What is the recommended treatment for a patient with a positive Treponema pallidum hemagglutination assay (TPHA) test result, indicating syphilis infection?

Treatment of TPHA-Positive Syphilis

Benzathine penicillin G 2.4 million units IM is the definitive treatment for syphilis regardless of HIV status, but the specific regimen depends entirely on staging the infection using nontreponemal test titers (RPR or VDRL) and clinical assessment. 1

Critical First Step: Determine Disease Activity and Stage

A positive TPHA alone cannot guide treatment because treponemal tests remain positive for life after infection, regardless of treatment or disease activity 2. You must immediately:

• Order a nontreponemal test (RPR or VDRL) to assess current disease activity, as titers correlate directly with active infection 2, 3
• Perform targeted physical examination looking for chancre, skin rash (especially palms/soles), mucocutaneous lesions, lymphadenopathy, neurologic symptoms (headache, vision/hearing changes, confusion), or cardiovascular manifestations 2, 3
• Test for HIV infection immediately in all patients, as coinfection affects monitoring frequency and neurosyphilis risk 4, 3

Treatment Algorithm Based on Staging

If RPR/VDRL is Positive (Active Infection):

Primary or Secondary Syphilis (chancre present, rash, mucocutaneous lesions, or symptoms <1 year):

• Benzathine penicillin G 2.4 million units IM as a single dose 1, 4
• For penicillin allergy: Doxycycline 100 mg orally twice daily for 14 days 1, 4, 5
• Follow-up at 6 and 12 months (or 3,6,9,12 months if HIV-positive) 4

Early Latent Syphilis (asymptomatic, infection acquired within past 12 months):

• Benzathine penicillin G 2.4 million units IM as a single dose 1
• For penicillin allergy: Doxycycline 100 mg orally twice daily for 14 days 1, 5

Late Latent Syphilis or Unknown Duration (asymptomatic, infection >12 months or unknown timing):

• Benzathine penicillin G 2.4 million units IM once weekly for 3 consecutive weeks (total 7.2 million units) 1, 3
• For penicillin allergy: Doxycycline 100 mg orally twice daily for 28 days 1, 5
• If HIV-positive, perform CSF examination first to exclude neurosyphilis before treating as late latent 1, 3

Neurosyphilis (neurologic symptoms, ocular symptoms, or CSF abnormalities):

• Aqueous crystalline penicillin G 18-24 million units daily IV (3-4 million units every 4 hours or continuous infusion) for 10-14 days 1, 3
• Alternative: Procaine penicillin 2.4 million units IM daily plus probenecid 500 mg orally four times daily for 10-14 days 1
• For penicillin allergy, desensitization is mandatory - ceftriaxone 2 g IV daily for 10-14 days is only acceptable if desensitization absolutely cannot be performed 1

If RPR/VDRL is Negative (Past Treated Infection):

• No treatment needed if adequately treated previously and no clinical signs of active disease 2
• Review treatment history to confirm appropriate penicillin regimen was given for the stage diagnosed 2
• If treatment history is uncertain or inadequate, treat as late latent syphilis 2

Special Populations

HIV-Infected Patients:

• Same treatment regimens as HIV-negative patients 1, 6
• More frequent monitoring required: every 3 months instead of 6 months 1, 2
• CSF examination mandatory for late latent syphilis or syphilis of unknown duration to exclude neurosyphilis 1, 3
• Higher risk of concomitant uveitis and meningitis - maintain heightened clinical suspicion 1

Pregnant Women:

• Only penicillin regimens are acceptable - stage-appropriate dosing as above 1, 3
• If penicillin allergic, desensitization is mandatory - no alternatives are acceptable in pregnancy 1

Monitoring Treatment Success

• Treatment success = fourfold decline in RPR/VDRL titer (e.g., 1:32 to 1:8) within 6-12 months for early syphilis or 12-24 months for late latent 2, 4, 3
• Use the same test method (RPR vs VDRL) from the same laboratory for all follow-up - titers are not interchangeable 2, 4
• Never use treponemal tests (TPHA, FTA-ABS) to monitor response - they remain positive for life regardless of cure 2, 4

Treatment Failure Indicators

Re-evaluate and consider re-treatment if:

• Nontreponemal titers fail to decline fourfold within expected timeframe 1, 4
• Clinical signs/symptoms persist or recur (new chancre, rash, neurologic symptoms) 1, 4
• Sustained fourfold increase in titer compared to post-treatment baseline 1, 4

For treatment failure: Re-treat with benzathine penicillin G 2.4 million units IM weekly for 3 weeks, perform CSF examination to exclude neurosyphilis, and retest for HIV 1

Critical Pitfalls to Avoid

• Do not treat based on TPHA alone - approximately 15-25% of patients remain serofast with persistent low RPR titers despite cure, which does not indicate treatment failure 2, 4
• Do not use azithromycin as first-line treatment - molecular resistance and treatment failures are well-documented 1
• Do not compare titers between different nontreponemal tests (VDRL vs RPR) - they are not directly comparable 2, 4
• Do not assume persistent low-titer RPR reactivity indicates failure - many patients remain serofast at titers <1:8 for life despite adequate treatment 2, 4