Treatment for Stage 3 (Tertiary) Syphilis

Critical First Step: Rule Out Neurosyphilis

The Centers for Disease Control and Prevention recommends performing a cerebrospinal fluid (CSF) examination to exclude neurosyphilis, particularly in patients with cardiovascular or gummatous disease, before initiating treatment for tertiary syphilis 4, 1
If neurosyphilis is present, the treatment regimen changes entirely to intravenous aqueous crystalline penicillin G 18-24 million units daily for 10-14 days, as recommended by the Centers for Disease Control and Prevention 4, 1, 5
The tertiary syphilis regimen is inadequate for CNS involvement, according to the Centers for Disease Control and Prevention 4
Some specialists treat all cardiovascular syphilis cases with neurosyphilis regimens due to this concern, as noted by the Centers for Disease Control and Prevention 1

The Centers for Disease Control and Prevention recommends benzathine penicillin G 2.4 million units intramuscularly once weekly for 3 consecutive weeks (total 7.2 million units) for the treatment of tertiary syphilis 1, 2, 3
This is the same regimen used for late latent syphilis, according to the Centers for Disease Control and Prevention 1, 2

The Centers for Disease Control and Prevention states that penicillin allergy is a major problem in tertiary syphilis management, and patients allergic to penicillin should be treated in consultation with an infectious disease specialist 1
Penicillin desensitization is strongly preferred over alternative antibiotics for tertiary disease, as recommended by the Centers for Disease Control and Prevention 4, 2

The Centers for Disease Control and Prevention recommends using the same treatment regimen as HIV-negative patients (three weekly doses of benzathine penicillin G 2.4 million units) for HIV-infected patients with tertiary syphilis 4, 2
Closer follow-up is mandatory to detect treatment failure or disease progression in HIV-infected patients, according to the Centers for Disease Control and Prevention 4

The Centers for Disease Control and Prevention states that only penicillin is proven effective for treating syphilis in pregnancy, and pregnant women with penicillin allergy must undergo desensitization followed by penicillin treatment 2, 3
No alternative antibiotics are acceptable in pregnancy, as noted by the Centers for Disease Control and Prevention 3

The Centers for Disease Control and Prevention recommends repeating quantitative nontreponemal serologic tests (RPR or VDRL) at 6, 12, and 24 months to monitor response to treatment 2, 3
Expect a fourfold decline in titer within 12-24 months, according to the Centers for Disease Control and Prevention 2
If titers increase fourfold, fail to decline appropriately, or neurological symptoms develop, perform CSF examination, as recommended by the Centers for Disease Control and Prevention 2

The Centers for Disease Control and Prevention warns against skipping the CSF examination before treating tertiary syphilis, as this may miss neurosyphilis that requires different treatment 4, 1
The Centers for Disease Control and Prevention advises against using oral penicillin preparations, as they are completely ineffective for any stage of syphilis 3
The Centers for Disease Control and Prevention recommends against substituting non-penicillin antibiotics without specialist consultation, as the complexity of tertiary syphilis management requires expert input 4, 1
The Centers for Disease Control and Prevention warns against using different serologic test methods (RPR vs VDRL) when monitoring response, as results cannot be directly compared 3
The Centers for Disease Control and Prevention notes that 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 5, 3

The Centers for Disease Control and Prevention defines treatment failure as persistent or recurring clinical signs/symptoms, sustained fourfold increase in nontreponemal test titers, or failure of titers to decline fourfold within expected timeframes 5, 2
If treatment failure occurs, the Centers for Disease Control and Prevention recommends re-evaluating for HIV infection, performing CSF examination, and retreating with three weekly injections of benzathine penicillin G 2.4 million units unless neurosyphilis is diagnosed 2