What are the treatment options for neurosyphilis in patients allergic to penicillin and ceftriaxone?

Treatment Options for Neurosyphilis in Patients Allergic to Penicillin and Ceftriaxone

For patients with neurosyphilis who are allergic to both penicillin and ceftriaxone, doxycycline 100 mg orally twice daily for 28 days is the recommended alternative treatment. 1

First-Line Treatment and Allergic Considerations

• Penicillin G is the gold standard treatment for neurosyphilis (18-24 million units per day IV for 10-14 days), but cannot be used in penicillin-allergic patients 1
• Ceftriaxone (2g daily IM or IV for 10-14 days) is typically the first alternative for penicillin-allergic patients, but cross-reactivity between penicillin and ceftriaxone allergies can occur 1, 2
• Patients allergic to both penicillin and ceftriaxone require alternative regimens 1

Recommended Alternative Treatment

• Doxycycline 100 mg orally twice daily for 28 days is the recommended regimen for patients allergic to both penicillin and ceftriaxone 1, 3
• The FDA-approved dosage for syphilis of more than one year's duration (including neurosyphilis) in penicillin-allergic patients is doxycycline 100 mg orally twice daily for 4 weeks (28 days) 3

Treatment Considerations and Monitoring

• All patients with neurosyphilis should be managed in consultation with an infectious disease specialist 1
• CSF examination should be performed before initiating therapy to establish baseline parameters 1
• Follow-up CSF examination should be repeated every 6 months until the cell count normalizes 1, 4
• The CSF leukocyte count is the most sensitive measure of treatment effectiveness 4

Evidence Quality and Limitations

• The effectiveness of alternatives to penicillin in neurosyphilis has not been well documented 1, 5
• Limited clinical trials exist comparing alternative treatments for neurosyphilis 6, 7
• Doxycycline achieves relatively high concentrations in the brain, which supports its use in neurosyphilis 8
• A 2019 Cochrane review found insufficient evidence to determine differences between ceftriaxone and penicillin G for neurosyphilis treatment 6

Special Populations

• All persons with syphilis should be tested for HIV 1
• The efficacy of alternative regimens in HIV-infected persons has not been well studied 1, 9
• Patients with syphilitic eye disease should be managed in collaboration with an ophthalmologist 1

Follow-Up Recommendations

• Quantitative nontreponemal serologic tests should be repeated at 6,12, and 24 months 1
• Treatment failure should be suspected if titers increase fourfold, high titers fail to decline, or new symptoms develop 1
• Close clinical and serological follow-up is essential when using alternative regimens 1, 9