What oral regimen should be used to treat early and late syphilis in non‑pregnant patients without severe penicillin allergy, including dosing and alternatives?

Oral Treatment for Syphilis in Non-Pregnant Penicillin-Allergic Patients

For non-pregnant adults with penicillin allergy, doxycycline 100 mg orally twice daily is the preferred oral treatment: 14 days for early syphilis (primary, secondary, or early latent) and 28 days for late latent syphilis or syphilis of unknown duration. 1, 2

Early Syphilis (Primary, Secondary, or Early Latent ≤1 Year)

First-Line Oral Alternative

• Doxycycline 100 mg orally twice daily for 14 days is the preferred alternative to penicillin for early syphilis 1, 2
• Doxycycline offers superior compliance compared to tetracycline due to less frequent dosing and fewer gastrointestinal side effects 3, 1

Second-Line Oral Alternative

• Tetracycline 500 mg orally four times daily for 14 days is an acceptable alternative when doxycycline cannot be used 3, 4
• The FDA-approved dosing for early syphilis (less than one year's duration) is tetracycline 500 mg four times daily for 15 days 4
• Tetracycline causes more gastrointestinal side effects and requires four-times-daily dosing, which reduces adherence 3, 1

Late Latent Syphilis or Syphilis of Unknown Duration (>1 Year)

First-Line Oral Alternative

• Doxycycline 100 mg orally twice daily for 28 days is the recommended alternative regimen 1, 2
• CSF examination must be performed before initiating any oral therapy to exclude neurosyphilis, as oral regimens are inadequate for CNS infection 2

Second-Line Oral Alternative

• Tetracycline 500 mg orally four times daily for 28 days is acceptable when doxycycline cannot be used 1, 2
• The FDA label specifies tetracycline 500 mg four times daily for 30 days for syphilis of more than one year's duration (except neurosyphilis) 4

Less Effective Alternatives (Use Only When Compliance Can Be Assured)

Ceftriaxone

• Ceftriaxone 1 gram IM or IV daily for 8-10 days may be considered, but clinical data remain limited 3, 1
• Single-dose ceftriaxone is completely ineffective and must never be used 3
• Ceftriaxone is a beta-lactam antibiotic and carries cross-reactivity risk in patients with severe penicillin allergy (urticaria, angioedema, anaphylaxis) 5
• The optimal dose and duration have not been definitively established 1

Erythromycin (Least Effective)

• Erythromycin 500 mg orally four times daily for 14 days is the least effective alternative and should only be used when compliance with therapy and follow-up can be absolutely ensured 3, 1
• Erythromycin has documented lower efficacy compared to doxycycline and tetracycline 3

Critical Contraindications and Warnings

Azithromycin Must Not Be Used

• Azithromycin is contraindicated in the United States due to widespread macrolide resistance and documented treatment failures 1, 6
• Despite a 2002 pilot study showing promise 7, subsequent resistance patterns have rendered azithromycin unreliable 1

When Oral Therapy Is Absolutely Contraindicated

• Penicillin desensitization is mandatory when patient compliance with oral alternatives or follow-up cannot be ensured 3, 1
• Skin testing for penicillin allergy may clarify true allergy status before proceeding with desensitization 3, 1
• All pregnant patients with penicillin allergy must undergo desensitization followed by penicillin treatment—no oral alternatives are acceptable during pregnancy 1, 2

Mandatory Follow-Up Protocol

Serologic Monitoring

• Perform quantitative nontreponemal tests (RPR or VDRL) at 6 and 12 months after treatment for early syphilis 2
• For late latent syphilis, repeat testing at 6,12, and 24 months 2
• Close serologic monitoring is essential for all patients on alternative therapies due to limited efficacy data compared to penicillin 1

Treatment Failure Indicators

• Sustained fourfold increase in nontreponemal titers indicates treatment failure 3, 2
• Failure of titers to decline fourfold within 6 months for early syphilis or 12-24 months for late syphilis suggests treatment failure 2
• Persistent or recurring signs/symptoms warrant re-evaluation 3

Management of Treatment Failure

• Re-evaluate for HIV infection 3, 2
• Perform lumbar puncture to exclude neurosyphilis unless reinfection is clearly documented 3
• Re-treat with three weekly injections of benzathine penicillin G 2.4 million units IM unless CSF examination indicates neurosyphilis 3

Special Population Considerations

HIV-Infected Patients

• Same oral regimens apply (doxycycline or tetracycline at same doses and durations) 2
• More frequent monitoring is required: serologic testing every 3 months instead of 6 months 1
• Efficacy data for oral alternatives in HIV-infected patients are limited; closer surveillance is mandatory 1

Neurosyphilis

• Oral regimens are inadequate for neurosyphilis 1
• Penicillin desensitization is strongly preferred for neurosyphilis treatment 1
• If CSF examination reveals neurosyphilis, oral therapy must be abandoned in favor of IV aqueous crystalline penicillin G 2

Common Pitfalls to Avoid

• Never use oral penicillin preparations—they are ineffective for syphilis treatment 2
• Do not switch between different nontreponemal tests (RPR vs. VDRL) when monitoring response, as results cannot be directly compared 2
• Do not assume all penicillin allergies are real—approximately 90-95% of patients labeled as penicillin-allergic test negative on formal testing 5
• Do not use ceftriaxone in patients with severe penicillin allergy (Stevens-Johnson syndrome, anaphylaxis) due to beta-lactam cross-reactivity 1
• Remember that 15-25% of successfully treated patients remain "serofast" with persistent low titers (<1:8) that do not indicate treatment failure 1