What is the current recommendation for management of syphilis?

Current Recommendations for Syphilis Management

Benzathine penicillin G remains the definitive treatment for all stages of syphilis, with dosing and duration determined by disease stage—no alternative has proven superior efficacy or safety. 1

Primary and Secondary Syphilis

Administer benzathine penicillin G 2.4 million units intramuscularly as a single dose. 1, 2 This regimen achieves 90–100% treatment success based on decades of clinical experience. 1, 3

Follow-Up Protocol

• Perform quantitative nontreponemal tests (RPR or VDRL) at 3,6, and 12 months after treatment. 1
• Expect a fourfold decline in titer within 6 months for early syphilis. 1
• Treatment failure is defined as: persistent symptoms, sustained fourfold titer increase, or failure of titers to decline fourfold within 6 months. 1

Early Latent Syphilis (≤1 Year Duration)

Give benzathine penicillin G 2.4 million units IM as a single dose. 1 Early latent syphilis is defined by documented seroconversion within the past year, fourfold titer increase, recent symptoms of primary/secondary syphilis, or a sex partner with confirmed early syphilis. 1

Late Latent Syphilis and Tertiary Syphilis (>1 Year or Unknown Duration)

Administer benzathine penicillin G 7.2 million units total as three weekly doses of 2.4 million units IM each. 1, 4

Critical Pre-Treatment Step

Perform CSF examination before treatment if any of the following are present: 1, 4

• Neurologic signs or symptoms (cognitive dysfunction, motor/sensory deficits, cranial nerve palsies, meningismus)
• Ophthalmic involvement (uveitis, neuroretinitis, optic neuritis)
• Evidence of active tertiary disease (cardiovascular syphilis, gummas)
• Treatment failure
• HIV infection with late latent syphilis
• Nontreponemal titer ≥1:32

If neurosyphilis is identified, the tertiary regimen is inadequate—switch to the neurosyphilis protocol immediately. 4

Follow-Up for Late Disease

• Repeat quantitative nontreponemal tests at 6,12, and 24 months. 1, 4
• Expect fourfold titer decline within 12–24 months. 1, 4

Neurosyphilis

Administer aqueous crystalline penicillin G 18–24 million units IV daily (given as 3–4 million units every 4 hours or continuous infusion) for 10–14 days. 1, 4

Alternative Outpatient Regimen (Only if Compliance Assured)

Procaine penicillin 2.4 million units IM once daily PLUS probenecid 500 mg orally four times daily for 10–14 days. 1

Critical caveat: Procaine penicillin without probenecid is completely inadequate because it fails to achieve therapeutic CSF levels. 1 Never use this regimen in patients with sulfonamide allergy due to cross-reactivity with probenecid. 1

Neurosyphilis Follow-Up

• If initial CSF pleocytosis was present, repeat lumbar puncture every 6 months until WBC count normalizes. 1
• Retreat if: CSF cell count has not decreased after 6 months OR CSF remains abnormal after 2 years. 1

Penicillin-Allergic Patients (Non-Pregnant)

Early Syphilis (Primary, Secondary, Early Latent)

Doxycycline 100 mg orally twice daily for 14 days is the preferred alternative. 1 Tetracycline 500 mg orally four times daily for 14 days is acceptable but doxycycline has better adherence. 1

Ceftriaxone 1 gram IM or IV daily for 10–14 days may be considered based on moderate-quality evidence from one randomized trial showing comparable efficacy to benzathine penicillin. 1, 5 However, patients with severe penicillin allergy may also react to ceftriaxone due to beta-lactam cross-reactivity. 1

Late Latent Syphilis (Non-Pregnant)

Doxycycline 100 mg orally twice daily for 28 days. 1 Tetracycline 500 mg orally four times daily for 28 days is an alternative. 1

Mandatory before any non-penicillin regimen: Perform CSF examination to exclude neurosyphilis, as oral regimens are inadequate for CNS disease. 1

Neurosyphilis in Penicillin-Allergic Patients

Penicillin desensitization followed by standard IV penicillin is strongly preferred. 1 If desensitization is absolutely not feasible, ceftriaxone 2 grams IV daily for 10–14 days may be considered, but evidence is extremely limited. 1

Pregnancy

All pregnant patients with syphilis MUST receive penicillin—no exceptions. 1, 4 Penicillin is the only therapy with documented efficacy for preventing congenital syphilis and treating fetal infection. 1, 2

Penicillin-Allergic Pregnant Patients

Mandatory penicillin desensitization followed by stage-appropriate penicillin therapy. 1, 4 Tetracycline, doxycycline, erythromycin, azithromycin, and ceftriaxone are absolutely contraindicated—erythromycin does not reliably cure fetal infection. 1

Additional Pregnancy Considerations

• Some experts recommend a second dose of benzathine penicillin 2.4 million units IM one week after the initial dose for women with primary, secondary, or early latent syphilis. 1
• Jarisch-Herxheimer reaction in the second half of pregnancy can precipitate preterm labor or fetal distress—advise women to seek immediate care if they notice contractions or decreased fetal movement. 1
• Screen all pregnant women at first prenatal visit, at 28 weeks, and at delivery. 1
• If a pregnant woman misses any weekly dose, restart the entire three-dose sequence—no partial courses are acceptable. 1

HIV-Infected Patients

HIV-infected patients receive the same penicillin regimens as HIV-negative patients for all disease stages. 6, 1 However, closer monitoring is essential due to higher rates of atypical serologic responses and treatment failure. 6

Enhanced Follow-Up for HIV-Positive Patients

Evaluate clinically and serologically at 3,6,9,12, and 24 months after therapy. 6, 1

Special Considerations

• For late latent syphilis with HIV infection, consider CSF examination before treatment to exclude neurosyphilis. 6
• Limited data suggest no benefit to multiple doses of benzathine penicillin for early syphilis in HIV-infected patients compared to a single dose. 1
• Penicillin-allergic HIV-infected patients should undergo desensitization and receive penicillin. 6, 1

Management of Sexual Partners

Presumptively treat all sexual partners exposed within 90 days before diagnosis of primary, secondary, or early latent syphilis—even if seronegative. 1 Give benzathine penicillin G 2.4 million units IM as a single dose. 1

Time windows for presumptive treatment: 1

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

Partners exposed >90 days prior should also be treated presumptively when serologic results are unavailable and reliable follow-up cannot be ensured. 1

Critical Pitfalls to Avoid

Never use oral penicillin preparations for syphilis—they are completely ineffective. 1

Never use azithromycin in the United States due to widespread macrolide resistance and documented treatment failures. 1, 7

Never switch between RPR and VDRL when monitoring serologic response—results cannot be directly compared. 1

Never skip CSF examination before treating late latent or tertiary syphilis in high-risk patients—you may miss neurosyphilis requiring different treatment. 4

Never use procaine penicillin without probenecid for neurosyphilis—CSF levels will be inadequate. 1

Do not rely on treponemal test titers to assess treatment response—they correlate poorly with disease activity. 1

Jarisch-Herxheimer Reaction

Warn all patients about the Jarisch-Herxheimer reaction—an acute febrile reaction with headache, myalgia, and other symptoms occurring within 24 hours of treatment, most common in early syphilis. 1 No proven preventive measures exist; antipyretics may provide symptomatic relief. 1

HIV Testing

Test all patients diagnosed with syphilis for HIV at the time of diagnosis. 1, 2