What is the recommended treatment regimen for syphilis at each stage, including considerations for pregnancy, penicillin allergy, and HIV co‑infection?

Treatment of Syphilis

Benzathine penicillin G remains the only proven effective treatment for all stages of syphilis, with dosing and duration determined by disease stage, and no acceptable alternatives exist for pregnant patients. 1

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

Administer benzathine penicillin G 2.4 million units intramuscularly as a single dose. 1, 2 This regimen achieves 90-100% treatment success rates in most patients. 3

Special Considerations for HIV Co-infection

• Use the same single-dose benzathine penicillin G regimen (2.4 million units IM once) for HIV-positive patients with early syphilis. 1, 4
• Do not routinely add extra doses—a randomized trial demonstrated that three weekly doses provided no additional benefit over single-dose therapy in HIV-infected individuals (93% vs 80% success, P=0.17). 4
• However, intensify monitoring: obtain clinical assessment and quantitative nontreponemal serology at 3,6,9,12, and 24 months after treatment. 1
• If titers fail to decline fourfold by 3 months, perform lumbar puncture and consider retreatment with benzathine penicillin G 7.2 million units (three weekly doses of 2.4 million units). 1

Late Latent Syphilis and Syphilis of Unknown Duration

Administer benzathine penicillin G 7.2 million units total, given as 2.4 million units IM weekly for three consecutive weeks. 1, 2

Critical Pre-Treatment Evaluation

Before initiating therapy, evaluate for neurologic, ocular, or auditory symptoms—any such findings mandate CSF examination and treatment as neurosyphilis. 1

In HIV-infected patients with late latent syphilis, strongly consider CSF examination before treatment to exclude asymptomatic neurosyphilis, as this population has higher risk of CNS involvement. 1

Neurosyphilis, Ocular Syphilis, and Otic Syphilis

Administer aqueous crystalline penicillin G 18-24 million units per day (given as 3-4 million units IV every 4 hours) for 10-14 days. 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
• Some experts add benzathine penicillin G 2.4 million units IM weekly for up to 3 weeks after completing the IV/IM course to provide comparable total duration. 1

Neurosyphilis Follow-Up

• 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, retreatment is indicated. 1

Tertiary (Gummatous or Cardiovascular) Syphilis

Administer benzathine penicillin G 7.2 million units total (three weekly doses of 2.4 million units IM). 1

Perform CSF examination before initiating therapy to exclude neurosyphilis, as symptomatic tertiary disease requires this evaluation. 1 Some experts recommend treating all cardiovascular syphilis with the neurosyphilis regimen (IV aqueous crystalline penicillin G). 1 Consultation with an infectious disease specialist is advised. 1

Treatment in Pregnancy

Pregnant women must receive parenteral penicillin G—it is the only therapy with documented efficacy for preventing congenital syphilis. 5, 6, 7

Stage-Specific Regimens

• Primary, secondary, or early latent syphilis: Benzathine penicillin G 2.4 million units IM as a single dose. 7
  • Some experts recommend an additional dose of 2.4 million units IM one week later, particularly in the third trimester or when treating secondary syphilis. 1, 7
• Late latent or unknown duration: Benzathine penicillin G 7.2 million units total (three weekly doses of 2.4 million units IM). 7

Critical Pregnancy-Specific Precautions

• Treatment must occur more than 4 weeks before delivery for optimal fetal outcomes. 1
• Warn patients to seek immediate obstetric care if they experience fever, uterine contractions, or decreased fetal movements within 24 hours of treatment—these may signal a Jarisch-Herxheimer reaction. 6, 7
• For gestations beyond 20 weeks, consider fetal and uterine-contraction monitoring for 24 hours after treatment, especially when ultrasound suggests possible fetal infection. 7
• Do not delay treatment due to fear of Jarisch-Herxheimer reaction—untreated syphilis poses far greater fetal risk. 7

Screening Requirements in Pregnancy

• Screen all pregnant women at the first prenatal visit. 7
• In high-risk populations or high-prevalence areas, perform additional screening at 28-32 weeks gestation and at delivery. 7, 2
• Repeat serologic titers in the third trimester and at delivery; consider monthly titers in women at high risk of reinfection. 7
• No newborn should be discharged without documented maternal syphilis screening at least once during pregnancy. 1, 7

Management of Penicillin Allergy

In Pregnant Patients

Penicillin desensitization is mandatory—there are no acceptable alternatives for treating syphilis in pregnancy. 1, 6, 7

• Perform skin testing followed by desensitization before penicillin administration. 6, 7
• Never use tetracyclines (including doxycycline) in pregnancy—they cause maternal hepatotoxicity and fetal bone/tooth staining. 1, 6
• Never use erythromycin—it does not reliably cure fetal infection. 1, 6
• Azithromycin and ceftriaxone are inadequate and do not prevent congenital syphilis. 1

In Non-Pregnant Patients

For early syphilis (primary, secondary, or early latent):

• Doxycycline 100 mg orally twice daily for 2 weeks is the preferred alternative. 1
• Tetracycline 500 mg orally four times daily for 2 weeks is an alternative. 1

For late latent syphilis:

• Doxycycline 100 mg orally twice daily for 4 weeks. 1
• Tetracycline 500 mg orally four times daily for 4 weeks is an alternative. 1

Critical Caveat for Non-Penicillin Regimens

Perform lumbar puncture (CSF examination) before using any non-penicillin regimen to exclude neurosyphilis, as these alternatives are ineffective for CNS disease. 1

The efficacy of doxycycline or tetracycline in HIV-infected patients has not been studied—use with extreme caution and ensure close follow-up. 1

Monitoring Treatment Response

Definition of Treatment Success

A fourfold (two-dilution) decline in quantitative nontreponemal test titers (e.g., from 1:32 to 1:8) indicates successful treatment. 1

Follow-Up Schedule

• Primary and secondary syphilis: Clinical and serological evaluation at 6 and 12 months. 1
• Latent syphilis: Evaluation at 6,12,18, and 24 months. 1
• HIV-infected patients: More intensive monitoring at 3,6,9,12, and 24 months. 1

Expected Timeline for Serologic Response

• Early syphilis: Titers should decline by 6 months. 3
• Latent syphilis: Response is slower, typically 12-24 months. 3

Indications for Retreatment

Retreatment is indicated if:

• Nontreponemal titers increase fourfold (two dilutions) from the post-treatment nadir. 1
• An initial titer ≥1:32 fails to decline fourfold within 12-24 months. 1
• New clinical signs or symptoms of syphilis develop. 1

When retreatment is needed, perform lumbar puncture before retreating to exclude neurosyphilis. 1

Partner Management

Presumptively treat sexual partners exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis, even if seronegative. 5, 7 Use the same single-dose benzathine penicillin G regimen. 5

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

Common Pitfalls to Avoid

• Do not use oral penicillin preparations or combinations of benzathine and procaine penicillin—these are not appropriate for syphilis treatment. 5
• Do not compare RPR and VDRL titers directly—they are not interchangeable, and sequential tests should use the same method and ideally the same laboratory. 1
• Do not use azithromycin—widespread resistance makes it unreliable. 1
• Do not skip CSF examination when indicated—failure to diagnose neurosyphilis leads to inadequate treatment and progression of disease. 1
• If a pregnant woman misses a weekly benzathine penicillin dose, repeat the entire three-dose course to ensure adequate fetal treatment. 1

Jarisch-Herxheimer Reaction

Inform all patients about the Jarisch-Herxheimer reaction—an acute febrile reaction with headache and myalgia that typically occurs within 24 hours of treatment. 5, 1 This reaction is most common in early syphilis. 5 Antipyretics may be used but have not been proven to prevent the reaction. 5 In pregnant women, the reaction may induce early labor or fetal distress, but this concern should never prevent or delay therapy. 5