What is the recommended treatment for neurosyphilis?

Treatment of Neurosyphilis

The recommended treatment for neurosyphilis is intravenous 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, 2, 3

Primary Treatment Regimen

• Aqueous crystalline penicillin G is the first-line therapy, dosed at 18-24 million units daily for 10-14 days, given either as divided doses of 3-4 million units IV every 4 hours or as continuous infusion 1, 2, 3

• This regimen ensures adequate CSF penetration with penicillin concentrations continuously above the minimal treponemicidal level needed to eradicate Treponema pallidum 4

• The FDA-approved dosing for neurosyphilis specifically states 12-24 million units/day as 2-4 million units every 4 hours for 10-14 days 3

Alternative Regimen for Outpatient Management

• Procaine penicillin 2.4 million units IM once daily PLUS probenecid 500 mg orally four times daily for 10-14 days can be used as an alternative 1, 2

• This regimen allows outpatient treatment but requires strict adherence to the probenecid dosing schedule 1

• Do not use probenecid in patients with sulfa allergies due to potential cross-reactivity 1

Extended Therapy Consideration

• Because neurosyphilis treatment duration (10-14 days) is shorter than late-latent syphilis regimens, consider adding benzathine penicillin G 2.4 million units IM weekly for 3 weeks after completing the neurosyphilis regimen to provide comparable total treatment duration 1, 2, 3

• Many experts recommend this supplemental therapy, though it is not universally required 3

Management of Penicillin Allergy

• Penicillin desensitization is the preferred approach for penicillin-allergic patients requiring neurosyphilis treatment 1

• Ceftriaxone 2 g daily IM or IV for 10-14 days may be used as an alternative, though data are limited 1, 2, 5

• Be aware that cross-reactivity between penicillin and ceftriaxone can occur, so this option carries risk in truly penicillin-allergic patients 2

• The single randomized trial comparing ceftriaxone to penicillin G showed insufficient evidence to determine equivalence, with very low-quality evidence 6

Special Populations: HIV-Infected Patients

• HIV-infected patients should receive the same treatment regimen (aqueous crystalline penicillin G 18-24 million units daily for 10-14 days) 1, 2

• HIV-positive patients with early syphilis have higher risk of neurological complications and increased rates of serological treatment failure 2, 5

• Prior treatment with benzathine penicillin G for early syphilis may fail in HIV-infected patients, leading to subsequent neurosyphilis development 7

• Even high-dose IV penicillin is not consistently effective in all HIV-infected patients with neurosyphilis 7

Ocular Syphilis Management

• Syphilitic eye disease (uveitis, neuroretinitis, optic neuritis) should be treated with the neurosyphilis regimen 1, 2, 8

• Management must be in collaboration with an ophthalmologist 1, 2, 5, 8

• Perform CSF examination in all patients with ocular syphilis to identify those with CSF abnormalities 1

Follow-Up Protocol

• Repeat CSF examination every 6 months until the cell count normalizes if pleocytosis was present initially 1, 2, 5

• CSF leukocyte count is the most sensitive measure of treatment effectiveness 1, 2, 5

• CSF-VDRL and protein levels change more slowly than cell counts and may remain abnormal longer 1

Criteria for Retreatment

• Consider retreatment if CSF cell count has not decreased after 6 months of initial therapy 2, 5

• Consider retreatment if CSF cell count or protein are not normal after 2 years 2, 5

• Use the same regimen for retreatment: aqueous crystalline penicillin G 18-24 million units daily for 10-14 days 5

Essential Concurrent Testing

• All patients with syphilis must be tested for HIV regardless of risk factors 1, 2, 5, 8

Important Caveats

• The duration of neurosyphilis treatment (10-14 days) differs from other tetracyclines and late-latent syphilis regimens—exceeding recommended dosing may increase adverse events 1

• Doxycycline is NOT recommended for neurosyphilis treatment, as it has not been adequately studied for CNS penetration in this indication 9

• Older studies from the 1980s showed no clinical advantage of high-dose IV penicillin over intramuscular procaine penicillin regimens, though IV therapy remains the guideline-recommended standard 10, 11