What is the recommended approach for confirming and treating syphilis?

Syphilis Confirmation and Treatment

Confirm syphilis using both nontreponemal (RPR or VDRL) and treponemal tests (FTA-ABS, TP-PA), as using only one test type is insufficient for diagnosis, and treat all confirmed cases with parenteral penicillin G, with the specific preparation and duration determined by disease stage. 1, 2

Diagnostic Confirmation Strategy

Direct Detection (When Lesions Present)

• Darkfield microscopy of lesion exudate or tissue is the gold standard for diagnosing primary syphilis when mucocutaneous lesions are available. 1
• Direct fluorescent antibody (DFA-TP) staining serves as an alternative when darkfield is unavailable. 1

Serologic Testing Algorithms

Traditional Algorithm (Preferred by CDC):

• Screen with nontreponemal test (VDRL or RPR) first 1, 2
• Confirm all reactive nontreponemal tests with treponemal test (FTA-ABS, TP-PA, or MHA-TP) 1
• Report nontreponemal results quantitatively as titers correlate with disease activity 1, 2

Reverse Algorithm (Alternative):

• Screen with treponemal enzyme immunoassay (EIA) or chemiluminescent assay 2
• Follow with nontreponemal test for confirmation of active disease 2
• This approach increases detection in late latent and early primary stages but may increase false-positives 3

Interpreting Test Results

Nontreponemal Tests (VDRL/RPR):

• A fourfold change in titer (two dilutions, e.g., 1:16 to 1:4) represents clinically significant difference in disease activity or treatment response 4, 2
• Sequential tests must use the same method (VDRL or RPR) and preferably the same laboratory 4
• False-positives occur with various medical conditions; never diagnose on nontreponemal test alone 4

Treponemal Tests:

• Remain reactive for life in most patients regardless of treatment 4, 2
• Do not correlate with disease activity; never use to assess treatment response 4
• 15-25% of patients treated during primary stage may revert to nonreactive after 2-3 years 4

Special Diagnostic Situations

HIV-Infected Patients:

• Standard serologic tests remain accurate and reliable for most HIV-infected patients 1, 4
• Unusual responses (unusually high, low, or fluctuating titers) can occur; consider biopsy or direct microscopy if serologic results don't match clinical presentation 4
• False-positive nontreponemal tests not confirmed by treponemal tests occur more commonly 1

Neurosyphilis Diagnosis:

• Diagnose based on CSF examination showing reactive CSF-VDRL plus CSF WBC >10 cells/µL 1
• CSF-VDRL is highly specific but insensitive—reactive test confirms neurosyphilis, but nonreactive test does not exclude it 1
• CSF white blood cell count typically elevated at 10-200 cells/µL with mononuclear predominance 1
• Blood contamination can cause false-positive CSF-VDRL; interpret carefully 1

Critical Pitfall:

• Beware the prozone phenomenon where false-negative nontreponemal tests occur with very high antibody titers; dilute serum if clinical suspicion is high despite negative screening test. 1

Treatment Recommendations by Stage

Primary, Secondary, and Early Latent Syphilis (<1 Year)

Recommended Regimen:

• Benzathine penicillin G 2.4 million units IM as single dose 4
• Treatment success rates of 90-100% reported 5

HIV-Infected Patients:

• Same benzathine penicillin G 2.4 million units IM single dose 4
• Some experts recommend three weekly doses (total 7.2 million units) though evidence is limited 4
• Consider CSF examination before therapy if CNS involvement suspected 4

Late Latent Syphilis (>1 Year or Unknown Duration)

• Benzathine penicillin G 7.2 million units total, administered as 2.4 million units IM weekly for 3 weeks 4

Neurosyphilis

Recommended Regimen:

• Aqueous crystalline penicillin G 18-24 million units daily, administered as 3-4 million units IV every 4 hours for 10-14 days 2
• Alternative: Procaine penicillin G 2.4 million units IM daily plus probenecid 500 mg orally four times daily, both for 10-14 days 4

Penicillin-Allergic Patients

Non-Pregnant Adults (Not Neurosyphilis):

• Doxycycline is the recommended alternative 2
• Ceftriaxone may be considered but data are limited 4

Pregnant Women or Neurosyphilis:

• Penicillin desensitization is mandatory; no acceptable alternatives exist. 4, 2
• Skin testing to confirm penicillin allergy may be useful before desensitization 4

HIV-Infected Penicillin-Allergic Patients:

• Manage according to recommendations for penicillin-allergic HIV-negative patients 4
• Desensitization strongly preferred over alternatives 4

Follow-Up and Treatment Response

Monitoring Schedule

• Clinical and serologic evaluation at 6 and 12 months after treatment 2
• For HIV-infected patients: evaluate at 3,6,9,12, and 24 months 4

Defining Treatment Success

• A fourfold decline in nontreponemal test titers indicates adequate treatment response. 2
• Response should be evident by 6 months in early syphilis but takes 12-24 months for latent syphilis 5
• Some patients remain "serofast" with persistently low titers despite successful treatment 4

Treatment Failure Criteria

• Persistent or recurrent signs/symptoms 2
• Sustained fourfold increase in nontreponemal titer 2
• Failure of nontreponemal titer to decrease fourfold within 6-12 months 4

Management of Treatment Failure:

• Perform CSF examination to rule out neurosyphilis 4
• Re-treat with benzathine penicillin G 7.2 million units (three weekly doses of 2.4 million units) if CSF is normal 4
• Consider HIV testing if not previously performed 4

Pregnancy-Specific Considerations

• Screen all pregnant women at first prenatal visit 1
• Evaluate all infants born to seropositive mothers with quantitative nontreponemal test on infant serum (not cord blood, which can be contaminated with maternal blood) 4, 1
• Maternal serologic status must be documented at least once during pregnancy and preferably again at delivery 4