Syphilis Diagnosis and Treatment

Diagnostic Considerations

• The Centers for Disease Control and Prevention (CDC) recommends a two-step diagnostic approach, starting with a nontreponemal test (RPR or VDRL), and if positive, confirming with a treponemal test (TP-PA, FTA-ABS, EIA, or chemiluminescent immunoassay), which has a lower false-positive rate and is cost-effective for low-prevalence settings 1, 2
• Non-treponemal tests (RPR or VDRL) detect antibodies to cardiolipin and are used for screening and monitoring treatment response, but can yield false-positive results in many conditions unrelated to syphilis 1
• A cerebrospinal fluid (CSF) examination should be performed in patients with neurologic or ocular symptoms, evidence of active tertiary syphilis, treatment failure, or HIV-infected patients with late latent syphilis or unknown duration, or HIV-infected patients with CD4 <350 cells/μL and RPR ≥1:32 3
• CSF findings suggestive of neurosyphilis include a reactive CSF-VDRL, CSF WBC >10 cells/μL, and elevated protein (>40 mg/dL) 3
• The sensitivity and specificity of syphilis tests are as follows:

4

• Interpretation of syphilis test results:

Treatment Recommendations

• The CDC recommends benzathine penicillin G 2.4 million units IM as a single dose for early syphilis (primary, secondary, early latent) 5, 6, 2, 7, 4
• The CDC recommends benzathine penicillin G 2.4 million units IM weekly for 3 consecutive weeks for late latent or unknown duration syphilis 5, 6, 2, 7, 4
• Aqueous crystalline penicillin G 18-24 million units IV daily for 10-14 days is recommended for neurosyphilis 5, 6
• Doxycycline 100 mg orally twice daily for 14 days or 28 days is recommended for non-pregnant, non-neurosyphilis patients who are allergic to penicillin 6, 8, 4, 7
• The CDC recommends penicillin as the only treatment for pregnant patients, with desensitization required for penicillin-allergic patients 2

Follow-up and Monitoring

• Treatment failure is indicated by persistent or recurring clinical signs/symptoms of disease, or a sustained fourfold increase in serum nontreponemal titers after an initial reduction 3
• Failure to achieve at least a fourfold decrease in nontreponemal test titers 6-12 months after therapy for early syphilis is considered treatment failure 3
• The CDC recommends a follow-up schedule of quantitative nontreponemal tests at 3, 6, 9, 12, and 24 months after treatment, with clinical evaluation at 6 and 12 months 5, 3
• Recommended follow-up testing for syphilis:

8, 7, 6

• Successful treatment is indicated by a fourfold decline in titer within 6-12 months, according to the CDC 2

Special Considerations

• HIV-infected patients should be evaluated more carefully as they may have unusual serologic responses 6
• The CDC recommends the same treatment regimens for HIV co-infected patients as for HIV-negative patients, with more intensive follow-up due to higher risk of treatment failure 2
• Patients with HIV and syphilis require careful monitoring and may progress more rapidly to neurosyphilis 5, 4
• Patients with late latent syphilis, CD4 count <350 cells/mm³ with high-titer VDRL (>1:32), or treatment failure should be evaluated for neurosyphilis with lumbar puncture 4, 9

Prevention and Partner Management

• Practicing safe sex and undergoing regular screenings for sexually transmitted infections (STIs) can help prevent reinfection, as recommended by the CDC, with a strength of evidence rated as high 6, 4
• The CDC recommends that partners exposed within 90 days preceding diagnosis should be treated presumptively even if seronegative, and partners exposed >90 days before diagnosis should be treated presumptively if serologic results are not immediately available and follow-up is uncertain 6