What is the recommended treatment for a patient testing positive for syphilis via a Treponema Pallidum Hemagglutination Assay (TPHA) test?

Treatment for TPHA Positive Syphilis

A positive TPHA test requires immediate confirmation with a quantitative nontreponemal test (RPR or VDRL) to distinguish between active infection requiring treatment and past treated infection, followed by stage-appropriate benzathine penicillin G therapy if active disease is confirmed. 1

Initial Diagnostic Workup

A positive TPHA alone is insufficient for diagnosis or treatment decisions because treponemal tests remain positive for life in 75-85% of patients regardless of treatment status 1, 2. You must:

• Order a quantitative nontreponemal test (RPR or VDRL) immediately to determine if this represents active infection versus past treated disease 1
• Obtain the actual titer (e.g., 1:4,1:16,1:64), not just "positive/negative," as titers correlate with disease activity and guide treatment monitoring 1
• Test for HIV infection in all patients with reactive syphilis serology, as HIV coinfection affects monitoring frequency (every 3 months instead of 6 months) and increases neurosyphilis risk 1, 2

Interpretation of Combined Results

TPHA Positive + RPR/VDRL Positive (Active Infection)

This pattern indicates active syphilis requiring treatment. The RPR/VDRL titer helps determine disease stage:

• High titers (≥1:8) are highly specific for true active infection with false-positives being extremely rare 1
• Low titers (1:1 to 1:4) may represent early latent disease, late latent disease, or a serofast state after prior treatment 3

TPHA Positive + RPR/VDRL Negative (Past Treated or Late Disease)

This pattern requires careful evaluation:

• Most commonly represents adequately treated past infection 1
• However, nontreponemal tests have reduced sensitivity in late-stage disease (only 61-75% sensitive in late latent syphilis and 47-64% in tertiary syphilis) 1
• Screen for symptoms of neurosyphilis (headache, vision changes, hearing loss, cranial nerve deficits) or tertiary syphilis (cardiovascular or gummatous manifestations) 1
• If symptomatic or high clinical suspicion, proceed with CSF examination and treat accordingly despite negative RPR/VDRL 1

Stage-Specific Treatment Regimens

Primary and Secondary Syphilis

• Benzathine penicillin G 2.4 million units IM as a single dose 4, 1, 2
• Primary syphilis presents with painless anogenital chancre 5
• Secondary syphilis presents with diffuse rash, mucocutaneous lesions, and lymphadenopathy 5

Early Latent Syphilis (Infection <1 Year)

• Benzathine penicillin G 2.4 million units IM as a single dose 2
• Early latent is defined as infection acquired within the past 12 months based on documented seroconversion, fourfold titer increase, history of symptoms within the past year, or sex partner with documented early syphilis 2

Late Latent Syphilis or Unknown Duration (Infection >1 Year)

• Benzathine penicillin G 2.4 million units IM once weekly for 3 consecutive weeks (total 7.2 million units) 1, 2
• This is the default treatment when duration cannot be established 3

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 1, 2
• CSF examination is mandatory before treatment if neurologic symptoms, ocular symptoms, treatment failure, HIV infection with late latent syphilis, or serum nontreponemal titer ≥1:32 are present 2

Penicillin Allergy Alternatives

Non-Pregnant Adults with Early Syphilis

• Doxycycline 100 mg orally twice daily for 14 days 2
• Ceftriaxone 1 gram IM/IV daily for 10-14 days may be considered based on randomized trial data, though it remains second-line 2
• Never use azithromycin in the United States due to widespread macrolide resistance and documented treatment failures 2

Non-Pregnant Adults with Late Latent Syphilis

• Doxycycline 100 mg orally twice daily for 28 days 2
• Penicillin desensitization is strongly preferred over alternatives 3

Pregnant Women and Neurosyphilis

• Penicillin desensitization is mandatory—no exceptions 2
• Penicillin is the only therapy with documented efficacy for preventing maternal transmission and treating fetal infection 2
• Doxycycline, tetracycline, erythromycin, azithromycin, and ceftriaxone are inadequate in pregnancy 2

Follow-Up and Monitoring

Primary and Secondary Syphilis

• Clinical and serologic evaluation at 6 and 12 months using quantitative nontreponemal tests 4, 2
• Expected response: Fourfold decline in titer within 6 months 2
• 15-25% of patients treated during primary syphilis may revert to serologically nonreactive after 2-3 years 1

Latent Syphilis

• Clinical and serologic evaluation at 6,12, and 24 months 1, 2
• Expected response: Fourfold decline in titer within 12-24 months 1, 2
• Many patients remain "serofast" with persistent low titers (<1:8) that do not indicate treatment failure 1, 2

HIV-Infected Patients

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

Treatment Failure Indicators

Treatment failure or reinfection should be suspected if:

• Clinical signs or symptoms persist or recur (new chancre, rash, neurologic symptoms, ocular symptoms) 1, 2
• Sustained fourfold increase in nontreponemal titer compared to post-treatment baseline 1, 2
• Failure of titer to decline fourfold within 6 months for early syphilis or 12-24 months for late syphilis 1, 2

Management of Treatment Failure

• Re-evaluate for HIV infection if not previously tested 2
• Perform CSF examination to rule out neurosyphilis 2
• Re-treat with three weekly injections of benzathine penicillin G 2.4 million units IM unless neurosyphilis is confirmed 4, 2

Critical Pitfalls to Avoid

• Never use treponemal test titers (like TPHA) to assess treatment response—they remain positive for life and correlate poorly with disease activity 1, 2
• Never switch between RPR and VDRL when monitoring treatment response—use the same test method, preferably by the same laboratory, as results are not directly comparable 1, 2
• Never assume persistent low-titer reactivity (<1:8) necessarily indicates treatment failure—this "serofast" state is common and does not require retreatment 1, 2
• Never use oral penicillin preparations for syphilis treatment—they are ineffective 2
• Never delay treatment in pregnant women with penicillin allergy—desensitization is mandatory as no alternative prevents congenital syphilis 2

Partner Management

• Identify and treat sexual contacts from the past 3 months plus duration of symptoms for primary syphilis, 6 months plus duration of symptoms for secondary syphilis, and 1 year for early latent syphilis 4, 2
• Treat partners presumptively if exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis, even if seronegative 2