What is the best antibiotic to use to treat syphilis?

Best Antibiotic Treatment for Syphilis

Penicillin G remains the treatment of choice for syphilis at all stages, regardless of HIV status. 1 This first-line therapy has decades of proven efficacy and is the only therapy with documented effectiveness for neurosyphilis and syphilis during pregnancy.

Treatment Recommendations by Stage

Primary and Secondary Syphilis

• First-line treatment: Benzathine penicillin G, 2.4 million units IM in a single dose 1
• For HIV-infected persons: Same regimen, though some specialists recommend additional doses (benefit unproven) 1

Early Latent Syphilis (less than 1 year duration)

• First-line treatment: Benzathine penicillin G, 2.4 million units IM in a single dose 1

Late Latent Syphilis or Unknown Duration

• First-line treatment: Benzathine penicillin G, 2.4 million units IM once weekly for 3 consecutive weeks (total 7.2 million units) 1

Neurosyphilis

• First-line treatment: Aqueous crystalline penicillin G, 18-24 million units daily, administered as 3-4 million units IV every 4 hours or continuous infusion for 10-14 days 1
• Alternative: Procaine penicillin 2.4 million units IM once daily PLUS probenecid 500 mg orally four times daily, both for 10-14 days 1

Alternative Regimens for Penicillin-Allergic Patients

For non-pregnant, penicillin-allergic patients:

• Primary and Secondary 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

Important Considerations

1. Penicillin allergy: Patients with true penicillin allergy who have neurosyphilis or who are pregnant should undergo penicillin desensitization rather than using alternative antibiotics 1

2. Treatment failures with alternatives: While doxycycline appears effective, a retrospective study showed slightly lower success rates compared to penicillin, particularly for late latent syphilis 2

3. Azithromycin limitations: Despite some evidence of efficacy 3, molecular resistance of T. pallidum to macrolides has been reported in multiple geographical areas in the United States 1. Therefore, azithromycin should not be routinely used for syphilis treatment 1

4. HIV co-infection: Management is similar to HIV-negative individuals, but closer follow-up is recommended to detect potential treatment failure 1

5. Jarisch-Herxheimer reaction: Patients should be advised about this acute febrile reaction that may occur within 24 hours of treatment 1

Follow-up Recommendations

• Clinical and serologic evaluation should be performed at 6 and 12 months after treatment for early syphilis 1
• For neurosyphilis, repeat CSF examination every 6 months until the cell count normalizes 1

Common Pitfalls to Avoid

• Inadequate follow-up: Ensure proper serologic monitoring after treatment
• Using azithromycin as first-line: Due to documented resistance patterns, azithromycin should not be used routinely
• Insufficient treatment duration: Particularly for late latent syphilis, complete the full 3-week course
• Missing neurosyphilis: Consider CSF examination in patients with neurological, ocular, or otologic symptoms

Despite newer research into alternative treatments, penicillin G remains the gold standard for syphilis treatment with the strongest evidence base for effectiveness and prevention of long-term complications.