What is the recommended treatment for syphilis?

Treatment of Syphilis

Benzathine penicillin G is the recommended first-line treatment for all stages of syphilis, with specific dosing regimens based on disease stage. 1, 2

Treatment Regimens by Stage

Primary, Secondary, and Early Latent Syphilis

• Single dose of benzathine penicillin G 2.4 million units IM 1, 2
• For children with acquired primary or secondary syphilis: benzathine penicillin G 50,000 units/kg IM (up to adult dose of 2.4 million units) 1

Late Latent Syphilis or Syphilis of Unknown Duration

• Benzathine penicillin G 2.4 million units IM weekly for 3 weeks (total 7.2 million units) 1, 2

Tertiary Syphilis

• Benzathine penicillin G 2.4 million units IM weekly for 3 weeks (total 7.2 million units) 1

Neurosyphilis

• Aqueous crystalline penicillin G 18-24 million units daily, administered as 3-4 million units IV every 4 hours for 10-14 days 2

Special Populations

HIV Co-infection

• Same penicillin regimens as HIV-negative patients 1, 2
• More frequent follow-up recommended (every 3 months rather than every 6 months) 2
• Despite some specialists recommending additional doses for HIV-infected patients with early syphilis, data suggest no significant benefit of multiple doses over a single dose 2, 3

Pregnant Patients

• Only penicillin G is proven effective for preventing maternal transmission 1
• Pregnant women with penicillin allergy should undergo desensitization and be treated with penicillin 1, 2

Alternative Treatments for Penicillin-Allergic Non-Pregnant Patients

Primary and Secondary Syphilis

• Doxycycline 100 mg orally twice daily for 14 days 1, 2, 4
• Tetracycline 500 mg orally four times daily for 14 days (though compliance is likely better with doxycycline due to less frequent dosing) 2
• Ceftriaxone 1 g daily (IM or IV) for 8-10 days may be considered, though optimal dosing is not well established 2

Late Latent Syphilis or Syphilis of Unknown Duration

• Doxycycline 100 mg orally twice daily for 28 days 1, 4

Follow-Up and Monitoring

• Quantitative nontreponemal serologic tests should be repeated at 6,12, and 24 months 1, 4
• A 4-fold decline in titer is expected within 6 months for primary/secondary syphilis and within 12-24 months for late syphilis 1
• For HIV-infected patients, monitoring should occur more frequently (every 3 months) 2
• CSF examination is recommended if titers increase 4-fold, an initially high titer fails to decline at least 4-fold within 12-24 months, or neurological signs/symptoms develop 1

Treatment Failure

• Defined as persistent or recurring signs/symptoms, or a sustained fourfold increase in nontreponemal test titers 2
• Re-treatment with weekly injections of benzathine penicillin G 2.4 million units IM for 3 weeks is recommended 1

Common Pitfalls and Caveats

• Jarisch-Herxheimer reaction (fever, headache, myalgia) may occur within 24 hours after treatment, especially in early syphilis 2
• Despite some evidence of efficacy, azithromycin is not recommended due to widespread macrolide resistance in T. pallidum in the United States 5, 2
• Serologic tests may decline more slowly in patients who have had previous syphilis infections 2
• Bacteriostatic antibiotics (chloramphenicol, erythromycins, sulfonamides, tetracyclines) may antagonize the bactericidal effect of penicillin if used concurrently 6
• Current benzathine penicillin G shortages may necessitate use of alternative treatments in some settings 7

Management of Sex Partners

• Persons exposed to a patient with primary, secondary, or early latent syphilis within the preceding 90 days should be treated presumptively, even if seronegative 1
• Long-term sex partners of patients with late syphilis should be evaluated clinically and serologically 1