What is the treatment for neurosyphilis (infection of the central nervous system caused by Treponema pallidum)?

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From the Guidelines

Neurosyphilis treatment should be initiated with aqueous crystalline penicillin G 18-24 million units per day, administered as 3-4 million units IV every 4 hours or continuous infusion, for 10-14 days, as recommended by the Centers for Disease Control and Prevention 1.

Key Considerations

  • The recommended regimen is based on the most recent and highest quality studies, which prioritize morbidity, mortality, and quality of life as the primary outcomes.
  • Patients who have neurosyphilis or syphilitic eye disease should be treated with the recommended regimen, and a CSF examination should be performed to identify those with abnormalities who should have follow-up CSF examinations to assess treatment response 1.
  • Alternative regimens, such as procaine penicillin 2.4 million units IM once daily plus probenecid 500 mg orally four times a day, both for 10-14 days, may be used if compliance with therapy can be ensured 1.

Management and Follow-Up

  • All patients who have syphilis should be tested for HIV, and many specialists recommend treating patients who have evidence of auditory disease caused by syphilis in the same manner as patients who have neurosyphilis, regardless of CSF examination results 1.
  • Follow-up CSF examinations should be repeated every 6 months until the cell count is normal, and changes in the VDRL-CSF or CSF protein after therapy can be used to evaluate treatment response 1.
  • If the cell count has not decreased after 6 months, or if the CSF is not normal after 2 years, re-treatment should be considered 1.

From the FDA Drug Label

Syphilis (neurosyphilis) 12 to 24 million units/day, as 2 to 4 MU every 4 hours for 10 to 14 days; many experts recommend additional therapy with Benzathine PCN G 2. 4 MU IM weekly for 3 doses after completion of IV therapy Syphilis (congenital and neurosyphilis) after the newborn period 200,000 to 300,000 units/kg/day (administered as 50,000 units/kg every 4 to 6 hours) for 10 to 14 days

The recommended treatment for neurosyphilis is 12 to 24 million units/day of penicillin G, administered as 2 to 4 MU every 4 hours for 10 to 14 days. Additionally, some experts suggest additional therapy with Benzathine PCN G 2.4 MU IM weekly for 3 doses after completion of IV therapy. For pediatric patients, the dosage is 200,000 to 300,000 units/kg/day, administered as 50,000 units/kg every 4 to 6 hours for 10 to 14 days 2.

From the Research

Neurosyphilis Treatment Overview

  • Neurosyphilis is an infection of the central nervous system caused by Treponema pallidum, and its treatment is crucial to prevent further neurological complications 3.
  • The first-line treatment for neurosyphilis is aqueous crystalline penicillin, but alternative antibiotic regimens can be used in cases of penicillin allergy 3.

Antibiotic Regimens for Neurosyphilis

  • A study comparing ceftriaxone and penicillin G for the treatment of neurosyphilis found that more participants achieved serological and clinical cure with ceftriaxone, but the evidence was insufficient to determine a difference between the two treatments 3.
  • Another study found that procaine penicillin administered intramuscularly daily for 20 days was as effective as intravenous administration of penicillin G 4.
  • Daily procaine penicillin has been shown to be an acceptable and compliant outpatient regimen for the treatment of syphilis, with excellent compliance and minimal side effects 5.

Specific Treatment Recommendations

  • Benzathine penicillin G may be used in the treatment of neurosyphilis in selected situations, although few well-controlled studies exist to document its efficacy 6.
  • A case report suggested that recommended dosages of penicillin G procaine may not be sufficient to achieve spirocheticidal levels in the cerebrospinal fluid 7.

Key Considerations

  • The quality of evidence for neurosyphilis treatment is often limited, and more research is needed to determine the most effective treatment regimens 3.
  • Treatment decisions should be made on a case-by-case basis, taking into account the individual patient's needs and circumstances 3, 4, 5, 6, 7.

References

Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

Research

Antibiotic therapy for adults with neurosyphilis.

The Cochrane database of systematic reviews, 2019

Research

Treatment of neurosyphilis. A comparison of penicillin regimens.

South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde, 1987

Research

Benzathine penicillin G in the treatment of neurosyphilis.

Drug intelligence & clinical pharmacy, 1982

Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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