What is the recommended treatment for syphilis?

Treatment of Syphilis

Benzathine penicillin G is the recommended first-line treatment for syphilis across all stages, with dosing regimens specific to the stage of infection. 1

Treatment Regimens by Stage

Primary, Secondary, and Early Latent Syphilis

• First-line treatment: Benzathine penicillin G, 2.4 million units IM in a single dose 1, 2
• For children: Benzathine penicillin G, 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose 2

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
• If a dose is missed during weekly therapy, clinical experience suggests an interval of 10-14 days between doses might be acceptable before restarting the sequence, though 7-9 days may be more optimal 3

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
• CSF examination should be performed to diagnose neurosyphilis in persons with neurological signs/symptoms, tertiary syphilis, or when serological titers don't decline appropriately after treatment 3

Alternative Treatments for Penicillin-Allergic Patients (Non-Pregnant)

• Doxycycline: 100 mg orally twice daily for 14 days (early syphilis) or 28 days (late syphilis) 1, 3
• Tetracycline: 500 mg orally four times daily for 14 days (early syphilis) or 28 days (late syphilis) 1
• For pregnant patients with penicillin allergy: Desensitization to penicillin followed by standard treatment is required, as no alternatives are effective 1, 4

Special Populations

Pregnant Women

• Penicillin is the only recommended treatment, regardless of allergy status 1
• Missed doses are not acceptable for pregnant women 3

HIV-Infected Patients

• Treatment regimens are the same as for HIV-negative patients 1
• Requires closer follow-up monitoring 1
• No added benefit to enhanced antimicrobial therapy when treating HIV-infected persons with syphilis 3

Follow-Up and Monitoring

• Non-treponemal quantitative tests (RPR or VDRL) should be repeated at 6,12, and 24 months after treatment 1
• Treatment success is indicated by a fourfold decrease in titers within 6-12 months for primary/secondary syphilis and 12-24 months for latent/late syphilis 4
• CSF examination should be performed if:
  • Titers increase fourfold
  • An initially high titer (≥1:32) fails to decline at least fourfold within 12-24 months
  • Signs or symptoms attributable to syphilis develop 1

Contact Tracing and Prevention

• All sexual contacts exposed within 90 days of diagnosis of primary, secondary, or early latent syphilis should be treated presumptively, even if seronegative 1, 2
• For contacts exposed >90 days before examination, treat presumptively if serologic test results aren't immediately available and follow-up is uncertain 2
• Long-term contacts of patients with late latent syphilis should be evaluated clinically and serologically 2, 1

Important Clinical Considerations

• All patients with syphilis should be tested for HIV 2
• Patients with high-risk behaviors should undergo frequent serological screening 3
• Current BPG shortages may necessitate use of alternative regimens in some settings 5, but penicillin remains the gold standard treatment
• The Jarisch-Herxheimer reaction (fever, chills, headache) may occur within 24 hours of treatment, especially in patients with secondary syphilis 6

Despite decades of experience with penicillin treatment for syphilis, it remains highly effective with minimal resistance, making it the cornerstone of syphilis management for reducing morbidity, mortality, and improving quality of life.