What is the recommended treatment for syphilis, including regimens for early infection, late infection, neurosyphilis, pregnancy, and penicillin allergy?

Treatment of Syphilis

Benzathine penicillin G remains the only proven effective treatment for all stages of syphilis, with dosing determined by disease stage: a single 2.4 million unit IM injection for early infection, three weekly doses for late latent disease, and IV aqueous crystalline penicillin for neurosyphilis. 1, 2

Treatment by Disease Stage

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

• Benzathine penicillin G 2.4 million units IM as a single dose is the standard regimen, achieving 90-100% cure rates 1, 2, 3
• For penicillin-allergic, non-pregnant patients: doxycycline 100 mg orally twice daily for 14 days 1, 2
• Alternative for penicillin allergy: tetracycline 500 mg orally four times daily for 14 days 4, 2
• Ceftriaxone 1 gram IV/IM daily for 10 days shows comparable efficacy in randomized trials 1

Late Latent Syphilis (> 1 year or unknown duration)

• Benzathine penicillin G 2.4 million units IM weekly for 3 consecutive weeks (total 7.2 million units) 1, 2
• For penicillin-allergic, non-pregnant patients: doxycycline 100 mg orally twice daily for 28 days 2
• Alternative: tetracycline 500 mg orally four times daily for 28 days 2
• Critical: CSF examination must be performed before using non-penicillin alternatives to exclude neurosyphilis 4, 2

Neurosyphilis, Ocular Syphilis, or Otic Syphilis

• Aqueous crystalline penicillin G 18-24 million units per day (administered as 3-4 million units IV every 4 hours) for 10-14 days 4, 1, 2
• Alternative when IV access is problematic: procaine penicillin 2.4 million units IM daily plus probenecid 500 mg orally four times daily, both for 10-14 days 4, 2
• 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 2
• All ocular manifestations (uveitis, neuroretinitis, optic neuritis) must be treated as neurosyphilis regardless of other clinical features 2

Tertiary (Gummatous or Cardiovascular) Syphilis

• Benzathine penicillin G 7.2 million units total, given as three IM doses of 2.4 million units at 1-week intervals 2
• CSF examination is mandatory before treatment to exclude neurosyphilis 1, 2
• Some experts treat all cardiovascular syphilis with the neurosyphilis IV regimen 4, 2
• Consultation with infectious disease specialists is strongly advised 2

Special Populations

Pregnancy

Pregnant women MUST receive penicillin—it is the only therapy proven to prevent congenital syphilis and treat fetal infection. 1, 2, 5, 6

• Use the penicillin regimen appropriate for the maternal disease stage 1, 2
• Pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment—no alternatives are acceptable 1, 2, 5, 6
• Some experts recommend an additional benzathine penicillin G 2.4 million units IM dose one week after the initial dose for primary, secondary, or early latent syphilis, particularly in the third trimester 2, 5
• Administer the first dose in a labor and delivery setting with continuous fetal monitoring for at least 24 hours due to risk of Jarisch-Herxheimer reaction causing preterm labor or fetal distress 2, 7, 5
• Treatment must occur more than 4 weeks before delivery for optimal outcomes 2
• Screen three times during pregnancy: at first prenatal visit, during third trimester, and at delivery 8

Critical pitfall: Tetracyclines cause maternal hepatotoxicity and fetal bone/tooth staining and are absolutely contraindicated 2. Erythromycin does not reliably eradicate fetal infection and should never be used 2. Azithromycin and ceftriaxone are inadequate alternatives because they do not reliably cure fetal infection 2.

HIV-Infected Patients

• Use the same penicillin regimens as HIV-negative patients for all disease stages 1, 2
• More intensive monitoring is mandatory: clinical and serological evaluation at 3,6,9,12, and 24 months 1, 2
• Consider CSF examination for late latent syphilis to exclude neurosyphilis, as HIV-infected patients have higher risk of neurologic complications 2
• If nontreponemal titers fail to decline fourfold within 3 months for primary/secondary syphilis, perform CSF examination and consider retreatment 2
• When CSF is normal after treatment failure, retreat with benzathine penicillin G 7.2 million units (three weekly doses) 2

Important caveat: The efficacy of doxycycline or tetracycline alternatives in HIV-infected patients has not been studied; use with extreme caution 2.

Indications for CSF Examination

Perform lumbar puncture in the following situations:

• Neurologic signs or symptoms (cognitive dysfunction, motor/sensory deficits, cranial nerve palsies, meningismus) 2
• Ocular or auditory symptoms 2
• Evidence of active tertiary syphilis (aortitis, gummas, iritis) 2
• Treatment failure (persistent symptoms or rising titers) 2
• HIV infection with late latent syphilis or unknown duration 2
• Nontreponemal titer ≥ 1:32 when infection duration is ≥ 1 year 2
• Before using non-penicillin therapy for late latent syphilis 4, 2

Follow-Up and Monitoring

Early Syphilis (Primary, Secondary, Early Latent)

• Repeat quantitative nontreponemal tests (RPR or VDRL) at 6 and 12 months 1, 2
• Treatment success: fourfold (two-dilution) decline in titers within 6 months 1, 2, 3
• For HIV-infected patients: add additional monitoring at 3,9, and 24 months 1, 2

Late Latent Syphilis

• Repeat quantitative nontreponemal tests at 6,12,18, and 24 months 1, 2
• Treatment success: fourfold decline in titers within 12-24 months 4, 2, 3

Neurosyphilis

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

Treatment Failure Criteria

Retreatment is indicated when:

• Nontreponemal titers increase fourfold (two dilutions) compared with post-treatment nadir 2
• Initial titer ≥ 1:32 fails to decline fourfold within 12-24 months 4, 2
• New clinical signs or symptoms attributable to syphilis develop 4, 2

Critical pitfall: Always use the same nontreponemal test method (RPR vs VDRL) and ideally the same laboratory for serial monitoring, as RPR titers are often slightly higher than VDRL titers and cannot be directly compared 2.

Jarisch-Herxheimer Reaction

• Occurs in approximately 24% of patients with early syphilis, typically within the first 12 hours after injection and resolves within 24 hours 7
• Presents as acute febrile syndrome with headache and myalgia 2
• Management: antipyretic agents for symptom relief; no specific therapy prevents the reaction 7
• The reaction is self-limited and should not delay or contraindicate treatment 7
• Counsel all patients before injection that this reaction is expected, benign, and will resolve within 24 hours 2, 7
• In pregnancy, may trigger premature labor or fetal distress; instruct patients to seek immediate care for uterine contractions or decreased fetal movements within 24 hours 2, 7, 5

Important distinction: Do not interpret new symptoms within 24 hours of injection as treatment failure or allergy; most represent Jarisch-Herxheimer reaction 7.

Additional Recommendations

• All patients diagnosed with syphilis must be tested for HIV infection 1, 2
• Presumptively treat sexual partners exposed within 90 days preceding diagnosis, even if seronegative 2
• For sexually active people aged 15-44 years: screen at least once, and at least annually for those at increased risk 8
• Consider doxycycline 200 mg within 72 hours after sex as postexposure prophylaxis for men who have sex with men and transgender women with a history of sexually transmitted infection in the past year 8