What are the recommended treatment regimens for syphilis by stage and special situations such as pregnancy and penicillin allergy?

Syphilis Treatment Guidelines

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

Treatment by Disease Stage

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

• Administer benzathine penicillin G 2.4 million units IM as a single dose. 1
• This regimen achieves 90-100% treatment success rates for early syphilis. 2
• Serologic follow-up should occur at 6 and 12 months after treatment. 1

Late Latent Syphilis (infection >1 year or unknown duration)

• Administer benzathine penicillin G 2.4 million units IM weekly for 3 consecutive weeks (total 7.2 million units). 1
• Before initiating treatment, evaluate for neurologic or ocular symptoms; if present, perform CSF examination and treat as neurosyphilis. 1
• Serologic monitoring should occur at 6,12,18, and 24 months post-treatment. 1

Neurosyphilis, Ocular Syphilis, or 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: procaine penicillin 2.4 million units IM once daily plus probenecid 500 mg orally four times daily, both for 10-14 days. 1
• Consider adding 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
• If CSF pleocytosis was present initially, repeat CSF examination every 6 months until cell count normalizes. 1

Special Populations

Pregnancy

Pregnant women with syphilis must receive penicillin therapy appropriate for their disease stage—there are no acceptable alternatives. 1, 3, 4

• For primary, secondary, or early latent syphilis: benzathine penicillin G 2.4 million units IM as a single dose. 4
• Some experts recommend an additional dose of 2.4 million units IM one week after the initial dose, particularly in the third trimester or for women with secondary syphilis. 5, 4
• For late latent or unknown duration syphilis: benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM each at weekly intervals. 4
• Treatment must occur >4 weeks before delivery for optimal outcomes. 1

Critical Pregnancy Considerations

• All pregnant women should be screened for syphilis at the first prenatal visit. 4
• In high-risk populations, perform additional screening at 28-32 weeks gestation and at delivery. 4
• Repeat serologic titers in the third trimester and at delivery; check monthly in high-risk women. 4
• Women treated in the second half of pregnancy are at risk for premature labor or fetal distress if Jarisch-Herxheimer reaction occurs; advise them to seek immediate care if they notice contractions or decreased fetal movements within 24 hours of treatment. 5, 4
• Treatment should never be delayed due to concerns about Jarisch-Herxheimer reaction—untreated syphilis poses far greater fetal harm. 4
• No newborn should be discharged without documented maternal syphilis screening at least once during pregnancy. 5, 4

Penicillin Allergy in Pregnancy

Pregnant women with penicillin allergy must undergo desensitization and then receive penicillin—no alternatives are acceptable for preventing congenital syphilis. 1, 3, 4

• Tetracyclines cause maternal hepatotoxicity and fetal bone/tooth staining and are absolutely contraindicated. 5, 3, 4
• Erythromycin does not reliably cure fetal infection and should never be used. 5, 3, 4
• Skin testing followed by desensitization is mandatory before penicillin administration. 5, 4

Penicillin Allergy in Non-Pregnant Patients

For non-pregnant, penicillin-allergic patients with early syphilis (primary, secondary, or early latent), doxycycline 100 mg orally twice daily for 2 weeks is the preferred alternative. 5, 1

• Alternative: tetracycline 500 mg orally four times daily for 2 weeks. 5
• For late latent syphilis: doxycycline 100 mg orally twice daily for 4 weeks OR tetracycline 500 mg orally four times daily for 4 weeks. 1
• CSF examination must exclude neurosyphilis before using non-penicillin therapy. 1
• Close follow-up is essential as these alternatives have less clinical experience and documented effectiveness. 5
• Ceftriaxone has insufficient data; erythromycin is less effective than other regimens. 5
• Azithromycin is not recommended due to widespread resistance. 1

HIV-Infected Patients

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

• More intensive monitoring is required: clinical and serological evaluation at 3,6,9,12, and 24 months after treatment. 1
• Failure to achieve a fourfold decrease in nontreponemal titers within 3 months for primary/secondary syphilis indicates treatment failure. 1
• When treatment failure occurs with normal CSF, retreat with benzathine penicillin G 7.2 million units (three weekly doses of 2.4 million units each). 1
• Consider CSF examination for late latent syphilis in HIV-infected patients to exclude neurosyphilis before treatment. 1
• One study found that adding doxycycline 100 mg orally twice daily for 7 days to single-dose benzathine penicillin G improved serologic response rates in HIV-infected patients with early syphilis (79.5% vs 70.3%). 6

Monitoring Treatment Response

Definition of Treatment Success

• A fourfold (two-dilution) decline in nontreponemal test titers indicates successful treatment. 1
• For primary/secondary syphilis, this decline should occur by 6 months; for latent syphilis, by 12-24 months. 1, 2

Indicators of Treatment Failure

• A fourfold increase in titers. 1
• An initial titer ≥1:32 that does not fall fourfold within 12-24 months. 1
• Development of new clinical signs or symptoms attributable to syphilis. 1
• When treatment failure is suspected, perform CSF examination and consider retreatment. 1

Important 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
• HIV-infected patients may have atypical serologic responses (unusually high, low, or fluctuating titers), but this does not change treatment. 1

Additional Management Considerations

Partner Management

• Presumptively treat sexual partners exposed within 90 days preceding diagnosis, even if seronegative. 1
• Long-term sexual partners of patients with late syphilis should be clinically and serologically evaluated. 4

HIV Testing

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

Jarisch-Herxheimer Reaction

• Warn all patients about this acute febrile reaction with headache and myalgia that may occur within 24 hours of treatment. 1
• This is particularly important for pregnant women in the second half of pregnancy. 5, 4

Common Pitfalls to Avoid

• Never use non-penicillin regimens in pregnancy—desensitization is mandatory if penicillin-allergic. 1, 3, 4
• Do not delay treatment in pregnancy due to fear of Jarisch-Herxheimer reaction. 4
• Do not compare titers between different test types (RPR vs VDRL). 1
• Do not use serologic titers alone to differentiate early from late latent syphilis when determining treatment duration. 1
• Do not discharge newborns without documented maternal syphilis screening. 5, 4