What is the recommended treatment for syphilis?

Syphilis Treatment

Benzathine penicillin G 2.4 million units intramuscularly as a single dose is the definitive first-line treatment for primary, secondary, and early latent syphilis, while late latent or tertiary syphilis requires three weekly doses of 2.4 million units IM. 1, 2, 3

First-Line Treatment by Stage

Early Syphilis (Primary, Secondary, Early Latent)

• Benzathine penicillin G 2.4 million units IM as a single injection is the CDC-recommended regimen for all patients with early syphilis (infection acquired within the past year) 1, 2, 3
• Early latent syphilis is defined by documented seroconversion, fourfold increase in titer, history of symptoms within the past year, or having a sex partner with documented early syphilis 2
• This single-dose regimen is equally effective in HIV-infected patients—do not give multiple doses to HIV-positive patients as data show no benefit over single-dose therapy 1, 4

Late Latent Syphilis and Tertiary Syphilis

• Benzathine penicillin G 7.2 million units total: three doses of 2.4 million units IM given at weekly intervals for late latent syphilis (>1 year duration), syphilis of unknown duration, or tertiary syphilis 1, 2, 3
• If a dose is missed, an interval of 10-14 days between doses is acceptable before restarting the sequence 2

Neurosyphilis

• Aqueous crystalline penicillin G 18-24 million units daily IV (administered as 3-4 million units every 4 hours or continuous infusion) for 10-14 days 1, 2
• CSF examination is mandatory before treatment for patients with neurologic/ophthalmic symptoms, tertiary syphilis, treatment failure, HIV with late latent syphilis, or nontreponemal titer ≥1:32 2

Alternative Treatments for Penicillin Allergy

Non-Pregnant Adults

• Doxycycline 100 mg orally twice daily for 14 days for primary, secondary, or early latent syphilis 1, 2, 3
• Doxycycline 100 mg orally twice daily for 28 days for late latent syphilis 2, 3
• Tetracycline 500 mg orally four times daily (14 days for early, 28 days for late) is an alternative, though compliance is worse than doxycycline 1
• Ceftriaxone 1 gram IM or IV daily for 8-10 days may be considered, though optimal dosing is not well-established 1

Critical Caveat: Azithromycin

• Never use azithromycin in the United States—widespread macrolide resistance in T. pallidum has led to documented treatment failures despite some older evidence suggesting efficacy 1, 2, 5

Pregnant Patients

• All pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment—no alternatives are adequately studied or proven effective for preventing congenital syphilis 1, 2, 3
• Screen all pregnant women at first prenatal visit, during third trimester, and at delivery 2
• Jarisch-Herxheimer reaction during the second half of pregnancy may precipitate premature labor or fetal distress; women should seek immediate care if they notice changes in fetal movements or contractions 2

HIV Co-infection Considerations

• Use the same penicillin regimen as HIV-negative patients—single dose for early syphilis, three weekly doses for late syphilis 1, 2, 3
• The 2017 randomized trial definitively showed no benefit of three doses over single dose for early syphilis in HIV-infected patients (93% vs 100% success rates, not statistically significant) 4
• Implement closer follow-up: every 3 months rather than every 6 months for HIV-infected patients 1
• All patients with syphilis should be tested for HIV 2

Follow-Up Protocol

Timing of Serologic Testing

• For primary/secondary syphilis: quantitative nontreponemal tests (RPR or VDRL) at 6 and 12 months 1, 2
• For latent syphilis: at 6,12, and 24 months 2, 3
• For HIV-infected patients: every 3 months 1, 2

Expected Response

• Fourfold decline in titer within 6 months for primary/secondary syphilis 2, 3
• Fourfold decline within 12-24 months for late syphilis 2, 3

Treatment Failure Criteria

• Persistent or recurring signs/symptoms 1, 2
• Sustained fourfold increase in nontreponemal titers 1, 2
• Failure of initially high titer to decline at least fourfold within the expected timeframe 2
• If treatment failure occurs: re-evaluate for HIV, perform CSF examination, and re-treat 2

Management of Sex Partners

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

Pediatric Dosing

• Benzathine penicillin G 50,000 units/kg IM (up to adult dose of 2.4 million units) as a single dose for primary, secondary, or early latent syphilis 2, 3
• For late latent: 50,000 units/kg IM for three doses at weekly intervals (total 150,000 units/kg up to 7.2 million units) 2
• All children require CSF examination to exclude neurosyphilis before treatment 2

Critical Pitfalls to Avoid

• Never use oral penicillin preparations—they are ineffective for syphilis treatment 2
• Do not switch between VDRL and RPR when monitoring serologic response, as results cannot be directly compared 2
• Do not rely on treponemal test titers to assess treatment response—they correlate poorly with disease activity 2
• Jarisch-Herxheimer reaction (fever, headache, myalgia) may occur within 24 hours after treatment, especially in early syphilis—inform patients of this expected reaction 1, 2, 3
• Avoid concurrent bacteriostatic antibiotics (chloramphenicol, erythromycins, sulfonamides, tetracyclines) as they may antagonize penicillin's bactericidal effect 6