What is the treatment for tertiary syphilis?

Treatment for Tertiary Syphilis

For tertiary syphilis (gummatous or cardiovascular disease, excluding neurosyphilis), treat with benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at 1-week intervals. 1, 2

Pre-Treatment Evaluation

Before initiating therapy, you must perform a CSF examination to exclude neurosyphilis in all patients with symptomatic tertiary syphilis 1. This is critical because:

• Patients with cardiovascular syphilis may require neurosyphilis treatment regimens according to some experts, given the complexity of managing aortitis and its complications 1
• If CSF shows abnormalities consistent with neurosyphilis, switch to aqueous crystalline penicillin G 18-24 million units per day IV (administered as 3-4 million units every 4 hours or continuous infusion) for 10-14 days 1
• Cardiovascular manifestations include aortic root dilation, aortic insufficiency, and coronary ostial stenosis—all of which can be life-threatening 3, 4

Standard Treatment Regimen

Benzathine penicillin G 7.2 million units total, given as 2.4 million units IM weekly for 3 consecutive weeks 1, 2, 5

This regimen is identical to late latent syphilis treatment because organisms divide slowly in tertiary disease, requiring prolonged therapy 1

Penicillin Allergy Management

For penicillin-allergic patients:

• Non-pregnant patients: Doxycycline 100 mg orally twice daily for 28 days OR tetracycline 500 mg orally four times daily for 28 days 1, 5, 6
• Pregnant patients: Must undergo penicillin desensitization and receive penicillin—there are no acceptable alternatives 1, 5
• The FDA label confirms doxycycline dosing for syphilis of more than one year's duration at 100 mg orally twice daily for 4 weeks 6

Special Populations

HIV-Infected Patients

• Perform CSF examination before treatment to rule out neurosyphilis 1
• Use the same benzathine penicillin regimen (7.2 million units total over 3 weeks) if CSF is normal 1
• Management complexity requires consultation with an infectious disease specialist 1

Cardiovascular Syphilis Considerations

• Some experts treat all cardiovascular syphilis cases with neurosyphilis regimens due to the severity and irreversible nature of complications 1
• Cardiovascular involvement includes aortitis, aortic valve disease, and coronary ostial stenosis—conditions that can cause acute myocardial infarction 3, 4
• These patients require multidisciplinary management involving infectious disease specialists and cardiovascular surgeons 1, 3

Follow-Up Protocol

Limited data exist for tertiary syphilis follow-up, but clinical response depends on the nature of lesions 1:

• Monitor quantitative nontreponemal tests at 6,12, and 24 months 1, 5
• Perform CSF examination if titers increase fourfold, fail to decline appropriately, or new symptoms develop 1, 5
• Clinical improvement in gummatous lesions should be evident, though cardiovascular damage may be irreversible 7, 8

Critical Pitfalls to Avoid

• Never skip CSF examination in symptomatic tertiary syphilis—neurosyphilis requires different treatment and missing it leads to progressive neurological damage 1
• Do not use alternative antibiotics without close monitoring—azithromycin has documented treatment failures due to resistance 1, 7
• Do not assume serologic tests will be positive—some tertiary syphilis cases have low or negative VDRL titers, making diagnosis challenging 9
• Always evaluate for both cardiovascular AND neurological involvement—these determine prognosis and may require surgical intervention 9, 3, 4