Is amoxicillin effective for treating syphilis?

Amoxicillin for Syphilis Treatment

Direct Answer

Amoxicillin is NOT recommended as standard therapy for syphilis and should only be considered in exceptional circumstances when benzathine penicillin G is unavailable, and only in specific formulations with close monitoring. 1, 2

Evidence-Based Recommendations

Standard Treatment Remains Penicillin

• Benzathine penicillin G remains the only FDA-approved and guideline-recommended first-line treatment for all stages of syphilis. 2, 3
• The CDC explicitly states that enhanced penicillin therapy (standard benzathine penicillin combined with high-dose oral amoxicillin and probenecid) did not improve clinical outcomes in early-stage syphilis and is not recommended. 1
• A large randomized controlled trial (541 patients) demonstrated that adding amoxicillin plus probenecid to standard benzathine penicillin provided no additional benefit, with identical treatment failure rates of 17-18% at 6 months regardless of HIV status. 4

When Amoxicillin May Be Considered

If benzathine penicillin G is genuinely unavailable, the following amoxicillin regimens have shown efficacy in research settings but are NOT guideline-endorsed:

High-Dose Regimen (Most Evidence)

• Amoxicillin 3 g/day plus probenecid for 14-30 days showed 95.5% efficacy in HIV-infected patients with syphilis (286 patients, retrospective study). 5
• This regimen achieved ≥4-fold RPR decline in 96.3% of successfully treated patients within 12 months. 5
• However, 9.8% experienced adverse events, with 7.3% requiring treatment change. 5, 6

Lower-Dose Alternative

• Amoxicillin 1.5 g/day without probenecid for 4-8 weeks demonstrated 94.9% serological cure rate (138 patients, 112 with HIV). 6
• This regimen had significantly better tolerability with only 1.5% switching due to adverse events. 6
• Treatment duration was not related to efficacy, suggesting shorter courses may be adequate. 6

Ultra-Short Course (Limited Data)

• Amoxicillin 3 g/day plus probenecid for only 5-11 days showed serological response in 7 of 8 HIV-infected patients with early syphilis. 7
• This approach requires substantially more validation before clinical use. 7

Critical Limitations and Warnings

All amoxicillin data comes from observational studies or small trials, NOT from guideline-endorsed protocols:

• The CDC explicitly rates enhanced penicillin therapy (benzathine penicillin + amoxicillin/probenecid) as DII recommendation (should not be offered) based on lack of benefit. 1
• No amoxicillin regimen is FDA-approved for syphilis treatment. 2, 3
• Oral penicillin preparations are completely ineffective and must never be used. 2, 3
• Amoxicillin efficacy for neurosyphilis is unknown and should never be used for CNS involvement. 1, 2

Preferred Alternatives to Benzathine Penicillin

Before considering amoxicillin, these guideline-endorsed alternatives should be prioritized:

• Doxycycline 100 mg orally twice daily: 14 days for early syphilis, 28 days for late latent syphilis (for penicillin-allergic non-pregnant adults). 2, 3
• Ceftriaxone 1 g IV/IM daily for 10 days: Randomized trial data showed comparable efficacy to benzathine penicillin. 2, 8
• Network meta-analysis demonstrated ceftriaxone had higher serological response rates than penicillin at 6-month follow-up (RR 1.12,95% CI 1.02-1.23). 8

Absolute Contraindications to Amoxicillin Use

Never use amoxicillin in these situations:

• Pregnancy: Only parenteral penicillin G prevents maternal transmission and treats fetal infection; pregnant women with penicillin allergy MUST undergo desensitization. 2, 3
• Neurosyphilis: Requires IV aqueous crystalline penicillin G 18-24 million units daily for 10-14 days. 1, 2
• Tertiary syphilis: Requires CSF examination to exclude neurosyphilis before any treatment. 2, 3

Monitoring Requirements If Amoxicillin Used

If amoxicillin is used due to genuine penicillin unavailability, mandatory close monitoring includes:

• Quantitative nontreponemal tests (RPR or VDRL) at 3,6,12, and 24 months. 2, 3
• Expected fourfold decline in titer within 6 months for primary/secondary syphilis. 2
• HIV testing for all patients, as HIV-infected individuals require more intensive monitoring. 3, 9
• Use the same nontreponemal test method (RPR vs VDRL) throughout follow-up—results cannot be compared between methods. 2, 3

Clinical Bottom Line

Amoxicillin should not be used for syphilis treatment when standard therapies are available. The CDC explicitly recommends against enhanced penicillin therapy with amoxicillin 1, and no amoxicillin-only regimen has guideline endorsement. If benzathine penicillin G is truly unavailable, doxycycline or ceftriaxone are superior alternatives with guideline support. 2, 3, 8 Amoxicillin may only be considered as a last resort in resource-limited settings where no other options exist, using high-dose regimens (3 g/day with probenecid or 1.5 g/day without) with mandatory close serological monitoring. 5, 6