Syphilis: Comprehensive Diagnostic and Treatment Guidelines
Diagnostic Testing
Screen with nontreponemal tests (RPR or VDRL) and confirm all reactive results with treponemal tests (FTA-ABS or TP-PA). 1, 2 Nontreponemal titers must be reported quantitatively because they correlate with disease activity and guide treatment monitoring. 1, 2 A fourfold change in titer (two dilutions, such as 1:16 to 1:4) is the threshold for clinical significance. 1, 3, 2
Alternative Diagnostic Approaches
- When clinical findings suggest syphilis but serologic tests are nonreactive or unclear, use darkfield examination, direct fluorescent antibody staining of lesion material, or biopsy. 4
- In HIV-infected patients, serologic responses may be atypical (unusually high, low, or fluctuating titers), but both treponemal and nontreponemal tests can be interpreted in the usual manner for most coinfected patients. 4, 3
Treatment by Stage
Primary and Secondary Syphilis
Benzathine penicillin G 2.4 million units IM as a single dose achieves 90–100% treatment success and is the definitive first-line therapy. 1, 2 This regimen reflects decades of clinical experience with the highest quality evidence. 1
For penicillin-allergic, non-pregnant adults: doxycycline 100 mg orally twice daily for 14 days is the preferred alternative. 1, 2 Tetracycline 500 mg orally four times daily for 14 days is acceptable but less preferred due to lower adherence. 1
Ceftriaxone 1 g IM or IV daily for 10–14 days may be considered for penicillin-allergic patients based on moderate-quality evidence from one randomized trial, though cross-reactivity with penicillin allergy is possible. 1 A single dose is ineffective; the full 10–14 day course is mandatory. 1
Early Latent Syphilis (≤1 Year Duration)
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, unequivocal primary/secondary symptoms within the past year, or a sexual partner with confirmed early syphilis. 1
For penicillin-allergic, non-pregnant adults: doxycycline 100 mg orally twice daily for 14 days. 1
Late Latent Syphilis or Unknown Duration (>1 Year)
Benzathine penicillin G 7.2 million units total, administered as three weekly doses of 2.4 million units IM. 1, 2 If a dose is missed, a 10–14 day interval before the next dose is acceptable, but pregnant women must repeat the entire course if any dose is missed. 1
For penicillin-allergic, non-pregnant adults: doxycycline 100 mg orally twice daily for 28 days. 1, 2 A CSF examination must exclude neurosyphilis before using any non-penicillin regimen for late latent disease. 1
Tertiary Syphilis
Benzathine penicillin G 7.2 million units total (three weekly IM doses of 2.4 million units). 1 CSF examination is mandatory before treatment to exclude neurosyphilis. 1 Some experts recommend treating all cardiovascular syphilis cases with the neurosyphilis regimen (IV aqueous crystalline penicillin G). 1 Consultation with an infectious disease specialist is advised. 1
Neurosyphilis
Aqueous crystalline penicillin G 18–24 million units per day IV (administered as 3–4 million units every 4 hours or continuous infusion) for 10–14 days is the preferred regimen. 4, 1 This dosing achieves CSF concentrations that eradicate Treponema pallidum. 1
Alternative outpatient regimen: procaine penicillin 2.4 million units IM once daily PLUS probenecid 500 mg orally four times daily for 10–14 days. 4, 1 Probenecid is mandatory; omitting it results in subtherapeutic CSF levels and treatment failure. 4, 1 This regimen is contraindicated in patients with sulfonamide allergy due to cross-reactivity with probenecid. 4, 1
Optional supplemental therapy: Some specialists add benzathine penicillin G 2.4 million units IM weekly for up to 3 weeks after completing the IV course to match the total treatment duration used for late syphilis. 4, 1
Indications for CSF Examination Before Treatment
- Neurologic signs or symptoms (cognitive dysfunction, motor/sensory deficits, cranial nerve palsies, meningismus). 1
- Ocular involvement (uveitis, neuroretinitis, optic neuritis)—treat as neurosyphilis regardless of other clinical features. 1
- Auditory symptoms. 4
- Evidence of active tertiary syphilis (aortitis, gummas, iritis). 1
- Treatment failure (persistent symptoms or rising titers). 1
- HIV infection with late latent syphilis or unknown duration. 4, 1
- Nontreponemal titer ≥1:32 when infection duration is ≥1 year. 1
Management of Penicillin Allergy
Non-Pregnant Patients
For early syphilis: doxycycline 100 mg orally twice daily for 14 days is first-line. 1, 2 Tetracycline 500 mg orally four times daily for 14 days is an alternative. 1
For late latent syphilis: doxycycline 100 mg orally twice daily for 28 days. 1, 2 CSF examination must exclude neurosyphilis before initiating any oral regimen. 1
For neurosyphilis: Penicillin desensitization is strongly preferred. 1 If desensitization is not feasible, ceftriaxone 2 g IV daily for 10–14 days may be considered, though evidence is extremely limited. 4, 1
Never use azithromycin due to widespread macrolide resistance and documented treatment failures. 1, 2
Pregnant Patients
All pregnant patients with penicillin allergy MUST undergo desensitization followed by penicillin treatment—no exceptions. 4, 1 Penicillin is the only therapy with documented efficacy for preventing congenital syphilis and treating fetal infection. 4, 1, 2
Skin testing should confirm penicillin allergy before desensitization. 1 A single desensitization procedure is sufficient; repeat desensitization before each dose is not required. 1
Tetracyclines, doxycycline, erythromycin, azithromycin, and ceftriaxone are absolutely contraindicated in pregnancy because they do not reliably cure fetal infection and may cause maternal or fetal toxicity. 4, 1
Syphilis in Pregnancy
Treat with the penicillin regimen appropriate for the disease stage, completed at least 4 weeks before delivery. 4, 1 For primary, secondary, or early latent syphilis, some experts recommend an additional dose of benzathine penicillin G 2.4 million units IM one week after the initial dose, especially in the third trimester or when treating secondary syphilis. 4, 1
Screening Requirements
- Screen all pregnant women at the first prenatal visit, at 28 weeks gestation, and at delivery. 1, 2
- In high-risk populations or high-prevalence areas, perform monthly titer checks until delivery. 1
- Test any woman who delivers a stillborn infant after 20 weeks gestation. 4, 1
- No newborn may be discharged without documented maternal syphilis screening. 4, 1
Jarisch-Herxheimer Reaction Precautions
Women treated in the second half of pregnancy are at risk for premature labor or fetal distress if a Jarisch-Herxheimer reaction occurs. 4, 1 Advise patients to seek immediate obstetric care if they develop fever, uterine contractions, or decreased fetal movements within 24 hours after treatment. 4, 1 For pregnancies >20 weeks gestation, consider fetal and uterine-contraction monitoring for 24 hours after therapy, especially when ultrasound shows fetal hepatomegaly or hydrops. 1 Do not delay treatment due to fear of this reaction; untreated syphilis poses far greater fetal risk. 1
Serologic Monitoring in Pregnancy
- Repeat quantitative nontreponemal titers in the third trimester and at delivery. 4, 1
- Most women will deliver before their serologic response can be definitively assessed. 4
Syphilis in HIV-Infected Patients
HIV-infected patients receive the same penicillin regimens as HIV-negative patients for all disease stages. 4, 1 Multiple doses of benzathine penicillin for early syphilis provide no additional benefit in HIV-infected patients. 1
Enhanced Monitoring Requirements
Clinical and serologic evaluations at 3,6,9,12, and 24 months after treatment are mandatory due to higher rates of treatment failure and atypical serologic responses. 4, 1, 3
Special Considerations
- For late latent syphilis, consider CSF examination before therapy if CD4 ≤350 cells/µL or RPR ≥1:32. 1
- If treatment failure occurs and CSF is normal, retreat with benzathine penicillin G 7.2 million units (three weekly doses). 1, 3
- If CSF indicates neurosyphilis, treat with IV aqueous crystalline penicillin G. 1
- Penicillin-allergic HIV-infected patients should undergo desensitization. 4, 1
Follow-Up and Monitoring
Primary and Secondary Syphilis
Perform quantitative nontreponemal 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, 2
Latent Syphilis
Repeat quantitative nontreponemal tests at 6,12,18, and 24 months. 1, 3, 2 A fourfold decline is expected within 12–24 months. 1, 3
Neurosyphilis
If CSF pleocytosis was present initially, repeat CSF examination every 6 months until the cell count normalizes. 4, 1 CSF white blood cell count is the most sensitive marker of treatment response. 1 Consider retreatment if the cell count has not decreased after 6 months or if CSF remains abnormal after 2 years. 4, 1
Treatment Failure Criteria
- Sustained fourfold increase in nontreponemal titers. 1, 3
- Failure of an initially high titer (≥1:32) to decline fourfold within 6–12 months for early syphilis or 12–24 months for late syphilis. 1, 3
- Development of new clinical signs or symptoms. 1
When treatment failure is identified, perform CSF examination to assess for neurosyphilis. 1, 3 If CSF is normal, retreat with benzathine penicillin G 7.2 million units (three weekly doses). 1 If CSF indicates neurosyphilis, use the IV aqueous crystalline penicillin G regimen. 1
Important Monitoring Principles
- Use the same laboratory and test method (RPR or VDRL) for serial monitoring; results cannot be directly compared between methods. 1, 3
- Do not rely on treponemal test titers to assess treatment response; they correlate poorly with disease activity. 1, 2
- 15–25% of successfully treated patients remain "serofast" with persistent low titers (<1:8) that do not indicate treatment failure. 1
Partner Notification and Management
Presumptively treat sexual partners exposed within 90 days before the index patient's diagnosis of primary, secondary, or early latent syphilis with benzathine penicillin G 2.4 million units IM, even if seronegative. 1 Partners exposed >90 days prior should also receive presumptive treatment when serologic results are unavailable and reliable follow-up cannot be ensured. 1
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
Long-term partners of patients with late syphilis should undergo clinical and serologic evaluation. 1
Critical Pitfalls to Avoid
- Never use oral penicillin preparations for any stage of syphilis—they are ineffective. 1, 2
- Never use procaine penicillin without probenecid for neurosyphilis; CSF levels will be inadequate. 4, 1
- Never substitute non-penicillin antibiotics in pregnancy; penicillin desensitization is mandatory. 4, 1, 2
- Never use azithromycin due to widespread resistance. 1, 2
- Never switch between RPR and VDRL when monitoring treatment response; titers are not directly comparable. 1, 3
- Never skip CSF examination before treating late latent syphilis with doxycycline; undiagnosed neurosyphilis will not respond. 1
- Never shorten the 28-day doxycycline course for late latent syphilis. 1
- Never use multiple benzathine penicillin doses for early syphilis in HIV-infected patients—evidence shows no benefit. 1
Additional Recommendations
All patients diagnosed with syphilis should be tested for HIV. 4, 1, 2 In high-prevalence areas, retest patients with primary syphilis for HIV three months after initial testing. 1
Counsel all patients about the Jarisch-Herxheimer reaction—an acute febrile reaction with headache, myalgia, and other systemic symptoms that may occur within 24 hours of treatment, especially in early syphilis. 1, 3 Antipyretics may provide symptomatic relief, but no proven preventive measures exist. 1