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

Treatment of Syphilis in Penicillin-Allergic Patients

For penicillin-allergic patients with syphilis, doxycycline is the recommended alternative treatment, with dosing and duration dependent on the stage of infection. 1, 2

Treatment Regimens by Stage of Syphilis

Primary and Secondary Syphilis (Early Syphilis)

• Doxycycline 100 mg orally twice daily for 14 days is the preferred alternative for non-pregnant, penicillin-allergic patients 1, 2
• Tetracycline 500 mg orally four times daily for 14 days is an alternative, though doxycycline is preferred due to better compliance with twice-daily versus four-times-daily dosing 1
• Research evidence supports doxycycline's effectiveness, with studies showing comparable serological response rates to benzathine penicillin G 3, 4

Late Latent Syphilis or Syphilis of Unknown Duration

• Doxycycline 100 mg orally twice daily for 28 days is the only acceptable alternative 1, 2, 5
• Tetracycline 500 mg orally four times daily for 28 days is also acceptable but less preferred 1
• These therapies must be used with close serologic and clinical follow-up 1

Neurosyphilis

• Doxycycline 100 mg orally twice daily for 28 days is recommended for patients allergic to both penicillin and ceftriaxone 6
• All neurosyphilis patients should be managed in consultation with an infectious disease specialist 6
• CSF examination should be performed before initiating therapy and repeated every 6 months until cell count normalizes 6

Tertiary Syphilis

• Patients allergic to penicillin should be treated in consultation with an infectious disease specialist 1
• The same doxycycline regimen as late latent syphilis applies (28 days) 1, 5

Alternative Considerations

Ceftriaxone

• Ceftriaxone 1 g daily IM or IV for 10-14 days may be effective for early syphilis, though optimal dosing is not well-defined 1
• For neurosyphilis, ceftriaxone 2 g daily IM or IV for 10-14 days is typically the first alternative before doxycycline 6
• Important caveat: Cross-reactivity between penicillin and ceftriaxone allergies can occur, so this option may not be suitable for all penicillin-allergic patients 6

Azithromycin

• Azithromycin 2 g orally as a single dose was previously considered for early syphilis 1
• This should be avoided: T. pallidum chromosomal mutations associated with azithromycin resistance and treatment failures have been documented in multiple U.S. geographic areas 1
• Azithromycin should not be used in men who have sex with men (MSM) or pregnant women 1

Critical Management Considerations

When Desensitization is Mandatory

• Pregnant women with syphilis at any stage must undergo penicillin desensitization, as penicillin is the only therapy with documented efficacy for preventing maternal transmission 5
• Patients with penicillin allergy whose compliance with therapy or follow-up cannot be ensured should be desensitized and treated with benzathine penicillin 1
• Skin testing for penicillin allergy may be useful when reagents and expertise are available 1

Follow-Up Requirements

• Quantitative nontreponemal serologic tests (RPR or VDRL) should be repeated at 6,12, and 24 months after treatment 1, 2, 5
• For HIV-infected patients, closer monitoring at 3-month intervals is recommended instead of 6-month intervals 2
• Close follow-up is essential for all patients receiving alternative therapies 1

Treatment Failure Indicators

• CSF examination should be performed if titers increase fourfold, an initially high titer (≥1:32) fails to decline at least fourfold within 12-24 months, or new signs/symptoms develop 1, 2
• A fourfold decline in titer is expected within 6 months for primary/secondary syphilis and within 12-24 months for late syphilis 5
• Even with negative CSF examination, retreatment for latent syphilis should be initiated if treatment failure is suspected 1

Common Pitfalls to Avoid

• Do not use oral penicillin preparations for syphilis treatment, as they are ineffective 5
• Do not switch between different nontreponemal tests (e.g., VDRL and RPR) when monitoring serologic response, as results cannot be directly compared 5
• Do not rely solely on treponemal test antibody titers to assess treatment response, as they correlate poorly with disease activity 5
• Be aware that some research suggests doxycycline may have a reduced success rate in late and undetermined syphilis infections compared to penicillin, though this remains controversial 7

Special Population Considerations

HIV-Infected Patients

• Treatment regimens are the same as for non-HIV-infected patients 5
• All patients with syphilis should be tested for HIV 1, 6, 5
• HIV-infected patients may have atypical serologic responses but generally respond well to standard treatment 5

Administration Guidance

• Doxycycline should be administered with adequate fluid to reduce risk of esophageal irritation and ulceration 8
• If gastric irritation occurs, doxycycline may be given with food or milk without significantly affecting absorption 8