What is the recommended treatment for syphilis?

Syphilis Treatment

Benzathine penicillin G is the recommended first-line treatment for syphilis, with dosing dependent on the stage of infection: 2.4 million units IM as 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 Recommendations by Stage

Early Syphilis (Primary, Secondary, Early Latent)

• First-line: Benzathine penicillin G 2.4 million units IM as a single dose 1
• Alternative regimens (for non-pregnant, penicillin-allergic patients without neurosyphilis):
  • Doxycycline 100 mg orally twice daily for 14 days 1
  • Tetracycline 500 mg orally four times daily for 14 days 1
  • Ceftriaxone 1 g IV/IM daily for 10 days 1

Late Latent Syphilis or Latent Syphilis of Unknown Duration

• First-line: Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM at 1-week intervals 1
• Alternative regimens (for non-pregnant, penicillin-allergic patients without neurosyphilis):
  • Doxycycline 100 mg orally twice daily for 28 days 1
  • Tetracycline 500 mg orally four times daily for 28 days 1

Neurosyphilis

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

Special Populations

Pregnant Women

• Only recommended treatment: Penicillin G (appropriate for stage) 1
• If penicillin allergic: Desensitization is required, as no alternative treatments are proven effective during pregnancy 1

HIV-Infected Patients

• Same regimens as HIV-negative patients, but with closer follow-up 1

Treatment 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 months for primary and secondary syphilis
  • 24 months for late latent syphilis 1
• Approximately 15% of patients may not meet standard criteria for serological cure 12 months after adequate treatment 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 Considerations and Precautions

• When administering penicillin G, monitor for potential allergic reactions, especially in patients with histories of significant allergies or asthma 2, 3
• For high-dose IV penicillin G (above 10 million units), administer slowly due to potential electrolyte imbalance from potassium content 3
• 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, but for pregnant women, the full course must be repeated if any dose is missed 1
• Treatment failure is indicated by persistent or recurrent signs/symptoms, a sustained fourfold increase in non-treponemal tests, or failure to observe the expected fourfold decrease in titers 1

While some studies have explored alternative treatments like azithromycin 4, 5, the CDC continues to recommend penicillin as the first-line treatment for all stages of syphilis due to its proven efficacy and the increasing concerns about antimicrobial resistance with other agents.