Co-Amoxiclav is NOT Appropriate for Primary Syphilis Treatment
Co-amoxiclav (amoxicillin/clavulanic acid) should not be used to treat primary syphilis—benzathine penicillin G 2.4 million units IM as a single dose remains the only recommended first-line treatment. 1
Why Co-Amoxiclav Fails as Syphilis Treatment
The critical issue is that clavulanic acid provides no benefit for treating Treponema pallidum, and the standard co-amoxiclav formulations do not deliver adequate amoxicillin dosing for syphilis treatment. 2, 1
Benzathine penicillin G is the gold standard for all stages of syphilis, with documented efficacy showing 100% clinical cure and seronegativity within one year for primary syphilis. 2, 1, 3, 4
The only scenario where oral amoxicillin has shown efficacy is when combined with probenecid (not clavulanic acid) at high doses—specifically 3 grams daily of amoxicillin with probenecid for 10-14 days. 5, 6
The Evidence for Amoxicillin (When Done Correctly)
While amoxicillin alone has been studied as an alternative, it requires specific conditions that co-amoxiclav does not meet:
A randomized trial demonstrated that amoxicillin 500 mg four times daily (2 grams/day total) plus probenecid for 10 days showed comparable efficacy to benzathine penicillin G, though this was used as enhanced therapy alongside benzathine penicillin. 5
Recent data suggest even shorter courses (5-11 days) of 3 grams daily amoxicillin with probenecid may be effective in HIV-infected patients, though this remains investigational. 6
The probenecid is essential because it blocks renal excretion of penicillin, maintaining adequate serum levels—clavulanic acid does not provide this pharmacokinetic benefit. 5
Recommended Treatment Algorithm
For non-pregnant, non-allergic patients:
For penicillin-allergic, non-pregnant patients:
- Doxycycline 100 mg orally twice daily for 14 days is the recommended alternative. 2, 1
- Tetracycline 500 mg orally four times daily for 14 days is a second alternative. 2, 1
For pregnant patients with penicillin allergy:
- Mandatory penicillin desensitization followed by benzathine penicillin G—no oral alternatives are acceptable as only penicillin prevents congenital syphilis. 1
Critical Pitfalls to Avoid
Do not use oral penicillin preparations (including co-amoxiclav) as they are ineffective for syphilis treatment. 1
Do not use azithromycin in the United States due to widespread macrolide resistance and documented treatment failures. 1
If considering amoxicillin as an alternative (in settings with benzathine penicillin shortages), it must be high-dose amoxicillin with probenecid, not co-amoxiclav. 5, 6
Ceftriaxone 1 gram IM/IV daily for 10-14 days is a reasonable alternative based on randomized trial data, but remains second-line. 1