What are the recommended treatment regimens for syphilis by stage, including management of neurosyphilis, ocular syphilis, penicillin allergy, and pregnancy?

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. 1

Primary, Secondary, and Early Latent Syphilis (≤1 year)

Administer benzathine penicillin G 2.4 million units IM as a single dose. 1, 2 This achieves 90-100% treatment success rates for early syphilis. 1, 3

Alternative Regimens for Penicillin-Allergic, Non-Pregnant Patients

• Doxycycline 100 mg orally twice daily for 14 days is the preferred alternative for penicillin-allergic adults. 1, 2
• Tetracycline 500 mg orally four times daily for 14 days is acceptable but adherence is generally worse. 1
• Azithromycin should NOT be used due to widespread macrolide resistance and documented treatment failures in the United States. 1
• Ceftriaxone 1 gram IM/IV daily for 10 days may be considered based on randomized trial data showing comparable efficacy, though it remains second-line. 1

Late Latent Syphilis, Latent of Unknown Duration, and Tertiary Syphilis (>1 year)

Administer benzathine penicillin G 7.2 million units total as three weekly doses of 2.4 million units IM each. 1, 2 This achieves 80-85% cure rates. 1

Alternative Regimens for Penicillin-Allergic, Non-Pregnant Patients

• Doxycycline 100 mg orally twice daily for 28 days is the preferred alternative. 1, 2
• Tetracycline 500 mg orally four times daily for 28 days is acceptable. 1
• CSF examination MUST exclude neurosyphilis before using any non-penicillin regimen for late latent infection. 1, 2

When to Perform CSF Examination Before Treatment

Lumbar puncture is mandatory in the following situations: 1

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

Neurosyphilis, Ocular Syphilis, and Otic Syphilis

Administer aqueous crystalline penicillin G 18-24 million units per day IV (given as 3-4 million units every 4 hours or continuous infusion) for 10-14 days. 1, 2 This achieves 90-95% cure rates. 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, 2
• Procaine penicillin without probenecid is inadequate because it fails to achieve therapeutic CSF penicillin levels. 2
• Patients with sulfonamide allergy should not receive this regimen as they are highly likely to be allergic to probenecid. 2

Additional Consideration

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

Ocular Syphilis Management

All ocular manifestations must be managed as neurosyphilis regardless of other clinical features. 1 Use the full neurosyphilis treatment regimen described above.

Pregnancy

Pregnant women MUST receive penicillin—it is the only therapy with documented efficacy for preventing congenital syphilis and treating fetal infection. 1, 4

Treatment Regimens

• Primary, secondary, or early latent syphilis: Benzathine penicillin G 2.4 million units IM as a single dose. 4
• Some experts recommend a second dose of 2.4 million units IM one week after the initial dose, particularly in the third trimester or for secondary syphilis. 1, 4
• Late latent or unknown duration: Benzathine penicillin G 7.2 million units total as three weekly doses of 2.4 million units IM each. 4
• If any dose is missed, pregnant women must repeat the entire course. 1

Penicillin Allergy in Pregnancy

All pregnant patients with penicillin allergy MUST undergo skin testing and desensitization, then be treated with penicillin—no exceptions. 1, 4

• Tetracyclines and doxycycline are contraindicated due to maternal hepatotoxicity and fetal bone/teeth staining. 1, 4
• Erythromycin should never be used as it does not reliably cure fetal infection. 1, 4
• Azithromycin and ceftriaxone are inadequate alternatives. 5

Critical Monitoring in Pregnancy

• Women treated during the second half of pregnancy are at risk for premature labor or fetal distress from Jarisch-Herxheimer reaction. 4
• Instruct patients to seek immediate obstetric attention if they notice contractions or decreased fetal movements within 24 hours of treatment. 1, 4
• Perform pretreatment ultrasound in viable pregnancies when feasible, particularly after 20 weeks gestation. 4
• Check serologic titers monthly until delivery in high-risk women, and repeat in the third trimester and at delivery. 4
• Treatment must occur >4 weeks before delivery for optimal outcomes. 1

Screening Requirements

• Screen all pregnant women at the first prenatal visit. 4
• High-risk populations require additional screening at 28-32 weeks gestation and at delivery. 4
• No newborn should be discharged without documented maternal syphilis screening. 4

HIV-Infected Patients

Use the same penicillin regimens as for HIV-negative patients for all disease stages. 1, 2

Enhanced Monitoring Requirements

HIV-infected patients require more intensive follow-up with clinical and serological evaluation at 3,6,9,12, and 24 months due to higher risk of treatment failure and atypical serologic responses. 1

Special Considerations

• Consider CSF examination for late latent syphilis in HIV-infected patients to exclude neurosyphilis before treatment. 1
• If nontreponemal titers do not decline fourfold within 3 months for primary/secondary syphilis, perform CSF examination and consider retreatment. 1
• When CSF is normal after treatment failure, retreat with benzathine penicillin G 7.2 million units (three weekly doses of 2.4 million units each). 1
• Limited data suggest no benefit to multiple doses of benzathine penicillin for early syphilis in HIV-infected patients compared to a single dose. 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%). 1

Follow-Up and Monitoring

Primary and Secondary Syphilis

• Perform quantitative nontreponemal serologic tests (RPR or VDRL) at 6 and 12 months after treatment. 1, 2
• Treatment success is defined as a fourfold (two-dilution) decline in titers within 6 months. 1, 3

Latent Syphilis

• Perform quantitative nontreponemal tests at 6,12,18, and 24 months after treatment. 1, 2
• Serologic response is generally slower, requiring 12-24 months for adequate decline. 3

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, consider retreatment. 1

Treatment Failure Indicators

Retreatment is indicated if any of the following occur: 1, 2

• A sustained fourfold increase in nontreponemal titers
• An initial titer ≥1:32 that fails to decline fourfold within 6-12 months for early syphilis or 12-24 months for late syphilis
• Development of new clinical signs or symptoms attributable to syphilis

Retreatment Approach

• Unless reinfection is likely, perform lumbar puncture to evaluate for neurosyphilis. 2
• Re-treatment typically involves three weekly injections of benzathine penicillin G 2.4 million units IM, unless CSF examination indicates neurosyphilis. 2

Management of Sexual Partners

Presumptively treat sexual partners exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis, even if seronegative. 1, 2

Time Windows for Presumptive Treatment

• Primary syphilis: 3 months plus duration of symptoms 1
• Secondary syphilis: 6 months plus duration of symptoms 1
• Early latent syphilis: 1 year 1

Partners exposed >90 days before diagnosis should be treated presumptively if serologic results are unavailable and reliable follow-up cannot be ensured. 1

Long-term sexual partners of patients with late syphilis should undergo clinical and serologic evaluation. 4

Important Warnings and Pitfalls

Jarisch-Herxheimer Reaction

Warn all patients about the Jarisch-Herxheimer reaction, an acute febrile reaction with headache, myalgia, and fever that may occur within 24 hours of treatment, especially in early syphilis. 1, 2 This is particularly important in pregnant women during the second half of pregnancy. 4

Common Pitfalls to Avoid

• Do not use oral penicillin preparations—they are ineffective. 2
• Do not switch between different nontreponemal tests (RPR vs VDRL) when monitoring response, as results cannot be directly compared. 1, 2
• Do not rely solely on treponemal test titers to assess treatment response—they correlate poorly with disease activity. 2
• Remember that 15-25% of successfully treated patients remain "serofast" with persistent low titers (<1:8) that do not indicate treatment failure. 1
• Do not delay treatment in pregnancy due to concerns about stillbirth risk from Jarisch-Herxheimer reaction—untreated syphilis causes far greater fetal harm. 4

HIV Testing

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