What is the recommended management for a VDRL‑positive syphilis infection?

Management of VDRL-Positive Syphilis

Treat immediately with benzathine penicillin G 2.4 million units IM as a single dose for early syphilis (primary, secondary, or early latent), or 2.4 million units IM weekly for 3 consecutive weeks for late latent or unknown-duration syphilis. 1, 2

Initial Diagnostic Workup

Before initiating treatment, obtain the following:

• Quantitative nontreponemal titer (VDRL or RPR) – document the baseline titer, which is essential for monitoring treatment response 2, 3
• Confirmatory treponemal test (FTA-ABS, TP-PA, or treponemal EIA) – both nontreponemal and treponemal tests must be reactive to confirm true syphilis infection versus biological false-positive 2, 3
• HIV testing – mandatory for all patients with syphilis, as HIV co-infection alters monitoring frequency (every 3 months instead of 6 months), increases neurosyphilis risk, and may modify serologic response 1, 2, 3
• Targeted physical examination – assess for stage-specific manifestations including genital ulcers (primary), palm-sole rash or mucocutaneous lesions (secondary), neurologic signs (cranial nerve palsies, confusion, meningismus), ocular symptoms (vision changes, uveitis), or cardiovascular/gummatous findings (tertiary) 2, 3

Stage-Specific Treatment Regimens

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

• Benzathine penicillin G 2.4 million units IM as a single dose 1, 2, 3
• This regimen achieves cure in >95% of patients when adherence and follow-up are ensured 2
• For penicillin-allergic non-pregnant patients: doxycycline 100 mg orally twice daily for 14 days 1, 2, 3

Late Latent Syphilis or Unknown Duration

• Benzathine penicillin G 2.4 million units IM once weekly for 3 consecutive weeks (total 7.2 million units) 1, 2, 3
• For penicillin-allergic non-pregnant patients: doxycycline 100 mg orally twice daily for 28 days, though this has not been sufficiently evaluated in HIV-infected persons 1

Neurosyphilis

Perform lumbar puncture with CSF examination if any of the following are present 1, 2, 3:

• Neurologic symptoms (cranial nerve palsy, confusion, headache, meningismus)
• Ocular involvement (uveitis, vision changes, eye pain)
• Auditory symptoms
• HIV infection with late latent syphilis
• Serum VDRL titer >1:32 with CD4 count <350 cells/mm³

If neurosyphilis is confirmed:

• 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 1, 2, 3
• Some experts recommend following IV therapy with benzathine penicillin G 2.4 million units IM weekly for 3 weeks to provide equivalent total duration 1, 2
• Penicillin desensitization is mandatory for penicillin-allergic patients with neurosyphilis, as no proven alternatives exist 1, 2
• Alternative regimen if desensitization is not feasible: procaine penicillin 2.4 million units IM daily PLUS probenecid 500 mg orally four times daily, both for 10–14 days 1

Follow-Up and Monitoring

Standard (Non-HIV) Patients

• Early syphilis: clinical and serologic evaluation at 6 and 12 months after treatment 1, 2, 4
• Late latent syphilis: serologic evaluation at 6,12,18, and 24 months after treatment 1, 2, 4
• Use the same nontreponemal test method (VDRL or RPR), preferably by the same laboratory, as titers are not directly comparable between methods 2, 4

HIV-Infected Patients

• More frequent monitoring every 3 months (at 3,6,9,12,18, and 24 months) instead of the standard 6-month intervals 1, 2, 4
• HIV-infected patients may exhibit atypical serologic responses with unusually high, low, or fluctuating titers 1, 2, 4
• Consider CSF examination for all HIV-infected patients with late latent syphilis or syphilis of unknown duration 1, 2

Neurosyphilis Follow-Up

• Repeat CSF examination every 6 months until the white-cell count normalizes 1, 2
• Consider re-treatment if CSF cell count has not decreased at 6 months or if CSF remains abnormal after 2 years 1, 2

Defining Treatment Success and Failure

Treatment Success

• Early syphilis: at least a fourfold decline in nontreponemal titer within 6–12 months (e.g., from 1:32 to 1:8) 1, 2, 4, 5
• Late latent syphilis: at least a fourfold decline in nontreponemal titer within 12–24 months 1, 2, 4, 5
• A fourfold change equals a change of two dilutions and is considered clinically significant 2, 4

Treatment Failure – Suspect When:

• No fourfold decline in titer within the stage-specific timeframe 1, 2, 4
• Sustained fourfold increase in titer after an initial decline 1, 2, 4
• Clinical signs or symptoms persist or recur (new chancre, rash, mucocutaneous lesions, neurologic or ocular symptoms) 1, 2, 4

Serofast State

• Approximately 15–25% of treated patients remain "serofast" with persistent low-level reactive titers (generally ≤1:8) for months or years 1, 2
• Serofast status does NOT represent treatment failure and does not require additional antibiotic therapy 1, 2
• Reinfection should be suspected when a fourfold rise occurs above the documented serofast baseline 1, 2

Management of Treatment Failure

When treatment failure is suspected:

1. Re-evaluate for HIV infection if not recently tested 1, 2, 4
2. Perform CSF examination to rule out neurosyphilis, unless reinfection is certain 1, 2, 4
3. If CSF is normal (no neurosyphilis): re-treat with benzathine penicillin G 2.4 million units IM weekly for 3 weeks 1, 2
4. If CSF indicates neurosyphilis: treat with aqueous crystalline penicillin G 18–24 million units per day IV for 10–14 days, followed by benzathine penicillin G 2.4 million units IM weekly for 3 weeks 1, 2

Special Populations

Pregnancy

• All pregnant women should be screened at the first prenatal visit 1, 2
• High-risk pregnant women require repeat screening at 28 weeks and at delivery 1, 2
• Penicillin is the only acceptable treatment for syphilis during pregnancy to prevent congenital syphilis 1, 2
• Penicillin-allergic pregnant women require desensitization – no alternatives are acceptable 1, 2, 3
• Some experts recommend a second injection of benzathine penicillin G 2.4 million units IM one week after the first for HIV-infected pregnant women with early syphilis 1

HIV-Infected Patients

• Serologic responses may be slower, and subtle variations in the temporal pattern of response may occur 1, 5
• Within primary syphilis, HIV patients with CD4 count <500 cells/µL have slower treatment response 5
• Concomitant uveitis and meningitis are more common among HIV-infected patients with syphilis 2

Critical Pitfalls to Avoid

• Never use treponemal test titers (FTA-ABS, TP-PA) to monitor treatment response – these remain positive for life in most patients regardless of cure 2, 3, 4
• Never compare VDRL and RPR titers directly – use the same test method throughout follow-up 2, 3, 4
• Do not delay treatment waiting for confirmatory test results if clinical suspicion is high and the patient is at risk for loss to follow-up 2, 3
• Do not assume treatment failure with persistent low titers (≤1:8) – this may represent serofast state 1, 2
• Do not use azithromycin as first-line treatment – molecular resistance and clinical treatment failures have been reported 1

Partner Management

• Evaluate and treat all sexual contacts within the past 90 days for primary syphilis, 6 months for secondary syphilis, and 1 year for early latent syphilis 2, 3
• Sexual transmission occurs primarily when mucocutaneous lesions are present 3

Jarisch-Herxheimer Reaction

• Warn patients about possible acute febrile reaction within 24 hours of treatment characterized by fever, headache, and myalgia 3
• This reaction is common in early syphilis and does NOT indicate treatment failure 3
• Antipyretics may be recommended, though no proven prevention methods exist 3