What is the recommended treatment for syphilis?

Treatment for Syphilis

Parenteral penicillin G is the treatment of choice for all stages of syphilis, with specific regimens determined by the stage of infection. 1

Treatment Regimens by Stage

Primary, Secondary, and Early Latent Syphilis (< 1 year duration)

• First-line treatment: Benzathine penicillin G 2.4 million units IM in a single dose 1
• Clinical experience over 50+ years supports this regimen with 90-100% success rates 2

Late Latent Syphilis (> 1 year duration) or Syphilis of Unknown Duration

• First-line treatment: Benzathine penicillin G 2.4 million units IM once weekly for 3 consecutive weeks (total 7.2 million units) 1
• CSF examination should be performed in patients with neurologic signs/symptoms to rule out neurosyphilis

Tertiary Syphilis (excluding neurosyphilis)

• First-line treatment: Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals 1
• CSF examination should be performed before therapy is initiated 1

Neurosyphilis

• First-line treatment: Aqueous crystalline penicillin G 18–24 million units per day, administered as 3–4 million units IV every 4 hours or by continuous infusion, for 10–14 days 1
• Alternative regimen: Procaine penicillin 2.4 million units IM once daily PLUS probenecid 500 mg orally four times a day, both for 10–14 days 1
• Some specialists recommend additional benzathine penicillin G 2.4 million units IM once weekly for up to 3 weeks after completing neurosyphilis treatment 1

Special Populations

HIV-Infected Persons

• Treatment regimens are the same as for HIV-negative individuals 1
• Closer follow-up is recommended to detect potential treatment failure or disease progression 1
• Some specialists recommend three doses of benzathine penicillin for early syphilis in HIV-infected persons, but the benefit remains unproven 1

Pregnant Women

• Penicillin is the only documented effective treatment for syphilis during pregnancy 1
• Pregnant women with penicillin allergy should undergo desensitization and receive penicillin therapy 1
• Treatment regimens are the same as for non-pregnant adults based on stage of infection

Alternative Treatments for Penicillin-Allergic Patients (non-pregnant, non-neurosyphilis)

Primary and Secondary Syphilis

• Doxycycline: 100 mg orally twice daily for 14 days 1
• Ceftriaxone: May be considered with close clinical and serologic monitoring 1

Late Latent Syphilis

• Doxycycline: 100 mg orally twice daily for 28 days 1
• Tetracycline: 500 mg orally four times daily for 28 days 1

Important Clinical Considerations

• Jarisch-Herxheimer reaction: An acute febrile reaction with headache, myalgia, and other symptoms may occur within 24 hours after treatment, especially in early syphilis 1
• Follow-up: Clinical and serologic responses should be monitored at 3,6,9,12, and 24 months after therapy for early syphilis 1
• Serofast state: Some patients may remain seropositive despite adequate treatment; serologic response should be evident by 6 months in early syphilis but may take 12-24 months for latent syphilis 2
• Partner management: Sexual partners exposed within 90 days of diagnosis should be treated presumptively even if seronegative 1

Pitfalls and Caveats

1. Azithromycin is not recommended for syphilis treatment in the United States due to documented resistance 1
2. Oral penicillin preparations are not appropriate for treating syphilis 1
3. Penicillin desensitization is preferred over alternative antibiotics for pregnant women and patients with neurosyphilis 1
4. Benzathine penicillin G should not be confused with other penicillin preparations; the long-acting formulation is essential for maintaining treponemicidal levels 1
5. When treating late syphilis, missing a dose in the weekly regimen may require restarting the sequence if the interval exceeds 10-14 days 3

The evidence supporting penicillin as the treatment of choice for syphilis is based on decades of clinical experience rather than randomized controlled trials, but remains the gold standard due to consistent efficacy across all stages of infection 2.