What are the recommended antibiotics and durations for treating syphilis?

Syphilis Treatment: Antibiotics and Duration

First-Line Treatment Recommendations

Benzathine penicillin G is the definitive treatment for syphilis, with dosing and duration determined by disease stage. 1, 2

Primary and Secondary Syphilis (Early Syphilis)

• Benzathine penicillin G 2.4 million units IM as a single dose 1, 2
• This single injection is highly effective and remains the gold standard after decades of clinical use 3, 4
• Treatment should achieve a fourfold decline in nontreponemal titers (RPR/VDRL) within 6 months 1, 5

Early Latent Syphilis (Acquired Within Past Year)

• Benzathine penicillin G 2.4 million units IM as a single dose 6, 7
• Early latent is defined by documented seroconversion, fourfold titer increase, symptoms within the past year, or partner with documented early syphilis 7, 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 6, 1, 7
• This extended regimen is necessary to prevent progression to tertiary complications 6

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 1, 8
• Some experts recommend additional therapy with benzathine penicillin G 2.4 million units IM weekly for 3 doses after completing IV therapy 8
• CSF examination is mandatory before treatment if neurologic/ophthalmic symptoms, tertiary syphilis signs, treatment failure, HIV with late latent syphilis, or nontreponemal titer ≥1:32 are present 6, 7

Tertiary Syphilis (Cardiovascular/Gummatous)

• Benzathine penicillin G 7.2 million units total: three doses of 2.4 million units IM at weekly intervals 6, 2

Alternative Regimens for Penicillin Allergy

For non-pregnant patients only (pregnant patients must undergo penicillin desensitization—no exceptions): 6, 2

Primary, Secondary, or Early Latent Syphilis

• Doxycycline 100 mg orally twice daily for 14 days 6, 1, 9
• Alternative: Tetracycline 500 mg orally four times daily for 14 days 6
• Doxycycline is preferred over tetracycline due to better compliance 6

Late Latent Syphilis or Unknown Duration

• Doxycycline 100 mg orally twice daily for 28 days 6, 1, 9
• Alternative: Tetracycline 500 mg orally four times daily for 28 days 6

Critical Caveat for Alternatives

• CSF examination must exclude neurosyphilis before using non-penicillin regimens 7
• Close follow-up is essential as clinical experience with alternatives is more limited than with penicillin 6

Special Population Considerations

Pregnancy

• Penicillin is the ONLY acceptable treatment—it is the only therapy proven to prevent congenital syphilis and treat fetal infection 2, 10
• Pregnant patients with penicillin allergy must undergo desensitization followed by stage-appropriate penicillin treatment 6, 1, 2
• Some experts recommend a second dose of benzathine penicillin 2.4 million units IM one week after initial dose for primary, secondary, or early latent syphilis in pregnancy 2
• Screen all pregnant patients at first prenatal visit, third trimester, and delivery 1, 10
• Warn patients about Jarisch-Herxheimer reaction risk during second half of pregnancy, which may precipitate premature labor or fetal distress 2

HIV-Infected Patients

• Use the same penicillin regimens as non-HIV-infected patients 2, 5
• More frequent follow-up is mandatory (every 3 months instead of 6 months) to detect treatment failure 6, 5
• CSF examination should be performed for all HIV-infected patients with late latent syphilis or unknown duration 6, 7
• HIV-infected patients with RPR titers ≥1:32 and/or CD4 counts <350 cells/mm³ may be at increased risk for asymptomatic neurosyphilis 5

Pediatric Dosing (Acquired Syphilis After Newborn Period)

• CSF examination required before treatment to exclude neurosyphilis 6, 7
• Early latent: Benzathine penicillin G 50,000 units/kg IM (up to adult dose of 2.4 million units) as single dose 6, 7
• Late latent or unknown duration: Benzathine penicillin G 50,000 units/kg IM (up to adult dose of 2.4 million units) given as three doses at weekly intervals (total 150,000 units/kg up to 7.2 million units) 6, 7

Follow-Up Protocol

Early Syphilis (Primary, Secondary, Early Latent)

• Repeat quantitative nontreponemal tests (RPR or VDRL) at 6 and 12 months 1, 5
• Expect fourfold decline in titer within 6 months 1, 2
• HIV-infected patients: follow-up at 3,6,9,12, and 24 months 6

Late Latent Syphilis

• Repeat quantitative nontreponemal tests at 6,12, and 24 months 6
• Expect fourfold decline within 12-24 months 2, 5

Indicators for Re-Treatment

Re-evaluate and consider re-treatment if: 6

• Titers increase fourfold
• Initially high titer (≥1:32) fails to decline at least fourfold within appropriate timeframe
• Signs or symptoms of syphilis develop
• When re-treating, use three weekly injections of benzathine penicillin G 2.4 million units IM unless CSF indicates neurosyphilis 6

Partner Management

Presumptive treatment is recommended for exposed partners even if seronegative: 2, 10

• Partners exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis should receive benzathine penicillin G 2.4 million units IM 1
• Time periods for at-risk partners: 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 2

Important Clinical Pitfalls to Avoid

What NOT to Use

• Azithromycin should NOT be used due to widespread macrolide resistance and documented treatment failures in the United States 2, 5
• Oral penicillin preparations are ineffective for syphilis treatment 2
• Erythromycin does not reliably cure fetal infection and is inadequate in pregnancy 2
• Single-dose ceftriaxone is not effective; if used, must be 1 gram daily for 10 days 6, 2

Jarisch-Herxheimer Reaction

• Inform all patients about this acute febrile reaction that may occur within 24 hours after treatment, especially in early syphilis 1, 2
• Symptoms include fever, headache, myalgia, and other flu-like symptoms 1
• In pregnant patients during second half of pregnancy, may precipitate premature labor or fetal distress—advise immediate medical attention for contractions or changes in fetal movements 2

Testing Considerations

• All patients with syphilis should be tested for HIV at diagnosis 1, 2
• Do not switch between different nontreponemal tests (RPR vs VDRL) when monitoring response, as results cannot be directly compared 2
• Treponemal antibody titers correlate poorly with disease activity and should not be used to assess treatment response 2