
  • Response rates above 90% when used in combination 1

• Quinolone-containing regimens: Ofloxacin 400 mg twice daily OR ciprofloxacin 500 mg twice daily for 6 weeks (CII recommendation) 5

  • Reserved as second or third agents in combination regimens due to higher cost and risk of promoting antimicrobial resistance 5, 1
  • Should not be used routinely to preserve efficacy against respiratory pathogens 5

Treatment of Complicated Brucellosis

Brucellar Spondylitis:

• Aminoglycoside-containing regimens (DOX-STR or DOX-GENT) may be superior to rifampin-containing regimens 3, 4
• Treatment duration may need extension beyond standard 6 weeks depending on clinical response 4
• Immobilization of the spine is crucial if cervical involvement is present to prevent devastating neurological complications 3

Neurobrucellosis:

• Consider combination of doxycycline and rifampin with an aminoglycoside (preferably gentamicin over streptomycin) 3
• MRI is mandatory when spinal involvement is suspected 3

Brucellar Endocarditis:

• Requires aggressive management with empirical antimicrobial selection and surgical intervention in most cases due to high mortality 4

Management of Treatment-Resistant or Relapsed Cases

Relapses occur in 5-15% of cases even with appropriate treatment and are usually mild; they can be successfully treated with the same initial regimen. 1, 4

Approach to Resistance/Relapse:

• Re-treat with the same regimen if initial treatment was appropriate 1, 4
• If relapse occurs after DOX-RIF, switch to DOX-STR or DOX-GENT for superior efficacy 4, 2
• Consider extending treatment duration beyond 6 weeks for complicated cases 4
• For patients with focal disease (spondylitis, endocarditis), longer courses are required based on clinical evolution 7
• Triple-drug regimens containing doxycycline plus TMP-SMX plus another agent may be considered for refractory cases 5

Key Pitfalls to Avoid:

• Monotherapy should be avoided except in carefully selected low-risk patients, as it carries unacceptably high relapse rates (13% vs 4.8% with combination therapy) 6
• Short-term treatment (<4 weeks) results in significantly higher relapse rates (22% vs 4.8%) 6
• Do not use rifampin-containing regimens in tuberculosis-endemic areas due to resistance concerns 1, 3, 4
• Avoid fluoroquinolones as first-line agents to prevent community-wide resistance development 5

Special Populations

Pregnant Women:

• Rifampin 900 mg once daily for 6 weeks is the drug of choice 8
• Tetracyclines are contraindicated 8

Children <8 Years Old:

• Rifampin plus cotrimoxazole for 45 days is the preferred regimen 8, 6
• Alternative: Rifampin for 45 days with gentamicin 5-6 mg/kg/day for first 5 days 8
• Tetracyclines are contraindicated 8

Treatment Monitoring

• Standard treatment duration is 6 weeks for uncomplicated cases 1, 4
• Monitor for clinical response and adverse effects throughout treatment 2
• Follow-up is essential as relapses typically occur after treatment completion 1