What is the recommended treatment for syphilis?

Syphilis Management

First-Line Treatment: Benzathine Penicillin G

Parenteral penicillin G is the only recommended treatment for all stages of syphilis, with dosing determined by disease stage. 1, 2

Primary and Secondary Syphilis

• Benzathine penicillin G 2.4 million units IM as a single dose is the definitive treatment 1, 2, 3
• Treponema pallidum typically clears from lesions within 7 hours of treatment 4
• For children: 50,000 units/kg IM (up to adult dose of 2.4 million units) as a single dose 1

Early Latent Syphilis

• Same regimen as primary/secondary: Benzathine penicillin G 2.4 million units IM as a single dose 1, 2
• Early latent is defined as infection acquired within the preceding year, documented by seroconversion, fourfold titer increase, recent symptoms, or partner with documented early syphilis 2

Late Latent Syphilis or Unknown Duration

• Benzathine penicillin G 7.2 million units total: three doses of 2.4 million units IM given at weekly intervals 1, 2, 3
• For children: 50,000 units/kg IM per dose (up to 2.4 million units), three doses at weekly intervals (total 150,000 units/kg up to 7.2 million units) 2

Tertiary Syphilis

• CRITICAL: Perform CSF examination BEFORE treatment to exclude neurosyphilis 5
• If CSF is normal: Benzathine penicillin G 7.2 million units total (three weekly doses of 2.4 million units IM) 1, 5
• If neurosyphilis is present: Treatment changes entirely to aqueous crystalline penicillin G 18-24 million units IV daily for 10-14 days 2, 5
• The tertiary syphilis regimen is completely inadequate for CNS involvement 5

Neurosyphilis (Any Stage)

• Aqueous crystalline penicillin G 18-24 million units IV daily (administered as 3-4 million units every 4 hours or continuous infusion) for 10-14 days 2, 5
• Alternative: Procaine penicillin G with probenecid (procaine penicillin without probenecid does NOT achieve adequate CSF levels) 2
• CSF examination is indicated for: neurologic/ophthalmic symptoms, active tertiary syphilis, treatment failure, HIV with late latent syphilis, or nontreponemal titer ≥1:32 2

Penicillin-Allergic Patients

Non-Pregnant Adults

• Primary/secondary/early latent syphilis: Doxycycline 100 mg orally twice daily for 14 days 1, 2
• Late latent syphilis: Doxycycline 100 mg orally twice daily for 28 days 1, 2
• Alternative: Tetracycline 500 mg orally four times daily (14 days for early, 28 days for late) 2
• Ceftriaxone 1 gram IV/IM daily for 10 days is a reasonable alternative based on randomized trial data showing comparable efficacy to benzathine penicillin 2

Pregnant Women

• Penicillin desensitization is MANDATORY—no alternatives are acceptable 1, 2, 5
• Only penicillin G prevents maternal transmission and congenital syphilis 1, 2
• Screen all pregnant women at first prenatal visit, third trimester, and delivery 2
• Jarisch-Herxheimer reaction during second half of pregnancy may precipitate premature labor or fetal distress 2

Tertiary Syphilis with Penicillin Allergy

• Penicillin desensitization is strongly preferred over alternative antibiotics 5
• Consult infectious disease specialist for all penicillin-allergic patients with tertiary disease 5

Special Populations

HIV-Infected Patients

• Use the same treatment regimens as HIV-negative patients 1, 2, 5
• A 2017 randomized trial showed no benefit to three doses versus single dose for early syphilis in HIV patients (93% vs 100% success rates, not statistically significant) 2, 6
• Closer follow-up is mandatory to detect treatment failure or disease progression 2, 5
• HIV-infected patients may have atypical serologic responses but generally respond well to standard treatment 2

Pediatric Patients

• All children with acquired syphilis require CSF examination to exclude neurosyphilis before treatment 2
• Incompletely developed renal function in newborns may delay penicillin elimination; adjust dosage and frequency accordingly 7, 8
• Monitor closely for clinical and laboratory evidence of toxic or adverse effects 7, 8

Follow-Up and Monitoring

Serologic Testing Schedule

• Primary/secondary syphilis: Repeat quantitative nontreponemal tests (RPR or VDRL) at 6 and 12 months 2
• Latent syphilis: Repeat at 6,12, and 24 months 1, 2
• Tertiary syphilis: Repeat at 6,12, and 24 months 5

Expected Response

• Primary/secondary syphilis: Fourfold decline in titer within 6 months 1, 2
• Late syphilis: Fourfold decline in titer within 12-24 months 1, 5

Treatment Failure Criteria

• Persistent or recurring clinical signs/symptoms 2
• Sustained fourfold increase in nontreponemal titers 2
• Failure of initially high titer to decline fourfold within expected timeframes 2
• If treatment failure occurs: Re-evaluate for HIV, perform CSF examination, and retreat with three weekly injections of benzathine penicillin G 2.4 million units unless neurosyphilis is diagnosed 1, 5

Management of Sex Partners

• Persons exposed within 90 days of diagnosis of primary, secondary, or early latent syphilis should be treated presumptively, even if seronegative 1, 2
• Persons exposed >90 days before diagnosis should be treated presumptively if serologic results are not immediately available and follow-up is uncertain 2
• Time periods for at-risk partners: 3 months plus duration of symptoms for primary, 6 months plus duration of symptoms for secondary, and 1 year for early latent 2
• Long-term sex partners of patients with late syphilis should be evaluated clinically and serologically 1

Critical Pitfalls to Avoid

Medication Errors

• Never use oral penicillin preparations—they are completely ineffective for any stage of syphilis 2, 5
• Do not use azithromycin in the United States due to widespread macrolide resistance and documented treatment failures 2
• Procaine penicillin without probenecid does not achieve adequate CSF levels and is inadequate for neurosyphilis 2
• Avoid bacteriostatic antibiotics (chloramphenicol, erythromycins, sulfonamides, tetracyclines) concurrently with penicillin as they may antagonize bactericidal effects 7, 8

Monitoring Errors

• Do not switch between different serologic test methods (RPR vs VDRL) when monitoring response—results cannot be directly compared 2, 5
• Do not rely solely on treponemal test antibody titers to assess treatment response, as they correlate poorly with disease activity 2

Clinical Assessment Errors

• Never skip CSF examination before treating tertiary syphilis—missing neurosyphilis leads to inadequate treatment 5
• All patients with syphilis should be tested for HIV infection 2
• Patients being treated for gonococcal infection should have serologic testing for syphilis before receiving penicillin 7, 8

Administration Considerations

• Administer penicillin G IV slowly when using high doses (>10 million units) due to potential electrolyte imbalance from potassium content 7, 8
• Penicillin G Potassium contains 1.7 mEq potassium and 1.02 mEq sodium per million units (IM formulation) 7
• IV formulation contains 6.9 mg sodium (0.3 mEq) and 65.8 mg potassium (1.68 mEq) per million units 8
• If a weekly dose is missed, an interval of 10-14 days between doses might be acceptable before restarting the sequence 2

Adverse Reactions

Jarisch-Herxheimer Reaction

• Acute febrile reaction occurring within 24 hours of treatment, especially in early syphilis 2, 5
• Symptoms include fever, headache, myalgia, and other constitutional symptoms 2
• Inform all patients about this possible reaction before treatment 2
• In pregnant women during second half of pregnancy, may precipitate premature labor or fetal distress—advise immediate medical attention for changes in fetal movements or contractions 2

Drug Interactions

• Probenecid blocks renal tubular secretion of penicillins and prolongs blood levels 7, 8
• Other drugs that compete for renal tubular secretion and prolong penicillin half-life: aspirin, phenylbutazone, sulfonamides, indomethacin, thiazide diuretics, furosemide, ethacrynic acid 7, 8

Prevention Strategies

• Screen sexually active people aged 15-44 years at least once, and at least annually for those at increased risk 3
• Screen pregnant individuals three times: first prenatal visit, third trimester, and delivery 3
• Counsel about condom use 3
• Offer doxycycline postexposure prophylaxis (200 mg within 72 hours after sex) to men who have sex with men and transgender women with history of sexually transmitted infection in the past year 3