What is the recommended testing and treatment approach for a patient suspected of having syphilis, considering their medical history and potential complications?

Syphilis Testing: Diagnostic Approach and Treatment

Diagnostic Algorithm

All suspected syphilis cases should be screened with a nontreponemal test (RPR or VDRL) and any reactive result must be confirmed with a treponemal-specific test (FTA-ABS, TP-PA, or MHA-TP) before initiating treatment. 1

Initial Screening Strategy

• Screen with RPR (Rapid Plasma Reagin) or VDRL as the first-line nontreponemal test, which detects antibodies against lipid material released from damaged cells during infection 1
• Confirm all reactive nontreponemal tests with treponemal testing (FTA-ABS, TP-PA, or MHA-TP) - do NOT repeat the RPR for confirmation 1
• The RPR has sensitivity of 85-90% and specificity of 95-98% for detecting active syphilis 1
• False-positive RPR results can occur at low titers (<1:8) in 1-5% of cases, particularly in injection drug users and various medical conditions 1

Quantitative Titer Interpretation

• Report RPR titers quantitatively (e.g., 1:4,1:16,1:32) as they correlate with disease activity 1
• A fourfold change in titer (equivalent to two dilutions, such as 1:16 to 1:4) is clinically significant with 80-90% positive predictive value 1
• Sequential RPR tests must use the same method and ideally the same laboratory, as RPR titers are often slightly higher than VDRL titers and cannot be directly compared 1

Staging Syphilis for Treatment

Primary Syphilis

• Painless ulcer or chancre at infection site, median duration 3-6 weeks 1
• Treatment: Benzathine penicillin G 2.4 million units IM as a single dose with 90-95% cure rate 1

Secondary Syphilis

• Diffuse rash, mucocutaneous lesions, and lymphadenopathy, median duration 2-6 months 1
• Treatment: Benzathine penicillin G 2.4 million units IM as a single dose with 90-95% cure rate 1

Early Latent Syphilis

• Asymptomatic infection acquired within the previous year, detected only by serology 1
• Treatment: Benzathine penicillin G 2.4 million units IM as a single dose with 85-90% cure rate 1

Late Latent or Unknown Duration Syphilis

• Asymptomatic infection acquired more than one year ago or unknown timing 1
• Treatment: Benzathine penicillin G 2.4 million units IM weekly for 3 weeks (total 7.2 million units) with 80-85% cure rate 1

Neurosyphilis

• Can occur at any stage and presents with meningitis, uveitis, hearing loss, stroke, or other neurologic symptoms 2
• Treatment: Aqueous crystalline penicillin G 18-24 million units per day (3-4 million units IV every 4 hours) for 10-14 days with 90-95% cure rate 1
• Consider adding benzathine penicillin G 2.4 million units IM weekly for up to 3 weeks after completing neurosyphilis treatment to provide comparable total duration 1

Critical Pre-Treatment Evaluations

When to Perform CSF Examination

CSF examination is NOT routinely required for primary or secondary syphilis unless neurologic or ophthalmic symptoms are present. 3, 1

Perform CSF examination before treatment if ANY of the following criteria are met: 3

• Neurologic or ophthalmic signs or symptoms (meningitis, uveitis, visual changes) 3
• Other evidence of active tertiary syphilis (aortitis, gumma, iritis) 3
• Treatment failure (persistent symptoms or fourfold titer increase) 3
• HIV infection with late latent syphilis 3, 1
• Serum nontreponemal titer ≥1:32 unless duration of infection is known to be <1 year 3
• Nonpenicillin therapy planned, unless duration of infection is known to be <1 year 3

Mandatory HIV Testing

All patients diagnosed with syphilis should be tested for HIV if status is unknown. 3, 1

• In high HIV prevalence areas, retest HIV-negative patients with primary syphilis after 3 months 3

Special Population Considerations

HIV-Infected Patients

• Use the same penicillin regimens as HIV-negative patients - no additional doses of benzathine penicillin are recommended 1
• HIV-infected patients require more intensive monitoring at 3,6,9,12, and 24 months due to higher risk of treatment failure 1
• Consider CSF examination for late latent syphilis in HIV-infected patients to exclude neurosyphilis 1
• HIV-infected patients may have atypical serologic responses (unusually high, low, or fluctuating titers) in 10-20% of cases 1

Pregnant Women

Pregnant women with syphilis must be treated with parenteral penicillin G appropriate for their stage of disease. 1

• Some experts recommend an additional dose of benzathine penicillin G 2.4 million units IM one week after the initial dose for pregnant women with primary, secondary, or early latent syphilis 1
• Treatment must occur >4 weeks before delivery for optimal outcomes 1
• Pregnant women with penicillin allergy must be desensitized and treated with penicillin - it is the only documented effective treatment to prevent congenital syphilis 1
• Screen pregnant patients 3 times: at first prenatal visit, during third trimester, and at delivery 2
• Up to 40% of fetuses with in-utero syphilis exposure are stillborn or die during infancy 2

Penicillin-Allergic Patients (Non-Pregnant)

• For primary, secondary, or early latent syphilis: Doxycycline 100 mg orally twice daily for 2 weeks 3, 1
• For late latent syphilis: Doxycycline 100 mg orally twice daily for 4 weeks 3
• Alternative: Tetracycline 500 mg orally 4 times daily (same duration as doxycycline) 3
• CSF examination must exclude neurosyphilis before using nonpenicillin therapy for latent syphilis 3

Pediatric Patients

• After the newborn period, children with syphilis should have CSF examination to detect asymptomatic neurosyphilis 3
• Review birth and maternal medical records to assess whether the child has congenital or acquired syphilis 3
• For acquired primary or secondary syphilis: Benzathine penicillin G 50,000 units/kg IM, up to adult dose of 2.4 million units in a single dose 3

Post-Treatment Follow-Up and Monitoring

Primary and Secondary Syphilis

• Clinical and serological evaluation at 6 and 12 months after treatment 3, 1
• Treatment success is defined as a fourfold decrease (2 dilutions) in nontreponemal test titers 1
• Failure of nontreponemal titers to decline fourfold within 6 months indicates probable treatment failure 3

Latent Syphilis

• Clinical and serological evaluation at 6,12,18, and 24 months after treatment 3, 1
• If titers increase fourfold or initially high titer (≥1:32) fails to decline fourfold within 12-24 months, perform CSF examination and re-treat 3

Neurosyphilis

• If CSF pleocytosis was present initially, repeat CSF examination every 6 months until cell count normalizes 1
• If cell count has not decreased after 6 months or CSF is not normal after 2 years, consider retreatment 1

Treatment Failure Criteria

Re-treat and perform CSF examination if any of the following occur: 3

• Signs or symptoms persist or recur 3
• Sustained fourfold increase in nontreponemal test titer compared with baseline 3
• Clinical symptoms develop after treatment 1

For HIV-infected patients, failure to achieve fourfold decrease in titers by 3 months for primary/secondary syphilis indicates treatment failure. 1

• Re-treat with benzathine penicillin G 7.2 million units (3 weekly doses of 2.4 million units each) if CSF is normal 1

Serofast Reactions and Low-Level Titers

• Patients with persistently low RPR titers (1:1 to 1:4) after appropriate treatment are "serofast" and do not require additional therapy in the absence of clinical findings 4
• An RPR titer of 1:1 in someone with prior treated syphilis typically represents a serologic scar occurring in 15-25% of treated patients and does not indicate active infection 4
• Do NOT retreat a patient with history of syphilis and RPR titer of 1:1 if there are no clinical signs/symptoms, the titer is stable or declining, and previous treatment was adequate 4

Partner Management

Presumptively treat sexual partners exposed within 90 days preceding diagnosis with benzathine penicillin G 2.4 million units IM, even if seronegative. 1

Time Periods for Partner Notification

• Primary syphilis: 3 months plus duration of symptoms 3
• Secondary syphilis: 6 months plus duration of symptoms 3
• Early latent syphilis: 1 year 3

Important Warnings and Common Pitfalls

Jarisch-Herxheimer Reaction

• Warn all patients about potential acute febrile reaction with headache and myalgia within 24 hours of treatment, particularly with early syphilis 1
• This reaction does not indicate treatment failure 1

Critical Pitfalls to Avoid

• Do NOT use azithromycin for syphilis treatment - widespread resistance makes it ineffective 1
• Penicillin G benzathine remains the only therapy with documented efficacy, particularly crucial for preventing complications 1
• Do NOT rely on serologic titers alone to differentiate early from late latent syphilis when determining treatment duration 1
• Failure to determine the stage of syphilis before treatment can lead to inadequate therapy 4
• Inadequate follow-up of serological response can lead to missed treatment failure 4

Screening Recommendations

• Screen sexually active people aged 15-44 years at least once, and at least annually for those at increased risk 2
• Men who have sex with men (MSM) comprised 32.7% of all males with primary and secondary syphilis in 2023 2
• Consider offering doxycycline postexposure prophylaxis (200 mg within 72 hours after sex) to MSM and transgender women with history of STI in the past year 2