What is the recommended treatment for neurosyphilis in an adult, and what is the approach if the patient has a penicillin allergy?

Treatment of Neurosyphilis

First-Line Treatment: Intravenous Penicillin G

Aqueous crystalline penicillin G 18-24 million units per day IV (administered as 3-4 million units every 4 hours or by continuous infusion) for 10-14 days is the gold standard treatment for neurosyphilis. 1, 2

• This regimen achieves adequate CSF penicillin levels necessary to eradicate Treponema pallidum from the central nervous system 3
• The duration of 10-14 days is critical and should not be shortened 1
• Some specialists recommend following this regimen with three weekly doses of benzathine penicillin G 2.4 million units IM to provide additional coverage, though no consensus exists on this practice 3

Alternative Penicillin Regimen (Outpatient Option)

• Procaine penicillin 2.4 million units IM once daily PLUS probenecid 500 mg orally four times daily for 10-14 days is an acceptable alternative if adherence can be assured 3
• Critical caveat: Procaine penicillin without probenecid is inadequate because it does not achieve sufficient CSF levels 3, 2
• Patients allergic to sulfa medications should NOT receive this regimen because they are very likely allergic to probenecid 3

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Management of Penicillin Allergy

Preferred Approach: Desensitization

All patients with neurosyphilis and penicillin allergy should undergo penicillin desensitization followed by standard penicillin G treatment—this is the only proven effective therapy with adequate evidence. 1, 2

• No alternative antibiotics have been systematically evaluated or proven effective for neurosyphilis treatment 1
• Desensitization should be performed even in patients with severe penicillin allergy, as penicillin remains the only therapy with documented efficacy 1, 2
• After successful desensitization, proceed with aqueous crystalline penicillin G 18-24 million units per day IV for 10-14 days 1

Alternative Option: Ceftriaxone (Second-Line)

If desensitization is refused or not feasible, ceftriaxone 2 grams daily IV for 10-14 days may be considered, but this carries substantial risk due to cross-reactivity. 1, 4

• Cross-reactivity between penicillin and ceftriaxone occurs in approximately 10% of penicillin-allergic patients 1
• The evidence supporting ceftriaxone for neurosyphilis is extremely limited, with only one small trial of 36 HIV-positive patients showing inconclusive results 5
• This trial found 16% serological cure with ceftriaxone versus 11% with penicillin G, but the evidence quality was very low and insufficient to determine true efficacy 5
• Ceftriaxone should NOT be used in patients with severe penicillin allergy (such as Stevens-Johnson syndrome) due to beta-lactam cross-reactivity 2

Last Resort: Doxycycline (Third-Line)

For patients allergic to both penicillin and ceftriaxone, doxycycline 100 mg orally twice daily for 28 days is the CDC-recommended alternative regimen. 4

• This recommendation is based on extrapolation from late latent syphilis treatment, not specific neurosyphilis data 4, 2
• The efficacy of doxycycline for neurosyphilis has never been adequately studied 4
• All patients treated with non-penicillin regimens require extremely close monitoring due to uncertain efficacy 4

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Essential Pre-Treatment Requirements

CSF Examination

• CSF examination must be performed before initiating therapy to establish baseline parameters 4
• CSF examination is mandatory for patients with neurologic or ophthalmic signs/symptoms, tertiary syphilis, treatment failure, HIV infection with late latent syphilis, or nontreponemal titers ≥1:32 2

HIV Testing

• All patients with neurosyphilis must be tested for HIV 1, 2
• HIV-positive patients require closer monitoring due to higher rates of neurologic complications and treatment failure 1
• HIV-infected patients should receive the same penicillin regimens as HIV-negative patients 2

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Critical Follow-Up Protocol

CSF Monitoring

Repeat CSF examination every 6 months until the cell count normalizes—the CSF white blood cell count is the most sensitive measure of treatment effectiveness. 1, 4

• If CSF pleocytosis has not decreased after 6 months or CSF is not normal by 2 years, consider retreatment 4
• CSF VDRL titers should also decline, though they may remain positive despite successful treatment 4

Serologic Monitoring

• Quantitative nontreponemal serologic tests (RPR or VDRL) should be repeated at 6,12, and 24 months 1, 4
• Treatment failure is suspected if titers increase fourfold, high titers fail to decline fourfold, or new symptoms develop 4

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Special Populations and Considerations

Syphilitic Eye Disease

• Patients with ocular syphilis should be treated with neurosyphilis regimens regardless of CSF findings 1
• Ophthalmology consultation is mandatory 1

Pregnant Women

• Pregnant women with neurosyphilis MUST undergo penicillin desensitization if allergic—no alternative antibiotics are acceptable 2
• Penicillin is the only therapy with documented efficacy for preventing maternal transmission and treating fetal infection 2

Jarisch-Herxheimer Reaction

• Patients should be warned about this acute febrile reaction that may occur within 24 hours of treatment 2
• Symptoms include fever, headache, myalgia, and may precipitate premature labor in pregnant women 2

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Common Pitfalls to Avoid

• Never use benzathine penicillin G alone for neurosyphilis—it does not achieve adequate CSF levels 6
• Never use oral penicillin preparations—they are completely ineffective 2
• Never use azithromycin—widespread macrolide resistance makes this unacceptable in the United States 2
• Never substitute inadequate alternatives in pregnancy—only penicillin prevents congenital syphilis 2
• Do not switch between different nontreponemal tests (RPR vs VDRL) when monitoring response, as results cannot be directly compared 2
• Do not rely on treponemal antibody titers to assess treatment response—they correlate poorly with disease activity 2

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Management Requires Specialist Consultation

All patients with neurosyphilis should be managed in consultation with an infectious disease specialist due to the complexity of diagnosis, treatment, and monitoring. 4