Treatment for Stage 3 (Tertiary) Syphilis
For tertiary syphilis, administer benzathine penicillin G 7.2 million units total as three weekly intramuscular injections of 2.4 million units each. 1, 2, 3, 4
Critical First Step: Rule Out Neurosyphilis
Before initiating treatment for tertiary syphilis, you must perform a cerebrospinal fluid (CSF) examination to exclude neurosyphilis, particularly in patients with cardiovascular or gummatous disease. 1 This is non-negotiable because:
- If neurosyphilis is present, the treatment regimen changes entirely to intravenous aqueous crystalline penicillin G 18-24 million units daily for 10-14 days 1
- The tertiary syphilis regimen is inadequate for CNS involvement 1
- Some specialists treat all cardiovascular syphilis cases with neurosyphilis regimens due to this concern 1
Standard Treatment Protocol
First-Line Therapy
- Benzathine penicillin G 2.4 million units intramuscularly once weekly for 3 consecutive weeks (total 7.2 million units) 1, 2, 3, 4
- This is the same regimen used for late latent syphilis 1, 2
- Administer via deep intramuscular injection in the upper outer quadrant of the buttock (dorsogluteal) or ventrogluteal site 4
Penicillin-Allergic Patients
Penicillin allergy is a major problem in tertiary syphilis management. 1 The guidelines are explicit:
- Patients allergic to penicillin should be treated in consultation with an infectious disease specialist 1
- Doxycycline 100 mg orally twice daily for 28 days is the alternative for late latent syphilis 1, 2, 5, but its efficacy in tertiary syphilis specifically has not been adequately studied 1
- Penicillin desensitization is strongly preferred over alternative antibiotics for tertiary disease 1, 2
Special Populations
HIV-Infected Patients
- Use the same treatment regimen as HIV-negative patients (three weekly doses of benzathine penicillin G 2.4 million units) 1, 2
- However, closer follow-up is mandatory to detect treatment failure or disease progression 1
- CSF examination should be performed more liberally in HIV-infected patients with tertiary syphilis 1
Pregnant Women
- Only penicillin is proven effective for treating syphilis in pregnancy 2, 3
- Pregnant women with penicillin allergy must undergo desensitization followed by penicillin treatment 2, 3
- No alternative antibiotics are acceptable in pregnancy 3
Follow-Up and Monitoring
Limited information exists on clinical response and follow-up for tertiary syphilis specifically. 1 However, based on late syphilis guidelines:
- Quantitative nontreponemal serologic tests (RPR or VDRL) should be repeated at 6,12, and 24 months 2
- Expect a fourfold decline in titer within 12-24 months 2
- If titers increase fourfold, fail to decline appropriately, or neurological symptoms develop, perform CSF examination 2
Critical Pitfalls to Avoid
Never skip the CSF examination before treating tertiary syphilis - you may miss neurosyphilis that requires different treatment 1
Do not use oral penicillin preparations - they are completely ineffective for any stage of syphilis 3
Do not substitute non-penicillin antibiotics without specialist consultation - the complexity of tertiary syphilis management requires expert input 1
Do not use different serologic test methods (RPR vs VDRL) when monitoring response - results cannot be directly compared 3
Be aware of Jarisch-Herxheimer reaction - an acute febrile reaction with headache and myalgia may occur within 24 hours of treatment, especially in early syphilis but can occur at any stage 6, 3
When to Retreat
Treatment failure is defined as:
- Persistent or recurring clinical signs/symptoms 6
- Sustained fourfold increase in nontreponemal test titers 6
- Failure of titers to decline fourfold within expected timeframes 2
If treatment failure occurs, re-evaluate for HIV infection, perform CSF examination, and retreat with three weekly injections of benzathine penicillin G 2.4 million units unless neurosyphilis is diagnosed. 2