What is the recommended retreatment regimen for syphilis in patients who do not respond to initial treatment?

Recommended Retreatment Regimen for Syphilis Treatment Failure

For patients who do not respond to initial syphilis treatment, the recommended retreatment regimen is benzathine penicillin G 2.4 million units IM administered at 1-week intervals for 3 weeks (total 7.2 million units), after excluding neurosyphilis through CSF examination. 1

Definition of Treatment Failure

Treatment failure in syphilis is defined by:

1. A sustained fourfold increase in serum nontreponemal titers after an initial reduction following treatment
2. Persistent or recurring clinical signs or symptoms of disease
3. Failure to achieve at least a fourfold decrease in nontreponemal titers within the expected timeframe:
   • 6-12 months for early syphilis
   • 12-24 months for late latent syphilis 1

Evaluation Before Retreatment

Before initiating retreatment, the following steps are essential:

• Perform CSF examination to rule out neurosyphilis
• Evaluate for HIV infection, as HIV-infected persons may be at increased risk for treatment failure 1
• Consider possibility of reinfection versus true treatment failure

Retreatment Regimens Based on Disease Stage

Early Syphilis (Primary, Secondary, Early Latent)

• If CSF examination is normal:

  • Benzathine penicillin G 2.4 million units IM weekly for 3 weeks 1

• If CSF examination suggests neurosyphilis:

  • Follow neurosyphilis treatment recommendations (see below)

Late Latent Syphilis or Syphilis of Unknown Duration

• If CSF examination is normal:

  • Benzathine penicillin G 2.4 million units IM weekly for 3 weeks 1
  • Some specialists also recommend adding a neurosyphilis regimen in this setting, though data supporting this practice are limited 1

• If CSF examination suggests neurosyphilis:

  • Follow neurosyphilis treatment recommendations

Neurosyphilis Retreatment

• Recommended regimen:

  • Aqueous crystalline penicillin G 18-24 million units daily, administered as 3-4 million units IV every 4 hours for 10-14 days 1

• Alternative regimen (if compliance can be ensured):

  • Procaine penicillin 2.4 million units IM daily PLUS
  • Probenecid 500 mg orally four times daily, both for 10-14 days 1

Special Considerations

Penicillin Allergy

For non-pregnant patients allergic to penicillin with no evidence of neurosyphilis:

• Early syphilis: Doxycycline 100 mg orally twice daily for 2 weeks OR Tetracycline 500 mg orally four times daily for 2 weeks 2, 3

• Late latent syphilis: Doxycycline 100 mg orally twice daily for 4 weeks OR Tetracycline 500 mg orally four times daily for 4 weeks 2, 3

• For pregnant patients allergic to penicillin: Desensitization followed by appropriate penicillin regimen is required 1

Post-Retreatment Monitoring

• Quantitative nontreponemal serologic tests should be repeated at 6,12, and 24 months 1
• For neurosyphilis retreatment: Repeat CSF examination at 6 months after completion of therapy 1
• If titers do not respond appropriately after retreatment, the value of additional CSF examination or therapy is not well established 1

Clinical Considerations and Pitfalls

• Recent research suggests limited benefit of retreatment in serofast patients. A study showed only 48.6% of serofast early syphilis patients achieved serological cure after retreatment 4, while another found no significant benefit from repeated retreatments 5

• Higher baseline nontreponemal titers may predict better response to retreatment 4

• Neurosyphilis is uncommon in HIV-negative patients with serological nonresponse, with one study finding only 3% meeting neurosyphilis criteria after retreatment 6

• The serofast state (persistent low-level titers despite adequate treatment) may not represent treatment failure but rather a serological scar 1

• Patients with HIV infection might be at increased risk for treatment failure and neurologic complications, though the magnitude of these risks is likely low 1