What is the treatment for a patient with late latent syphilis and a positive Cerebrospinal Fluid (CSF) Venereal Disease Research Laboratory (VDRL) test?

Treatment of Late Latent Syphilis with Positive CSF VDRL

A positive CSF VDRL confirms neurosyphilis and mandates treatment with intravenous 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. 1

Primary Treatment Regimen

The diagnosis of neurosyphilis with a positive CSF VDRL requires immediate escalation from standard late latent syphilis therapy to a neurosyphilis-specific regimen:

• Aqueous crystalline penicillin G 18-24 million units per day IV, given either as 3-4 million units every 4 hours or as continuous infusion, for 10-14 days 1
• This regimen ensures continuous treponemicidal penicillin concentrations in CSF throughout treatment, which is essential for eradicating CNS infection 2

Alternative Regimen (If Compliance Assured)

If outpatient compliance can be guaranteed, an alternative exists:

• Procaine penicillin 2.4 million units IM once daily PLUS Probenecid 500 mg orally four times daily, both for 10-14 days 1
• This combination achieves adequate CSF penicillin levels through probenecid's blockade of renal tubular secretion 1

Critical Post-Treatment Consideration

Because neurosyphilis regimens are shorter than late latent syphilis treatment, many specialists recommend supplemental benzathine penicillin G 2.4 million units IM weekly for 3 weeks after completing the neurosyphilis regimen to provide comparable total treatment duration 1

Penicillin Allergy Management

For penicillin-allergic patients, the approach differs significantly from non-neurologic syphilis:

• Penicillin desensitization followed by standard penicillin therapy is the preferred approach 1
• Ceftriaxone 2 grams daily (IM or IV) for 10-14 days may be considered as an alternative, though cross-reactivity with penicillin exists and efficacy data are limited 1
• Doxycycline and tetracycline are NOT adequate for neurosyphilis and should never be used 3

Important caveat: Patients with sulfa allergies should not receive the procaine penicillin/probenecid alternative, as they are likely allergic to probenecid 1

Mandatory Follow-Up Protocol

CSF monitoring is essential to confirm treatment success:

• Repeat CSF examination at 3 and 6 months after treatment completion, then every 6 months until CSF white blood cell count normalizes and CSF-VDRL becomes nonreactive 1
• If CSF pleocytosis was present initially, the cell count must normalize; if it hasn't decreased after 6 months or isn't normal after 2 years, re-treatment should be considered 1
• Serum nontreponemal tests (RPR/VDRL) should be monitored at 3,6,9,12, and 24 months, with at least a fourfold decline expected 1

HIV Co-infection Considerations

HIV status significantly impacts treatment response and monitoring:

• All patients with syphilis must be tested for HIV 1
• HIV-infected patients may have poorer CSF and serologic responses to neurosyphilis therapy 1, 4
• More frequent monitoring is required for HIV-positive patients, with evaluations at 3-month intervals rather than 6-month intervals 1
• Some data suggest that standard penicillin regimens may not be consistently effective in HIV-infected patients with neurosyphilis 4

Treatment Failure Indicators

Re-treatment should be considered if:

• CSF cell count has not decreased after 6 months of follow-up 1
• CSF is not normal after 2 years 1
• Serum nontreponemal titers fail to decline at least fourfold within 12-24 months 1
• Clinical signs or symptoms of neurosyphilis persist or recur 1

Common Pitfalls to Avoid

• Never treat confirmed neurosyphilis with benzathine penicillin alone—it does not achieve adequate CSF levels 1
• Do not use oral antibiotics (doxycycline, tetracycline, azithromycin) for neurosyphilis—they are inadequate for CNS infection 3, 5
• Do not skip CSF follow-up examinations—they are the only way to confirm treatment success in neurosyphilis 1
• In pregnant patients with neurosyphilis and penicillin allergy, desensitization is mandatory—no alternative antibiotics reliably treat neurosyphilis or prevent congenital syphilis 1