What is the recommended treatment for tertiary syphilis?

Treatment of Tertiary Syphilis

For patients with tertiary syphilis, a CSF examination must be performed before initiating therapy, followed by benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM at 1-week intervals. 1, 2

Initial Evaluation

Before initiating treatment for tertiary syphilis:

1. CSF examination is mandatory to rule out neurosyphilis 1, 2
2. Clinical assessment for:
   • Cardiovascular involvement (aortitis, aortic insufficiency)
   • Gummatous disease (granulomatous lesions)
   • Neurological symptoms (cognitive dysfunction, motor/sensory deficits)
   • Ocular manifestations (uveitis, neuroretinitis, optic neuritis)

Treatment Algorithm

If CSF examination is negative for neurosyphilis:

• First-line treatment: Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM at 1-week intervals 1, 2

If CSF examination confirms neurosyphilis:

• First-line treatment: Intravenous aqueous crystalline penicillin G, 18-24 million units daily, administered as 3-4 million units IV every 4 hours or by continuous infusion for 10-14 days 1, 2
• Alternative: Procaine penicillin 2.4 million units IM once daily plus probenecid 500 mg orally four times a day for 10-14 days 1
  • Note: Patients allergic to sulfa-containing medications should not receive probenecid due to potential allergic reactions 1

For penicillin-allergic patients:

• Preferred approach: Penicillin desensitization followed by standard penicillin treatment 1, 2
• Alternative for non-neurosyphilis tertiary syphilis: Doxycycline 100 mg orally twice daily for 28 days 1, 3
• Alternative for neurosyphilis: Ceftriaxone 2 g daily IV for 10-14 days (limited data) 1

Monitoring and Follow-up

• Quantitative nontreponemal tests (RPR or VDRL) should be repeated at 6,12, and 24 months after treatment 1, 2
• CSF examination should be performed if:
  1. Titers increase fourfold
  2. An initially high titer (≥1:32) fails to decline at least fourfold within 12-24 months
  3. Signs or symptoms attributable to syphilis develop 1

Special Considerations

• HIV co-infection: Management is similar to HIV-negative patients, but closer follow-up is recommended to detect potential treatment failure or disease progression 1, 2
• Complexity of management: Due to the complexity of tertiary syphilis, consultation with an infectious disease specialist is strongly recommended 1

Common Pitfalls and Caveats

1. Failure to perform CSF examination: Always perform CSF examination before initiating therapy for tertiary syphilis to rule out neurosyphilis
2. Inadequate follow-up: Serological non-response or "serofast state" (persistent low-level reactivity) may occur in 15-20% of patients after successful treatment 1
3. Improper dosing intervals: Maintaining the recommended 7-day interval between benzathine penicillin doses is important for therapeutic efficacy
4. Overlooking alternative diagnoses: The manifestations of tertiary syphilis can mimic other conditions, requiring careful differential diagnosis
5. Inadequate treatment of neurosyphilis: Using IM procaine penicillin without probenecid does not achieve sufficient penicillin levels in CSF to treat neurosyphilis 1

The evidence strongly supports penicillin as the cornerstone of treatment for tertiary syphilis, with specific regimens based on the presence or absence of neurosyphilis. Alternative regimens should be used with caution and only when penicillin cannot be administered.