What are the treatment guidelines for syphilis?

Syphilis Treatment Guidelines

Primary and Secondary Syphilis

For primary and secondary syphilis, administer benzathine penicillin G 2.4 million units intramuscularly as a single dose. This regimen has demonstrated 90-100% treatment success rates and represents the standard of care supported by four decades of clinical experience 1, 2, 3.

Alternative Regimens for Penicillin Allergy

• For non-pregnant, penicillin-allergic adults, use doxycycline 100 mg orally twice daily for 14 days 1, 2, 4.
• Tetracycline 500 mg orally four times daily for 14 days is an additional alternative, though compliance is typically better with doxycycline 1.
• Pregnant patients with penicillin allergy must undergo desensitization and receive penicillin, as no other therapy has documented efficacy for preventing maternal transmission 1, 2.

Follow-Up and Treatment Response

• Repeat quantitative nontreponemal serologic tests (RPR or VDRL) at 6 and 12 months 1, 2.
• Expect a fourfold decline in titer within 6 months for primary/secondary syphilis 2, 5.
• Treatment failure is defined as: persistent or recurrent symptoms, sustained fourfold increase in titers, or failure of titers to decline fourfold within 6 months 1, 2.
• If treatment failure occurs, re-evaluate for HIV infection and perform CSF examination unless reinfection is clearly established 2, 6.

Early Latent Syphilis

Treat early latent syphilis with benzathine penicillin G 2.4 million units intramuscularly as a single dose 1, 2.

• Early latent syphilis is defined as infection acquired within the preceding year, documented by seroconversion, fourfold titer increase, history of primary/secondary symptoms, or exposure to a partner with documented early syphilis 1, 2.

Late Latent and Tertiary Syphilis

For late latent syphilis, latent syphilis of unknown duration, or tertiary syphilis, administer benzathine penicillin G 7.2 million units total as three doses of 2.4 million units intramuscularly at weekly intervals 1, 2.

Alternative Regimens for Penicillin Allergy

• For non-pregnant adults allergic to penicillin: doxycycline 100 mg orally twice daily for 28 days 1, 2, 4.
• Tetracycline 500 mg orally four times daily for 28 days is an alternative 1.
• These alternatives require close serologic and clinical follow-up, and their efficacy in HIV-infected persons is uncertain 1.
• Pregnant patients must be desensitized and treated with penicillin 1, 2.

Follow-Up

• Repeat quantitative nontreponemal tests at 6,12, and 24 months 1, 2.
• Re-treat if titers increase fourfold, an initially high titer (>1:32) fails to decline at least fourfold within 12-24 months, or signs/symptoms develop 1.

Neurosyphilis

For neurosyphilis, administer aqueous crystalline penicillin G 18-24 million units per day intravenously (3-4 million units every 4 hours or continuous infusion) for 10-14 days 1, 2, 5.

Alternative Regimen

• If compliance can be ensured: procaine penicillin 2.4 million units intramuscularly once daily PLUS probenecid 500 mg orally four times daily, both for 10-14 days 1.

When to Suspect Neurosyphilis

• Perform CSF examination for patients with neurologic signs/symptoms (cognitive dysfunction, motor/sensory deficits, cranial nerve palsies, meningitis), ophthalmic symptoms (uveitis, neuroretinitis, optic neuritis), or auditory symptoms 1, 2.
• Syphilitic uveitis or other ocular manifestations are frequently associated with neurosyphilis and should be treated as neurosyphilis 1.
• Consider CSF examination for patients with symptomatic late syphilis before initiating therapy 1.

Special Populations

HIV-Infected Patients

• Use the same treatment regimens as non-HIV-infected patients 2, 5.
• All patients with syphilis should be tested for HIV 1, 5.
• HIV-infected patients may have atypical serologic responses but generally respond well to standard treatment 2, 6.
• Follow up more frequently at 3-month intervals instead of 6-month intervals 1, 6.

Pregnant Women

• Parenteral penicillin G is the only therapy with documented efficacy for preventing maternal transmission 2, 5.
• Treat according to the stage of syphilis 5.
• Pregnant women who miss any dose of therapy for late latent syphilis must repeat the full course 1.
• Screen pregnant individuals three times: at first prenatal visit, during third trimester, and at delivery 7.

Children

• After the newborn period, perform CSF examination to exclude neurosyphilis and review birth/maternal records to assess for congenital versus acquired syphilis 1.
• For acquired primary/secondary syphilis: benzathine penicillin G 50,000 units/kg intramuscularly, up to adult dose of 2.4 million units as a single dose 1.
• For early latent syphilis: benzathine penicillin G 50,000 units/kg intramuscularly, up to adult dose of 2.4 million units as a single dose 1.
• For late latent syphilis: benzathine penicillin G 50,000 units/kg intramuscularly for three doses (total 150,000 units/kg up to adult total of 7.2 million units) 1.

Management of Sexual 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 results are not immediately available and follow-up is uncertain 1, 2.
• Patients with syphilis of unknown duration and high nontreponemal titers (≥1:32) may be considered infected with early syphilis for partner notification purposes 1.
• Long-term partners of patients with late syphilis should be evaluated clinically and serologically 1.

Important Clinical Considerations

Jarisch-Herxheimer Reaction

• An acute febrile reaction may occur within 24 hours after any syphilis therapy, especially in early syphilis 1, 2.
• Inform patients about this possible reaction, which may include fever, headache, and myalgia 1, 2.
• Antipyretics may be recommended, but no proven prevention methods exist 1.
• In pregnant women, this reaction may induce early labor or fetal distress but should not prevent or delay therapy 1.

Missed Doses

• If a dose is missed during weekly therapy for late syphilis, an interval of 10-14 days between doses might be acceptable before restarting the sequence 1, 2.
• Pregnant women who miss any dose must repeat the full course of therapy 1.

Critical Pitfalls to Avoid

• Never use oral penicillin preparations for syphilis treatment—they are ineffective 2.
• Do not rely solely on treponemal test antibody titers to assess treatment response, as they correlate poorly with disease activity 2.
• Do not switch between different nontreponemal test methods (VDRL vs RPR) when monitoring serologic response, as results cannot be directly compared 2, 6.
• Do not assume persistent low-titer reactivity (serofast state) necessarily indicates treatment failure or reinfection 6.
• Never skip CSF examination in suspected treatment failure unless reinfection is clearly established 6.