What is the recommended treatment for a patient with secondary syphilis?

Treatment of Secondary Syphilis

The recommended treatment for secondary syphilis is benzathine penicillin G 2.4 million units intramuscularly as a single dose. 1, 2, 3

Standard Treatment Regimen

• Benzathine penicillin G 2.4 million units IM in a single dose is the gold standard treatment for secondary syphilis in adults, supported by over 40 years of clinical experience and CDC guidelines. 1, 2, 3
• This single-dose regimen effectively treats secondary syphilis and prevents progression to late-stage disease. 1, 2
• For children with acquired secondary syphilis, administer benzathine penicillin G 50,000 units/kg IM (up to the adult dose of 2.4 million units) as a single dose after CSF examination to exclude neurosyphilis. 1, 2

Essential Concurrent Testing

• All patients with secondary syphilis must be tested for HIV infection immediately, as coinfection affects monitoring frequency and may increase risk for neurologic complications. 1, 2, 3
• HIV-positive patients receive the same single-dose treatment but require more frequent follow-up at 3,6,9,12, and 24 months (instead of 6 and 12 months for HIV-negative patients). 1, 2

When to Consider CSF Examination

• CSF examination is not routinely recommended for secondary syphilis unless neurologic or ophthalmic symptoms are present (meningitis, uveitis, cranial nerve palsies). 1, 2
• However, some specialists recommend CSF examination before treatment in HIV-infected patients with secondary syphilis, given the higher risk of CNS involvement. 1, 2

Alternative Treatment for Penicillin Allergy

For non-pregnant adults with documented penicillin allergy:

• Doxycycline 100 mg orally twice daily for 14 days is the preferred alternative. 2, 3, 4
• Tetracycline 500 mg orally four times daily for 14 days is an option but has worse compliance due to gastrointestinal side effects. 2, 3

Critical caveat: Pregnant women with penicillin allergy must undergo desensitization followed by penicillin treatment—no exceptions—as penicillin is the only therapy proven to prevent maternal transmission and treat fetal infection. 2

Follow-Up Protocol

For HIV-negative patients:

• Perform quantitative nontreponemal tests (RPR or VDRL) at 6 and 12 months after treatment. 2, 3
• A successful response is defined as a fourfold decline in nontreponemal titer within 6 months. 1, 2, 3

For HIV-positive patients:

• Perform clinical and serologic evaluation at 3,6,9,12, and 24 months after treatment. 1, 2
• Some specialists recommend CSF examination 6 months after therapy, though this is of unproven benefit. 1

Treatment Failure Criteria

Re-treat and evaluate for HIV if any of the following occur:

• Nontreponemal titers fail to decline fourfold within 6 months after therapy. 1, 2, 3
• Clinical signs or symptoms persist or recur. 1, 2
• A sustained fourfold increase in nontreponemal titer compared to baseline. 1, 2

Management of treatment failure:

• Perform CSF examination to exclude neurosyphilis. 1, 2
• Re-treat with benzathine penicillin G 2.4 million units IM weekly for 3 weeks if CSF is normal. 1, 2
• If CSF indicates neurosyphilis, treat with aqueous crystalline penicillin G 18-24 million units IV daily for 10-14 days. 2

Management of Sexual Partners

• All sexual contacts from the past 6 months plus duration of symptoms should be evaluated and treated presumptively, even if seronegative. 2
• Partners should receive the same treatment regimen (benzathine penicillin G 2.4 million units IM as a single dose). 2

Important Clinical Considerations

• Jarisch-Herxheimer reaction may occur within 24 hours after treatment, presenting with fever, headache, and myalgia—this is especially common in secondary syphilis and does not indicate treatment failure. 2
• In pregnant women treated during the second half of pregnancy, this reaction may precipitate premature labor or fetal distress; patients should seek immediate medical attention if contractions or changes in fetal movements occur. 2

Common Pitfalls to Avoid

• Do not use treponemal tests (FTA-ABS, TP-PA) to monitor treatment response, as they remain positive for life and do not correlate with disease activity. 2, 3
• Do not compare titers between different test types (VDRL vs RPR), as they are not directly comparable. 2, 3
• Do not assume persistent low-titer reactivity indicates treatment failure, as approximately 15-25% of patients remain "serofast" with low unchanging titers despite cure. 2, 3
• Do not use azithromycin in the United States due to widespread macrolide resistance and documented treatment failures. 2
• Do not use oral penicillin preparations for syphilis treatment, as they are ineffective. 2