What is the recommended treatment for a patient with neurosyphilis?

Treatment for Neurosyphilis

The 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

Primary Treatment Regimen

Recommended first-line therapy:

• Aqueous crystalline penicillin G: 18-24 million units daily IV for 10-14 days 2, 1
• Administration: Either 3-4 million units IV every 4 hours OR continuous IV infusion 1
• This regimen achieves treponemicidal CSF levels continuously throughout treatment 3

Alternative Regimen (If Compliance Assured)

If outpatient compliance can be guaranteed:

• Procaine penicillin 2.4 million units IM once daily PLUS probenecid 500 mg orally four times daily, both for 10-14 days 2, 1
• Probenecid blocks renal tubular secretion of penicillin, increasing CSF penetration 4

Important consideration: Many experts recommend adding benzathine penicillin 2.4 million units IM as a single dose after completing the 10-14 day neurosyphilis regimen to provide total treatment duration comparable to late syphilis therapy 2

Penicillin Allergy Management

Critical pitfall: Never use oral antibiotics (doxycycline, tetracycline) or benzathine penicillin alone for neurosyphilis—these do not achieve adequate CSF levels 2, 4

For penicillin-allergic patients:

• Preferred approach: Penicillin desensitization followed by standard penicillin regimen 2
• Alternative (with caution): Ceftriaxone 2 g daily IM or IV for 10-14 days 1, 5
  • Note: Risk of cross-reactivity between ceftriaxone and penicillin exists 1
  • Recent French multicenter data (208 patients) showed ceftriaxone achieved 98% overall clinical response versus 76% with benzylpenicillin, with shorter hospital stays 6
  • However, a Cochrane review found only very low-quality evidence supporting ceftriaxone, with insufficient data to determine true equivalence 7

Special Populations

HIV-Positive Patients

• Use the same neurosyphilis treatment regimen as HIV-negative patients 2
• HIV-positive patients with early syphilis have higher risk of neurological complications and treatment failure 1, 5
• All patients with syphilis must be tested for HIV 2, 1, 5

Ocular Syphilis

• Treat as neurosyphilis regardless of CSF findings 2
• Perform CSF examination on all patients with ocular involvement to identify those requiring follow-up CSF monitoring 2
• Manage in collaboration with an ophthalmologist 1, 5

Auditory Syphilis

• Many experts recommend treating as neurosyphilis regardless of CSF examination results 2

Follow-Up Protocol

CSF monitoring is essential:

• If initial CSF pleocytosis was present: Repeat CSF examination every 6 months until cell count normalizes 2, 1, 5
• CSF white blood cell count is the most sensitive measure of treatment effectiveness 1, 5

Indications for retreatment:

• CSF cell count has not decreased after 6 months 1, 5
• CSF cell count or protein not normal after 2 years 2, 1, 5
• Use the same retreatment regimen: aqueous crystalline penicillin G 18-24 million units daily IV for 10-14 days 5

Critical Warnings

Avoid these common errors:

• Never administer benzathine penicillin for neurosyphilis—it does not achieve adequate CSF levels and is inappropriate for CNS infection 8, 9, 4
• Never inject penicillin intravenously when benzathine formulation is used—this has been associated with cardiorespiratory arrest and death 9
• Never use intramuscular benzathine penicillin alone for any patient with neurological symptoms, ocular involvement, or auditory symptoms 2, 8

Jarisch-Herxheimer Reaction

Patients should be warned about this expected reaction:

• Occurs 2-12 hours after first penicillin dose due to bacterial lysis 9
• Symptoms: Fever, headache, myalgia, tachycardia, transient hypotension 9
• Resolves within 10-12 hours 9
• This is a normal, transient response to antibiotic therapy, not an allergic reaction 9