What is the recommended treatment regimen for neurosyphilis, including first‑line intravenous aqueous crystalline penicillin G dosing, alternative intramuscular procaine penicillin with probenecid, management of severe penicillin allergy, and follow‑up recommendations for HIV‑coinfected patients?

Neurosyphilis Management

First-Line Treatment: Intravenous Aqueous Crystalline Penicillin G

The recommended first-line treatment for neurosyphilis is aqueous crystalline penicillin G 18–24 million units per day, administered as 3–4 million units IV every 4 hours or by continuous infusion, for 10–14 days. 1

This regimen achieves cerebrospinal fluid penicillin concentrations sufficient to eradicate Treponema pallidum from the central nervous system. 1 The CDC has consistently endorsed this approach across multiple guideline iterations. 2

Dosing Details

• Total daily dose: 18–24 million units 1
• Administration: Either 3–4 million units IV every 4 hours OR continuous IV infusion 2, 1
• Duration: 10–14 days 2, 1

Optional Supplemental Therapy

Some experts recommend adding benzathine penicillin G 2.4 million units IM weekly for up to 3 weeks after completing the IV course to provide a total duration of therapy comparable to late latent syphilis treatment. 2, 1 However, consensus on this practice has not been reached. 2, 1

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Alternative Regimen: Intramuscular Procaine Penicillin with Probenecid

For patients in whom compliance can be ensured, procaine penicillin 2.4 million units IM once daily PLUS probenecid 500 mg orally four times daily, both for 10–14 days, is an acceptable alternative. 2, 1

Critical Requirements for This Regimen

• Probenecid is mandatory: Procaine penicillin without probenecid does NOT achieve adequate CSF penicillin levels and is inadequate for neurosyphilis treatment. 2, 1
• Contraindication: Patients with sulfonamide allergy should NOT receive this regimen because they are highly likely to be allergic to probenecid. 2, 1
• Compliance assurance: This outpatient regimen requires daily attendance for 10–17 days; one study showed 88% overall compliance with excellent acceptability. 3

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Management of Severe Penicillin Allergy

Desensitization is Preferred

For penicillin-allergic patients, penicillin desensitization followed by one of the standard penicillin regimens is the preferred approach. 2, 1

Alternative: Ceftriaxone (Limited Data)

If desensitization is not feasible, ceftriaxone 2 grams daily IV for 10–14 days may be considered, though data are extremely limited. 2, 1, 4

Important Caveats About Ceftriaxone

• Patients with severe penicillin allergy (such as Stevens-Johnson syndrome) may also be allergic to ceftriaxone due to cross-reactivity between beta-lactam antibiotics. 1
• The optimal dose and duration have not been definitively established. 1
• Evidence in HIV-infected patients remains limited compared to penicillin. 1
• One Cochrane review found insufficient evidence to determine whether ceftriaxone differs from penicillin G in effectiveness, based on a single small trial with very low-quality evidence. 5

What NOT to Use

• Azithromycin should NOT be used due to widespread macrolide resistance and documented treatment failures. 1
• Doxycycline and tetracycline are NOT adequate for neurosyphilis treatment. 1

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Follow-Up Recommendations for All Patients

CSF Monitoring Protocol

If CSF pleocytosis was present initially, repeat CSF examination every 6 months until the cell count normalizes. 2, 1, 4

• The CSF white blood cell count is the most sensitive measure of treatment effectiveness. 4
• CSF VDRL and protein changes occur more slowly and persistent abnormalities may be less important. 2

Retreatment Criteria

Consider retreatment if:

• The CSF cell count has not decreased after 6 months 2, 1, 4
• The CSF is not normal after 2 years 2, 1, 4

The recommended retreatment regimen is the same: aqueous crystalline penicillin G 18–24 million units per day IV for 10–14 days. 4

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Special Considerations for HIV-Coinfected Patients

Treatment Regimen

HIV-infected patients should receive the same penicillin regimens as HIV-negative patients for neurosyphilis. 2, 1

• Aqueous crystalline penicillin G 18–24 million units per day IV for 10–14 days 2, 1
• OR procaine penicillin 2.4 million units IM daily plus probenecid 500 mg orally four times daily for 10–14 days 2, 1

Enhanced Monitoring Requirements

HIV-infected patients require more intensive post-treatment monitoring: clinical and serologic evaluation at 3,6,9,12, and 24 months. 2, 1

This enhanced surveillance is necessary because:

• HIV-positive individuals may have atypical serologic responses (unusually high, low, or fluctuating titers). 1, 6
• They have higher rates of treatment failure with currently recommended regimens. 4
• They may have increased risk of neurologic complications. 1, 4

CSF Examination Considerations

For HIV-infected patients with late latent syphilis, CSF examination should be considered before treatment to exclude neurosyphilis. 2, 1

Some specialists recommend CSF examination for all HIV-infected patients with syphilis, regardless of stage. 2

Management of Treatment Failure in HIV Patients

If nontreponemal titers do not decline fourfold within 3 months for primary/secondary syphilis (or within the expected timeframe for other stages), perform CSF examination and consider retreatment. 1, 6

• When CSF is normal after treatment failure, most experts retreat with benzathine penicillin G 7.2 million units (three weekly doses of 2.4 million units each). 1, 6
• When CSF remains abnormal, manage according to the neurosyphilis protocol (IV aqueous crystalline penicillin). 1

Penicillin Allergy in HIV Patients

HIV-infected patients with penicillin allergy should undergo skin testing and desensitization, then be treated with penicillin. 2, 1

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Indications for CSF Examination Before Treatment

CSF examination is mandatory before initiating therapy for patients with:

• Neurologic signs or symptoms (cognitive dysfunction, motor/sensory deficits, cranial nerve palsies, meningismus) 2, 1
• Ophthalmic symptoms (uveitis, neuroretinitis, optic neuritis) 2, 1
• Auditory symptoms 2, 1
• Evidence of active tertiary syphilis (aortitis, gummas, iritis) 2, 1
• Treatment failure (persistent symptoms or rising titers) 2, 1
• HIV infection with late latent syphilis or syphilis of unknown duration 2, 1
• Nontreponemal titer ≥1:32 when infection duration is ≥1 year 1

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Common Pitfalls to Avoid

Critical Errors in Medication Selection

• Never use procaine penicillin without probenecid for neurosyphilis—it fails to achieve therapeutic CSF levels. 2, 1
• Never use oral penicillin preparations—they are ineffective for any stage of syphilis. 1
• Never use azithromycin due to widespread resistance. 1

Monitoring Mistakes

• Do not use different testing methods (e.g., switching between VDRL and RPR) when monitoring serologic response—results cannot be directly compared. 1, 6
• Do not rely solely on treponemal test antibody titers to assess treatment response—they correlate poorly with disease activity. 1

Special Population Errors

• Never substitute non-penicillin alternatives in pregnancy—penicillin is the only therapy with documented efficacy for preventing congenital syphilis. 1, 6
• Do not skip CSF examination in HIV-infected patients with late latent syphilis before treatment. 2, 1

Follow-Up Lapses

• Do not assume treatment success without documented CSF normalization in patients who had initial pleocytosis. 2, 1, 4
• Do not delay retreatment if CSF cell count has not decreased after 6 months. 2, 1, 4