What is the recommended treatment for nodular syphilis?

Treatment of Nodular Syphilis

Nodular syphilis (also called nodular tertiary syphilid or syphilitic gumma) should be treated with benzathine penicillin G 2.4 million units intramuscularly weekly for 3 consecutive weeks (total 7.2 million units), the same regimen used for late latent and tertiary syphilis. 1, 2

Understanding Nodular Syphilis

Nodular syphilis represents a manifestation of late/tertiary syphilis, characterized by nodular skin lesions or gummatous infiltrations that typically occur years after initial infection. 3 This places it in the category requiring extended treatment beyond early-stage disease.

First-Line Treatment Regimen

• Benzathine penicillin G 2.4 million units intramuscularly once weekly for 3 consecutive weeks is the recommended treatment for tertiary syphilis, including nodular manifestations. 4, 1, 2

• This extended regimen (total 7.2 million units) is necessary because nodular syphilis represents late-stage disease requiring more prolonged treponemacidal levels than the single-dose regimen used for early syphilis. 2

• The injection can be given as a single 2.4 million unit dose or divided into two 1.2 million unit injections (one in each buttock) with equal tolerability and patient preference. 5

Critical Pre-Treatment Evaluation

• All patients with nodular/tertiary syphilis must undergo CSF examination to exclude neurosyphilis before initiating the standard tertiary syphilis regimen, as neurosyphilis requires different treatment (aqueous crystalline penicillin G 18-24 million units daily IV for 10-14 days). 4, 1, 2

• HIV testing is mandatory for all patients with syphilis, as HIV co-infection may affect treatment response and requires more frequent monitoring. 4, 1

• Evaluate for any neurologic symptoms (meningitis, hearing loss, cranial nerve palsies) or ophthalmic manifestations (uveitis, iritis) that would indicate neurosyphilis requiring alternative treatment. 4, 1

Alternative Regimens for Penicillin Allergy

• For non-pregnant penicillin-allergic patients, doxycycline 100 mg orally twice daily for 28 days is the preferred alternative for late syphilis. 2, 6

• Tetracycline 500 mg orally four times daily for 28 days is another option, though compliance is typically better with doxycycline due to less frequent dosing and fewer gastrointestinal side effects. 4

• Pregnant patients with penicillin allergy MUST undergo desensitization followed by penicillin treatment, as no alternative antibiotics are proven effective for preventing fetal complications. 4, 1, 2

Critical Caveat on Azithromycin

• Azithromycin should NOT be used for syphilis treatment in the United States due to widespread macrolide resistance in Treponema pallidum and documented treatment failures, despite some older evidence suggesting efficacy. 1, 2, 7, 8

Follow-Up Monitoring

• Clinical and serologic evaluation (quantitative nontreponemal tests like RPR or VDRL) should be performed at 6,12, and 24 months after treatment. 4, 1, 2

• A fourfold decline in nontreponemal test titers is expected within 12-24 months for late syphilis, though serologic response may be slower than in early-stage disease. 1, 2

• HIV-infected patients require more frequent monitoring at 3-month intervals (3,6,9,12,15,18, and 24 months) due to higher risk of treatment failure. 4, 1

Treatment Failure Management

• Treatment failure is defined as persistent or recurring clinical signs/symptoms, or a sustained fourfold increase in nontreponemal test titers. 4, 1

• Patients with suspected treatment failure should be re-evaluated for HIV infection and undergo CSF examination to exclude neurosyphilis. 4, 1, 2

• Re-treatment typically consists of benzathine penicillin G 2.4 million units intramuscularly weekly for 3 weeks, unless CSF examination indicates neurosyphilis requiring IV penicillin therapy. 4, 1

Important Clinical Considerations

• Jarisch-Herxheimer reaction (acute fever, headache, myalgia occurring within 24 hours of treatment) may occur, particularly in patients with active lesions, and patients should be counseled about this expected reaction. 1, 2

• If a weekly dose is missed during the 3-week regimen, an interval of 10-14 days between doses is acceptable before needing to restart the entire sequence. 2

• Serologic tests may remain positive indefinitely in patients with prior syphilis infections (serofast state), and treponemal tests (FTA-ABS, TP-PA) remain positive for life and should not be used to monitor treatment response. 1, 2