What is the recommended treatment for syphilis at each stage, including management of neurosyphilis, ocular syphilis, pregnancy, and penicillin‑allergic patients, and what follow‑up serologic monitoring is advised?

Syphilis Treatment by Stage

Benzathine penicillin G remains the only proven therapy for all stages of syphilis, with stage-specific dosing: a single 2.4 million unit IM dose for early disease, three weekly doses (7.2 million units total) for late latent disease, and IV aqueous crystalline penicillin G 18-24 million units daily for 10-14 days for neurosyphilis or ocular syphilis. 1

Primary, Secondary, and Early Latent Syphilis (< 1 year duration)

Recommended regimen:

• Benzathine penicillin G 2.4 million units IM as a single dose 1, 2
• Treatment success rates: 90-100% for primary/secondary syphilis, 85-90% for early latent 1

For penicillin-allergic, non-pregnant patients:

• Doxycycline 100 mg orally twice daily for 14 days (preferred alternative) 1, 3
• Tetracycline 500 mg orally four times daily for 14 days (alternative) 1, 3
• Critical caveat: CSF examination must exclude neurosyphilis before using non-penicillin therapy 4, 3
• Close serologic and clinical follow-up is mandatory due to less documented effectiveness 3

Late Latent Syphilis or Unknown Duration (> 1 year or unknown)

Recommended regimen:

• Benzathine penicillin G 2.4 million units IM weekly for 3 consecutive weeks (total 7.2 million units) 1, 5
• Cure rate: 80-85% 1

For penicillin-allergic, non-pregnant patients:

• Doxycycline 100 mg orally twice daily for 28 days 4, 3
• Tetracycline 500 mg orally four times daily for 28 days 4, 3
• Must perform CSF examination first to exclude neurosyphilis 4, 3

Important dosing pitfall: If a patient misses a weekly dose, an interval of 10-14 days between doses may be acceptable before restarting the sequence, except in pregnant women who must repeat the full course if any dose is missed 4

Tertiary Syphilis (Gummatous or Cardiovascular)

Recommended regimen:

• Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at 1-week intervals 4
• CSF examination should be performed before therapy in symptomatic patients 4
• Some experts treat all cardiovascular syphilis cases with a neurosyphilis regimen 4
• Consultation with infectious disease specialist is recommended 4

Neurosyphilis, Ocular Syphilis, and Otic Syphilis

These conditions require identical treatment regardless of stage 1

Recommended regimen:

• Aqueous crystalline penicillin G 18-24 million units per day, administered as 3-4 million units IV every 4 hours for 10-14 days 1
• Cure rate: 90-95% 1

Alternative regimen (when IV access is problematic):

• Procaine penicillin 2.4 million units IM once daily PLUS probenecid 500 mg orally four times daily, both for 10-14 days 1

Optional additional therapy:

• Some experts add benzathine penicillin G 2.4 million units IM weekly for up to 3 weeks after completing the neurosyphilis regimen to provide comparable total duration 1

Critical recognition: Ocular manifestations (uveitis, neuroretinitis, optic neuritis) are frequently associated with neurosyphilis and must be treated as neurosyphilis, not as the stage suggested by other clinical features 4, 1

Indications for CSF Examination Before Treatment

Perform lumbar puncture if any of the following are present:

• Neurologic signs or symptoms (cognitive dysfunction, motor/sensory deficits, cranial nerve palsies, meningismus) 4, 1
• Ocular or auditory symptoms 4, 1
• Evidence of active tertiary syphilis (aortitis, gummas, iritis) 4, 1
• Treatment failure (persistent symptoms or rising titers) 4, 1
• HIV infection with late latent syphilis or unknown duration 4, 1
• Nontreponemal titer ≥ 1:32, unless infection duration is known to be < 1 year 4, 1
• Non-penicillin therapy planned for late latent syphilis 4

Management in Pregnancy

Pregnant women must receive penicillin therapy appropriate to their disease stage—no exceptions 1, 6

For penicillin-allergic pregnant patients:

• Desensitization is mandatory; there are no acceptable alternatives 1, 6
• Tetracyclines cause maternal hepatotoxicity and fetal bone/tooth staining 1
• Erythromycin does not reliably eradicate fetal infection 1
• Skin testing followed by desensitization is required before penicillin administration 1

Enhanced regimen considerations:

• Some experts recommend an additional benzathine penicillin G 2.4 million units IM one week after the initial dose for pregnant women with primary, secondary, or early latent syphilis, particularly in the third trimester 1, 5
• Treatment must occur > 4 weeks before delivery for optimal outcomes 1

Critical monitoring in pregnancy:

• Screen at first prenatal visit, early third trimester, and at delivery 2, 6
• In high-risk populations, repeat nontreponemal titers monthly 6
• Jarisch-Herxheimer reaction risk: Pregnant patients treated in the second half of gestation should receive therapy in a labor-and-delivery setting with continuous fetal monitoring due to risk of preterm labor or fetal distress 1
• Patients should seek immediate care if they experience uterine contractions or reduced fetal movements within 24 hours of treatment 1

Regulatory requirement: No newborn may be discharged without documented maternal syphilis screening at least once during pregnancy 1

Management in HIV-Infected Patients

HIV-positive individuals receive the same penicillin regimens as HIV-negative patients for all disease stages 1, 5

However, more intensive monitoring is required:

• Clinical assessment and nontreponemal serology at 3,6,9,12, and 24 months (versus 6 and 12 months in HIV-negative patients) 1, 5
• For primary/secondary syphilis: if titers do not decline fourfold within 3 months, perform CSF examination and consider retreatment 1
• For late latent syphilis: consider CSF examination before treatment to exclude neurosyphilis 1, 5

Treatment failure management in HIV patients:

• When CSF is normal, retreat with benzathine penicillin G 7.2 million units (three weekly doses of 2.4 million units each) 1
• HIV-infected patients may have atypical serologic responses (unusually high, low, or fluctuating titers), but this does not change treatment 1, 5

Important caveat: The efficacy of doxycycline and tetracycline alternatives in HIV-infected persons has not been studied and must be used with extreme caution 4

Serologic Follow-Up Monitoring

For primary and secondary syphilis:

• Repeat quantitative nontreponemal tests (RPR or VDRL) at 6 and 12 months 1, 5
• Treatment success: ≥ fourfold (two-dilution) decline in titers within 6 months 1, 7

For latent syphilis:

• Repeat at 6,12,18, and 24 months 1, 5
• Treatment success: ≥ fourfold decline within 12-24 months 4

For neurosyphilis:

• If CSF pleocytosis was present initially, repeat CSF examination every 6 months until cell count normalizes 1
• If cell count has not decreased after 6 months or CSF is not normal after 2 years, consider retreatment 1

Indications for retreatment:

• Titers increase fourfold (two dilutions) 4, 1
• Initial titer > 1:32 fails to decline fourfold within 12-24 months 4
• Development of new clinical signs or symptoms attributable to syphilis 4, 1

The "serofast" state: Patients with persistently low RPR titers (1:1 to 1:4) after appropriate treatment do not require additional therapy in the absence of clinical findings 5, 7

Critical Testing Considerations

Sequential RPR tests should use the same method and ideally the same laboratory, as RPR titers are often slightly higher than VDRL titers and cannot be directly compared 1

All patients diagnosed with syphilis should be tested for HIV if status is unknown 1, 2

Jarisch-Herxheimer Reaction

Warn all patients about this acute febrile reaction (fever, headache, myalgia) that may occur within 24 hours of treatment, particularly in secondary syphilis 1, 8

Partner Management

Presumptively treat sexual partners exposed within 90 days preceding diagnosis, even if seronegative 1