What is the recommended management of syphilis, including penicillin regimens for each stage and alternatives for penicillin‑allergic patients?

Syphilis Management

Treatment Regimens by Stage

Benzathine penicillin G is the only proven effective treatment for all stages of syphilis, with specific dosing determined by disease stage. 1

Primary and Secondary Syphilis

• Benzathine penicillin G 2.4 million units IM as a single dose is the recommended treatment 2, 1, 3
• This regimen achieves cure rates of 90-95% for primary and secondary syphilis 3
• All patients diagnosed with syphilis should be tested for HIV if status is unknown 1, 3

Early Latent Syphilis

• Benzathine penicillin G 2.4 million units IM as a single dose 2, 1, 3
• Early latent syphilis is defined as infection acquired within the preceding year, documented by seroconversion, fourfold increase in titer, history of symptoms within the past year, or having a sex partner with documented early syphilis 1, 3
• Cure rate is 85-90% 3

Late Latent Syphilis and Tertiary Syphilis

• Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at weekly intervals 2, 1, 3
• This applies to late latent syphilis (acquired >1 year ago), syphilis of unknown duration, and tertiary syphilis (gummatous and cardiovascular disease) 2, 1
• Cure rate is 80-85% 3
• If a dose is missed during weekly therapy, an interval of 10-14 days between doses might be acceptable before restarting the sequence; however, missed doses are NOT acceptable for pregnant patients who must repeat the full course 2, 1

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 2, 1, 3
• Alternative regimen (if compliance can be ensured): Procaine penicillin 2.4 million units IM once daily PLUS probenecid 500 mg orally four times daily, both for 10-14 days 2, 3
• Some specialists add benzathine penicillin G 2.4 million units IM weekly for up to 3 weeks after completing neurosyphilis treatment to provide comparable total duration 2, 3
• CSF examination is indicated for patients with neurologic or ophthalmic signs/symptoms, evidence of active tertiary syphilis, treatment failure, HIV infection with late latent syphilis, or nontreponemal titer ≥1:32 2, 1, 3

Ocular Syphilis

• Treat according to neurosyphilis recommendations (aqueous crystalline penicillin G 18-24 million units per day IV for 10-14 days) 2, 3
• Syphilitic uveitis and other ocular manifestations are frequently associated with neurosyphilis 2
• CSF examination should be performed for all patients with ocular syphilis 2

Alternatives for Penicillin-Allergic Patients

Non-Pregnant Adults

For primary, secondary, and early latent syphilis:

• Doxycycline 100 mg orally twice daily for 14 days 2, 1
• Alternative: Tetracycline 500 mg orally four times daily for 14 days 2, 1
• Ceftriaxone 1 gram IM or IV daily for 10-14 days may be considered based on limited data, though optimal dose and duration are not definitively established 2, 1

For late latent syphilis or syphilis of unknown duration:

• Doxycycline 100 mg orally twice daily for 28 days 2, 1
• Alternative: Tetracycline 500 mg orally four times daily for 28 days 2, 1
• CSF examination must be performed before using non-penicillin therapy to exclude neurosyphilis 1, 3
• These alternative regimens have limited documentation of effectiveness, especially in HIV-infected persons 2, 3

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

Pregnant Patients

All pregnant patients allergic to penicillin MUST undergo desensitization followed by penicillin treatment—no exceptions 2, 1, 3

• Penicillin is the only therapy with documented efficacy for preventing maternal transmission to the fetus and treating fetal infection 2, 1, 3
• Tetracycline, doxycycline, erythromycin, azithromycin, and ceftriaxone are inadequate—erythromycin does not reliably cure fetal infection 1
• Some experts recommend an additional dose of benzathine penicillin G 2.4 million units IM one week after the initial dose for pregnant women with primary, secondary, or early latent syphilis 2, 1, 3
• Treatment must occur >4 weeks before delivery for optimal outcomes 1, 3

Jarisch-Herxheimer reaction warning: Women treated during the second half of pregnancy are at risk for premature labor and/or fetal distress; they should seek immediate medical attention if they notice contractions or changes in fetal movements 1, 3

Neurosyphilis in Penicillin-Allergic Patients

• Penicillin remains the only proven effective therapy for neurosyphilis 2, 1
• Patients must undergo desensitization and be treated with penicillin 2, 1

HIV-Infected Patients

HIV-infected patients should receive the same penicillin regimens as HIV-negative patients for all disease stages 2, 1, 3

• No additional doses of benzathine penicillin are recommended based on current evidence 1, 3
• Some experts recommend additional treatments (e.g., three weekly doses as for late syphilis) or CSF examination before therapy for primary/secondary syphilis, though most HIV-infected patients respond appropriately to standard therapy 2

More intensive follow-up is required:

• Clinical and serological evaluation at 3,6,9,12, and 24 months after therapy 2, 1, 3
• If nontreponemal titers do not decline fourfold within 3 months for primary/secondary syphilis, CSF examination and possible retreatment are strongly advised 2, 3
• For late latent syphilis in HIV-infected patients, consider CSF examination before treatment to rule out neurosyphilis 2, 3
• When CSF is normal, most experts would retreat with benzathine penicillin G 7.2 million units (three weekly doses of 2.4 million units each) 2, 3

Follow-Up and Monitoring

Primary and Secondary Syphilis

• Quantitative nontreponemal serologic tests (RPR or VDRL) at 6 and 12 months after treatment 2, 1, 3
• A fourfold decline in titer is expected within 6 months 2, 1, 4
• Treatment failure is indicated by: failure of titers to decline fourfold within 6 months, fourfold increase in titers at any time, or development of new clinical signs/symptoms 2, 3

Latent Syphilis

• Quantitative nontreponemal tests at 6,12,18, and 24 months 2, 1, 3
• For late latent syphilis, a fourfold decline is expected within 12-24 months 2, 3
• 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 2, 3

Neurosyphilis

• If CSF pleocytosis was present initially, repeat CSF examination every 6 months until cell count normalizes 3
• If cell count has not decreased after 6 months or CSF is not normal after 2 years, consider retreatment 3

Important testing considerations:

• Sequential RPR tests should use the same method and ideally the same laboratory, as RPR and VDRL titers cannot be directly compared 3
• Treponemal test antibody titers correlate poorly with disease activity and should not be used to assess treatment response 1
• Approximately 15% of successfully treated patients may remain "serofast" with persistent low-level titers (<1:8) that do not indicate treatment failure 1, 4

Management of Treatment Failure

When treatment failure occurs:

• Re-evaluate for HIV infection 2, 3
• Perform CSF examination to rule out neurosyphilis 2, 3
• Most specialists recommend re-treating with benzathine penicillin G 2.4 million units IM weekly for 3 weeks, unless CSF indicates neurosyphilis 2, 3
• If CSF is normal in HIV-infected patients, retreat with benzathine penicillin G 7.2 million units (three weekly doses) 2, 3

Management of Sex Partners

Presumptive treatment is required for exposed partners:

• Persons exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis should be treated presumptively with benzathine penicillin G 2.4 million units IM, even if seronegative 1, 4, 3
• 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, 4
• Persons exposed >90 days before diagnosis should be treated presumptively if serologic results are not immediately available and follow-up is uncertain 1

Sexual Activity Resumption

Patients should abstain from all sexual contact (including oral sex) until:

• Treatment is complete AND
• All visible lesions have completely healed AND
• Sex partners have been evaluated and treated 4

Pregnancy Screening

• All pregnant women should be screened for syphilis at first prenatal visit, during third trimester, and at delivery 2, 1
• Any woman who delivers a stillborn infant after 20 weeks gestation should be tested for syphilis 2
• No infant should leave the hospital without the mother's serologic status having been determined at least once during pregnancy 2

Common Pitfalls to Avoid

• Never use oral penicillin preparations for syphilis treatment—they are ineffective 1
• Do not use azithromycin in the United States due to widespread resistance 1
• Do not substitute alternatives for penicillin in pregnancy or neurosyphilis—desensitization is mandatory 2, 1, 3
• Procaine penicillin without probenecid does not achieve adequate CSF levels and is inadequate for neurosyphilis 1
• Do not switch between RPR and VDRL when monitoring serologic response—results cannot be directly compared 1, 3
• Warn all patients about Jarisch-Herxheimer reaction—an acute febrile reaction with headache and myalgia that may occur within 24 hours of treatment, especially in early syphilis 1, 3