What is the recommended treatment for acute syphilis?

Treatment for Acute Syphilis

Benzathine penicillin G 2.4 million units administered as a single intramuscular injection is the recommended first-line treatment for acute (early) syphilis, including primary and secondary stages. 1

First-Line Treatment

• Benzathine penicillin G 2.4 million units intramuscularly as a single dose is the treatment of choice for primary, secondary, and early latent syphilis (less than one year duration) 1
• Penicillin remains the treatment of choice for all stages of syphilis regardless of HIV status 1
• Although some specialists recommend additional doses for HIV-infected patients with early syphilis, data suggest no significant benefit of multiple doses over a single dose in terms of serologic outcomes 1

Alternative Treatments for Penicillin-Allergic Patients

• Doxycycline 100 mg orally twice daily for 14 days is the preferred alternative for non-pregnant patients with penicillin allergy 1, 2, 3
• Tetracycline 500 mg orally four times daily for 14 days is another alternative, though compliance is likely better with doxycycline due to less frequent dosing 1
• Ceftriaxone 1 g daily (IM or IV) for 8-10 days may be considered as an alternative, though optimal dosing is not well established 1
• Azithromycin is not recommended for treatment of syphilis in the United States due to documented macrolide resistance and treatment failures 1, 4

Special Considerations

HIV Co-infection

• HIV-infected patients should receive the same penicillin regimen as HIV-negative patients 1
• Closer follow-up is recommended for HIV-infected patients (every 3 months rather than every 6 months) 1
• Enhanced penicillin therapy (standard benzathine penicillin with high-dose oral amoxicillin and probenecid) did not improve clinical outcomes and is not recommended 1

Penicillin Allergy Management

• For patients whose compliance with therapy or follow-up cannot be ensured, desensitization and treatment with penicillin is recommended 1
• Pregnant patients with penicillin allergy should be desensitized and treated with penicillin, as alternatives are not adequately studied in pregnancy 1

Follow-Up Recommendations

• Clinical and serologic evaluation should be performed at 6 and 12 months after treatment 1
• HIV-infected patients should be monitored more frequently (every 3 months) 1
• Treatment failure is defined as persistent or recurring signs/symptoms, or a sustained fourfold increase in nontreponemal test titers 1
• Failure of nontreponemal test titers to decline fourfold within 6 months may indicate treatment failure and warrants reevaluation for HIV infection 1
• If treatment failure is suspected, CSF examination should be performed to rule out neurosyphilis 1

Treatment of Late Syphilis

• For late latent syphilis (more than one year duration) or syphilis of unknown duration, benzathine penicillin G 2.4 million units IM weekly for 3 weeks is recommended 1
• For neurosyphilis, aqueous crystalline penicillin G 18-24 million units daily, administered as 3-4 million units IV every 4 hours for 10-14 days is the recommended regimen 1
• Alternative therapy for neurosyphilis is procaine penicillin 2.4 million units IM daily plus probenecid 500 mg orally four times a day, both for 10-14 days 1

Common Pitfalls and Caveats

• Jarisch-Herxheimer reaction (fever, headache, myalgia) may occur within 24 hours after treatment, especially in early syphilis 1
• Patients should be warned about this potential reaction but it is not an indication to avoid or discontinue therapy 1
• Macrolide resistance in T. pallidum is widespread in the United States, making azithromycin an unsuitable alternative despite some evidence of efficacy 1, 4
• Current benzathine penicillin G shortages may necessitate use of alternative regimens, but efforts should be made to secure penicillin when possible 5
• Serologic tests may decline more slowly in patients who have had previous syphilis infections 1