What is the recommended treatment regimen for syphilis?

Syphilis Treatment Recommendations

The recommended treatment for syphilis is benzathine penicillin G, with dosing based on the stage of infection: 2.4 million units IM in a single dose for primary, secondary, and early latent syphilis, and 7.2 million units total (administered as 3 doses of 2.4 million units IM at 1-week intervals) for late latent syphilis or latent syphilis of unknown duration. 1

Treatment Regimens by Stage

Early Syphilis (Primary, Secondary, Early Latent)

• First-line treatment: Benzathine penicillin G 2.4 million units IM in a single dose 1
• Alternative treatment (for penicillin-allergic patients):
  • Doxycycline 100 mg orally twice daily for 14 days 1, 2
  • Ceftriaxone 1 g IV/IM daily for 10 days 1
  • Tetracycline 500 mg orally four times daily for 14 days 1

Late Latent Syphilis or Latent Syphilis of Unknown Duration

• First-line treatment: Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM at 1-week intervals 1
• Alternative treatment (for penicillin-allergic patients):
  • Doxycycline 100 mg orally twice daily for 4 weeks 1, 2
  • Tetracycline 500 mg orally four times daily for 28 days 1

Neurosyphilis

• First-line treatment: Penicillin G aqueous 18-24 million units IV daily, administered as 3-4 million units every 4 hours for 10-14 days 1, 3

Special Populations

Pregnant Women

• Only penicillin is proven effective for preventing congenital syphilis
• If penicillin allergic, desensitization is required (no alternatives) 1
• Missed doses are never acceptable; the full course must be repeated if any dose is missed 1

HIV-Infected Patients

• Same regimens as HIV-negative patients but with closer follow-up 1
• Research shows single-dose benzathine penicillin G is effective for early syphilis in HIV-infected patients 4

Treatment Administration Considerations

• If a patient misses a dose in the weekly therapy schedule for late latent syphilis, an interval of 10-14 days between doses might be acceptable before restarting the sequence 1
• For benzathine penicillin injections, both single-dose (2.4 million units) and divided doses (1.2 million units in each buttock) are equally well tolerated 5

Monitoring and Follow-up

• Quantitative nontreponemal serologic tests (RPR or VDRL) should be repeated at 6,12, and 24 months 1
• Treatment success is indicated by a fourfold decline in titers within 12-24 months 1
• Approximately 15% of patients may not meet standard criteria for serological cure 12 months after adequate treatment 1
• Treatment failure criteria:
  • Persistent or recurring signs/symptoms
  • Sustained fourfold increase in non-treponemal tests
  • Failure to observe expected fourfold decrease in titers 1

Partner Management

• All sexual partners should be evaluated clinically and serologically for syphilis 1
• Partners exposed within 90 days of diagnosis should be treated presumptively even if seronegative 1
• Partners exposed >90 days before diagnosis should be treated based on clinical and serological evaluation 1

Important Caveats

• Doxycycline appears effective for early syphilis treatment in penicillin-allergic patients 6, but penicillin remains the gold standard
• After late latent syphilis treatment, up to 56% of patients may have persistently positive reagin tests despite adequate therapy 7
• Azithromycin has shown efficacy equivalent to benzathine penicillin for early syphilis in non-HIV infected persons 8, but is not included in current CDC recommendations due to concerns about resistance

Treatment Algorithm

1. Determine syphilis stage based on clinical presentation and duration of infection
2. Assess for penicillin allergy
3. For non-allergic patients: Administer appropriate penicillin regimen based on stage
4. For penicillin-allergic patients:
   • If pregnant: Perform penicillin desensitization and treat with penicillin
   • If non-pregnant: Use appropriate alternative regimen based on stage
5. Schedule follow-up for serologic testing at 6,12, and 24 months
6. Evaluate and treat all sexual partners according to exposure timing