What is the recommended treatment for syphilis?

Treatment for Syphilis

Benzathine penicillin G is the first-line treatment for all stages of syphilis, with dosing determined by disease stage: 2.4 million units IM as a single dose for early syphilis (primary, secondary, and early latent), or 7.2 million units total given as three weekly doses of 2.4 million units IM for late latent, latent of unknown duration, and tertiary syphilis. 1, 2

Treatment by Stage

Primary and Secondary Syphilis

• Benzathine penicillin G 2.4 million units IM as a single injection is the definitive treatment 1, 2, 3
• This regimen applies to both HIV-infected and non-HIV-infected patients 1, 2
• For children with acquired syphilis: benzathine penicillin G 50,000 units/kg IM (up to adult dose of 2.4 million units) as a single dose 1, 2

Early Latent Syphilis

• Same regimen as primary/secondary: benzathine penicillin G 2.4 million units IM single dose 1, 2
• Early latent is defined as syphilis acquired within the preceding year, documented by seroconversion, fourfold titer increase, history of symptoms within the past year, or having a sex partner with documented early syphilis 1

Late Latent Syphilis and Latent of Unknown Duration

• Benzathine penicillin G 7.2 million units total: three doses of 2.4 million units IM given at weekly intervals 1, 2, 3
• If a dose is missed, an interval of 10-14 days between doses may be acceptable before restarting the sequence 1
• For children: benzathine penicillin G 50,000 units/kg IM (up to adult dose of 2.4 million units) for three total doses at 1-week intervals (total 150,000 units/kg up to 7.2 million units) 1

Tertiary Syphilis

• Benzathine penicillin G 7.2 million units total: three doses of 2.4 million units IM at weekly intervals 1, 2

Neurosyphilis

• Aqueous crystalline penicillin G 18-24 million units per day IV (administered as 3-4 million units every 4 hours or continuous infusion) for 10-14 days 1, 4
• CSF examination is recommended for patients with neurological signs/symptoms, tertiary syphilis, treatment failure, HIV infection with late latent syphilis, or serum nontreponemal titer ≥1:32 1

Alternative Treatments for Penicillin Allergy

Non-Pregnant Adults

• For primary, secondary, or early latent syphilis: doxycycline 100 mg orally twice daily for 14 days 1, 2, 4
• For late latent syphilis: doxycycline 100 mg orally twice daily for 28 days 1, 2, 4
• Tetracycline 500 mg orally four times daily is an alternative (14 days for early syphilis, 28 days for late latent) 1
• Ceftriaxone 1 gram IV/IM daily for 10 days is a reasonable alternative based on randomized trial data showing comparable efficacy to benzathine penicillin 1

Critical Caveat: Azithromycin

• Azithromycin should NOT be used in the United States due to widespread macrolide resistance and documented treatment failures 1

Pregnant Women and Neurosyphilis

• Penicillin is the ONLY proven effective therapy for preventing maternal transmission and treating neurosyphilis 1, 2
• All pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment—no exceptions 1, 2, 4
• Pregnant women should be screened for syphilis at first prenatal visit, during third trimester, and at delivery 1

Special Populations

HIV-Infected Patients

• Treatment regimens are identical to non-HIV-infected patients 1, 2
• Limited data suggest no benefit to multiple doses of benzathine penicillin for early syphilis in HIV-infected patients compared to a single dose 1
• Closer follow-up is mandatory to detect potential treatment failure or disease progression 1

Children

• Children require CSF examination to exclude neurosyphilis before treatment 1
• Dosing is weight-based at 50,000 units/kg IM (up to adult dose) 1, 2

Follow-Up and Monitoring

Serologic Testing Schedule

• For primary/secondary syphilis: quantitative nontreponemal tests (RPR or VDRL) at 6 and 12 months after treatment 1
• For latent syphilis: repeat tests at 6,12, and 24 months 1, 2
• A fourfold decline in titer is expected within 6 months for primary/secondary syphilis and within 12-24 months for late syphilis 1, 2, 4

Treatment Failure Criteria

• Failure of nontreponemal test titers to decline fourfold within 6 months after therapy for primary or secondary syphilis 1, 2, 4
• Persistent or recurring signs/symptoms 1
• Sustained fourfold increase in nontreponemal titers 1
• If treatment failure is suspected, re-evaluate for HIV infection and perform CSF examination 1, 2

Management of Sex Partners

• Persons exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis should be treated presumptively, even if seronegative 1, 2
• Persons exposed >90 days before diagnosis should be treated presumptively if serologic test results are not immediately available and follow-up is uncertain 1
• Time periods for at-risk partners: 3 months plus duration of symptoms for primary syphilis, 6 months plus duration of symptoms for secondary syphilis, and 1 year for early latent syphilis 1

Important Clinical Considerations

Jarisch-Herxheimer Reaction

• An acute febrile reaction may occur within 24 hours after any syphilis therapy, especially in early syphilis, with symptoms including headache, myalgia, and fever 1, 4
• In pregnant women during the second half of pregnancy, this reaction may precipitate premature labor or fetal distress 1
• Women should seek immediate medical attention if they notice changes in fetal movements or contractions after treatment 1

Critical Pitfalls to Avoid

• Do not use oral penicillin preparations for syphilis treatment—they are ineffective 1
• Do not rely solely on treponemal test antibody titers to assess treatment response, as they correlate poorly with disease activity 1
• Do not switch between different testing methods (e.g., VDRL and RPR) when monitoring serologic response, as results cannot be directly compared 1
• All patients with syphilis should be tested for HIV infection 1, 4