What is the treatment for syphilis in a patient with a penicillin allergy?

Treatment of Syphilis in Penicillin-Allergic Patients

For penicillin-allergic patients with syphilis, doxycycline 100 mg orally twice daily is the preferred alternative treatment, with duration depending on disease stage: 14 days for early syphilis and 28 days for late latent or unknown duration syphilis. 1, 2

Treatment by Stage of Syphilis

Early Syphilis (Primary, Secondary, or Early Latent <1 year)

• Doxycycline 100 mg orally twice daily for 14 days is the recommended alternative regimen 3, 1, 2, 4
• Tetracycline 500 mg orally four times daily for 14 days is an acceptable alternative, but doxycycline is preferred due to better compliance with twice-daily versus four-times-daily dosing 3, 2
• Clinical trial data demonstrate that doxycycline achieves serological cure rates comparable to benzathine penicillin G, with median time to successful serological response of 106 days versus 137 days for penicillin 5

Late Latent Syphilis or Syphilis of Unknown Duration

• Doxycycline 100 mg orally twice daily for 28 days 3, 1, 2, 4
• Tetracycline 500 mg orally four times daily for 28 days is an alternative option 3
• Close serologic and clinical follow-up is mandatory as the effectiveness of non-penicillin alternatives for late syphilis is not as well documented 3

Tertiary Syphilis

• Patients with tertiary syphilis who are penicillin-allergic should be managed in consultation with an infectious disease specialist 3
• The efficacy of alternative regimens for tertiary syphilis has not been established 3

Neurosyphilis

• Penicillin desensitization is required for neurosyphilis in penicillin-allergic patients, as no alternative regimens have proven efficacy 3
• All patients with syphilitic uveitis or other ocular manifestations should be treated as neurosyphilis cases 3

Critical Follow-Up Requirements

All patients treated with alternative regimens require intensive monitoring:

• Quantitative nontreponemal serologic tests (RPR or VDRL) should be repeated at 6,12, and 24 months 3, 1, 2
• Treatment failure is defined as: (1) fourfold increase in titers, (2) failure of initially high titer (≥1:32) to decline at least fourfold within 12-24 months, or (3) development of new signs or symptoms 3, 2
• CSF examination should be performed if any criteria for treatment failure are met 3

Special Populations

Pregnant Patients

• Pregnant patients with penicillin allergy must undergo penicillin desensitization and be treated with penicillin 3, 1
• Alternative antibiotics are not acceptable during pregnancy due to risk of congenital syphilis 1
• Up to 40% of fetuses with in-utero syphilis exposure are stillborn or die during infancy without proper treatment 6

HIV-Infected Patients

• The same doxycycline regimens are recommended for HIV-infected patients 3
• More frequent monitoring is required: serologic testing every 3 months instead of 6 months 1, 2
• The efficacy of alternative regimens in HIV-infected persons has not been well studied 3

Important Caveats

Ceftriaxone Considerations

• Ceftriaxone might be effective for late latent syphilis based on pharmacologic properties, but optimal dose and duration are undefined 3
• Cross-reactivity warning: Some penicillin-allergic patients may also be allergic to ceftriaxone 3
• Treatment decisions with ceftriaxone should be made in consultation with a specialist 3

Compliance Considerations

• If compliance with therapy or follow-up cannot be ensured, penicillin desensitization should be strongly considered 1
• Doxycycline absorption is not significantly affected by food or milk, which can be given to reduce gastrointestinal irritation 4
• Adequate fluid intake with doxycycline is recommended to reduce risk of esophageal irritation and ulceration 4