What is the algorithm for syphilis screening and treatment in a patient?

Syphilis Screening and Treatment Algorithm

Screening Algorithm

The screening approach depends on laboratory capabilities: use either the traditional algorithm (nontreponemal test first) or the reverse sequence algorithm (treponemal test first), but both require confirmatory testing and clinical correlation—a single positive test is never diagnostic. 1

Traditional Algorithm (Preferred in Most Settings)

• Initial screening: Perform nontreponemal test (RPR or VDRL) 2, 1
• If reactive: Confirm with treponemal test (TP-PA, enzyme immunoassay, or CMIA) 2, 1
• Advantage: Directly provides quantitative titers for disease activity monitoring 1

Reverse Sequence Algorithm (High-Volume Labs)

• Initial screening: Perform treponemal test (CMIA or enzyme immunoassay) 1
• If reactive: Follow with quantitative nontreponemal test (RPR or VDRL) on all positive specimens 1
• If discordant: Perform additional treponemal testing (different method) 1
• Critical caveat: Treponemal tests remain positive for life regardless of treatment and cannot distinguish active from past infection 1

Who to Screen

Screen all pregnant women at first prenatal visit, with high-risk women rescreened at 28 weeks and delivery to prevent congenital syphilis. 1

Additional screening populations (at least annually): 1, 3

• Men who have sex with men (MSM)—comprised 32.7% of male primary/secondary syphilis cases in 2023 3
• Commercial sex workers
• Persons exchanging sex for drugs
• Adults in correctional facilities
• Contacts of persons with infectious syphilis
• HIV-positive individuals (consider screening every 3 months if high-risk) 4

---

Diagnostic Interpretation

Diagnosis requires BOTH treponemal AND nontreponemal test results plus comprehensive clinical evaluation—never rely on a single positive test. 1

Key Principles

• Nontreponemal tests (RPR/VDRL): Correlate with disease activity; titers decline with successful treatment 1
• Treponemal tests: Remain positive lifelong; cannot be used for treatment monitoring 1
• Quantitative reporting: Essential for baseline and follow-up; a fourfold change in titer (two dilutions, e.g., 1:16 to 1:4) represents clinically significant change 1, 5
• False positives: Low-titer RPR (<1:8) can occur with injection drug use and other medical conditions (1-5% prevalence) 5

---

Treatment Algorithm by Stage

Primary and Secondary Syphilis

Benzathine penicillin G 2.4 million units IM as a single dose 5, 6, 3

• Cure rate: 90-95% 5
• Clinical features: Primary = painless chancre; Secondary = diffuse rash, mucocutaneous lesions, lymphadenopathy 3

Early Latent Syphilis (Acquired Within Past Year)

Benzathine penicillin G 2.4 million units IM as a single dose 5, 6

• Cure rate: 85-90% 5
• Asymptomatic; detected only by serology 5

Late Latent or Unknown Duration Syphilis

Benzathine penicillin G 2.4 million units IM weekly for 3 consecutive weeks (total 7.2 million units) 5, 6, 3

• Cure rate: 80-85% 5
• Critical step: Evaluate for neurologic or ophthalmic symptoms before treatment; perform CSF analysis and slit-lamp examination if present 6
• Routine CSF examination not required unless clinical signs present 6

Neurosyphilis (Any Stage)

Aqueous crystalline penicillin G 18-24 million units per day (3-4 million units IV every 4 hours) for 10-14 days 5, 6

• Cure rate: 90-95% 5
• Alternative: Procaine penicillin 2.4 million units IM once daily plus probenecid 500 mg orally four times daily for 10-14 days 5
• Consider adding: Benzathine penicillin G 2.4 million units IM weekly for up to 3 weeks after completing neurosyphilis treatment 5

---

Special Populations

HIV-Infected Patients

Use the same penicillin regimens as HIV-negative patients—no additional doses recommended based on current evidence. 5, 6

• More intensive monitoring required: at 3,6,9,12, and 24 months 5, 6
• May have atypical serologic responses (unusually high, low, or fluctuating titers in 10-20% of cases) 5
• Consider CSF examination for late latent syphilis to exclude neurosyphilis 5
• Higher risk of treatment failure 5

Pregnant Women

Treat with the penicillin regimen appropriate for the stage of syphilis—penicillin is the only therapy with documented efficacy for preventing congenital syphilis. 5, 6, 3

• Some experts recommend an additional dose of benzathine penicillin G 2.4 million units IM one week after initial dose for primary, secondary, or early latent syphilis 5, 6
• Treatment must occur >4 weeks before delivery for optimal outcomes 5
• If penicillin allergic: Must be desensitized and treated with penicillin 6, 7
• Up to 40% of fetuses with in-utero exposure are stillborn or die from infection during infancy 3

Penicillin-Allergic Patients (Non-Pregnant, No Neurosyphilis)

Doxycycline 100 mg orally twice daily for 2 weeks (early syphilis) or 4 weeks (late latent syphilis) 6, 8

• Critical caveat: Azithromycin is NOT recommended due to widespread resistance 5
• Pregnant women and neurosyphilis patients MUST receive penicillin after desensitization 6, 7

---

Follow-Up and Treatment Monitoring

Primary and Secondary Syphilis

• Clinical and serological evaluation at 6 and 12 months after treatment 5, 6
• Treatment success: Fourfold decrease in nontreponemal titers 5, 6

Latent Syphilis

• Clinical and serological evaluation at 6,12,18, and 24 months 5, 6
• Treatment success: Fourfold decrease in nontreponemal titers (may take 12-24 months) 5

Neurosyphilis

• If CSF pleocytosis present initially, repeat CSF examination every 6 months until cell count normalizes 5
• If cell count has not decreased after 6 months or CSF not normal after 2 years, consider retreatment 5

Treatment Failure Indicators

If clinical symptoms persist/recur OR nontreponemal titers increase fourfold, perform CSF examination and retreat. 5, 6

• For HIV-infected patients: Failure to achieve fourfold decrease by 3 months (primary/secondary) indicates treatment failure 5
• Retreatment: Benzathine penicillin G 7.2 million units (3 weekly doses) if CSF normal 5

---

Critical Caveats and Common Pitfalls

Testing Considerations

• Sequential RPR tests must use the same method and ideally the same laboratory—RPR titers are often slightly higher than VDRL titers and cannot be directly compared 5
• Never use treponemal tests (including CMIA) for treatment monitoring 1

Serofast State

• 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 6
• This represents a serologic scar in approximately 15-25% of treated patients 6

Jarisch-Herxheimer Reaction

• Warn all patients: Acute febrile reaction with headache and myalgia may occur within 24 hours of treatment 5, 6

Partner Management

• Presumptively treat sexual partners exposed within 90 days preceding diagnosis, even if seronegative 6

HIV Testing

• All patients diagnosed with syphilis should be tested for HIV if status unknown 5

Prevention Strategy

• Consider offering doxycycline postexposure prophylaxis (200 mg within 72 hours after sex) to MSM and transgender women with history of STI in past year 3