What is the recommended treatment for 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

First-Line Treatment

• Benzathine penicillin G 2.4 million units IM in a single dose is the standard of care for secondary syphilis. 1, 2
• This single-dose regimen has been extensively validated and remains the preferred treatment across all major guidelines. 1, 3
• The same regimen is used for both primary and secondary syphilis, as they are both classified as early syphilis. 1

Alternative Regimens for Penicillin-Allergic Patients

For non-pregnant adults with documented penicillin allergy:

• Doxycycline 100 mg orally twice daily for 14 days is the recommended alternative. 4, 1
• Doxycycline is preferred over tetracycline due to better compliance and fewer gastrointestinal side effects. 4
• Ceftriaxone 1 gram IV or IM daily for 10 days is a reasonable alternative based on randomized trial data showing comparable efficacy to benzathine penicillin. 1
• Azithromycin should NOT be used in the United States due to widespread macrolide resistance and documented treatment failures. 1

Critical caveat: If compliance with therapy or follow-up cannot be ensured in penicillin-allergic patients, desensitization followed by benzathine penicillin treatment is strongly recommended. 4

Special Populations

Pregnant Women

• Pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment—no exceptions. 1
• Only penicillin prevents congenital syphilis; no alternative antibiotics are acceptable in pregnancy. 1
• All pregnant women should be screened for syphilis at first prenatal visit, during third trimester, and at delivery. 1
• Warning: Jarisch-Herxheimer reaction during the second half of pregnancy may precipitate premature labor or fetal distress. 1

HIV-Infected Patients

• HIV-infected patients receive the same treatment regimen (single dose of benzathine penicillin G 2.4 million units IM) as HIV-negative patients. 1
• However, closer follow-up is mandatory at 3-month intervals (instead of 6-month intervals) to detect potential treatment failure or disease progression. 4, 1
• Limited data suggest no benefit to multiple doses of benzathine penicillin for early syphilis in HIV-infected patients compared to a single dose. 1

Follow-Up and Monitoring

• Quantitative nontreponemal serologic tests (RPR or VDRL) should be repeated at 3,6,12, and 24 months after treatment. 1
• A fourfold decline in titer is expected within 6 months for secondary syphilis. 1
• Failure of nontreponemal test titers to decline fourfold within 6 months indicates probable treatment failure. 4, 1

When Treatment Fails

If signs/symptoms persist, recur, or titers fail to decline appropriately:

• Re-evaluate for HIV infection. 4, 5
• Perform CSF examination to rule out neurosyphilis. 4, 5
• Re-treat with benzathine penicillin G 2.4 million units IM weekly for 3 weeks (unless neurosyphilis is diagnosed, which requires IV aqueous crystalline penicillin G). 4, 5

Management of Sexual Partners

• Persons exposed within 90 days preceding the diagnosis should be treated presumptively even if seronegative. 1
• Persons exposed more than 90 days before diagnosis should be treated presumptively if serologic test results are not immediately available and follow-up is uncertain. 1

Critical Pitfalls to Avoid

• Never use oral penicillin preparations—they are completely ineffective for syphilis treatment. 1, 6
• Do not switch between different nontreponemal test methods (RPR vs. VDRL) when monitoring serologic response, as results cannot be directly compared. 1, 5
• Do not rely solely on treponemal test antibody titers to assess treatment response, as they correlate poorly with disease activity. 1
• Inform patients about the Jarisch-Herxheimer reaction, an acute febrile reaction with headache and myalgia that may occur within 24 hours after treatment. 1, 6