What is the recommended treatment for secondary syphilis?

Secondary Syphilis Treatment

The recommended treatment for secondary syphilis is a single intramuscular injection of benzathine penicillin G 2.4 million units. 1

First-Line Treatment

• Benzathine penicillin G 2.4 million units IM as a single dose is the standard of care for secondary syphilis. 1, 2
• This single-injection regimen is highly effective and practical for widespread use, with serologic response expected within 6 months. 3, 4
• Parenteral penicillin G remains the preferred drug for all stages of syphilis, with the specific preparation and dosage determined by disease stage. 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. 1, 3
• Doxycycline is preferred over tetracycline due to better compliance and fewer gastrointestinal side effects. 3
• 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: Close follow-up is essential for all patients receiving non-penicillin alternatives, as efficacy data are limited compared to penicillin. 3

Special Populations

Pregnant Women

• Pregnant patients with penicillin allergy MUST undergo desensitization followed by penicillin treatment—no exceptions. 1, 5
• Only penicillin prevents congenital syphilis; alternative antibiotics are completely unacceptable in pregnancy. 1
• The Jarisch-Herxheimer reaction during the second half of pregnancy may precipitate premature labor or fetal distress, so patients should be counseled to seek immediate care if they notice changes in fetal movements or contractions. 1

HIV-Infected Patients

• Use the same single-dose benzathine penicillin G 2.4 million units IM regimen as for HIV-negative patients. 1, 5
• Limited data suggest no benefit to multiple doses of benzathine penicillin for early syphilis in HIV-infected patients compared to a single dose. 1
• However, HIV-infected patients require more frequent follow-up at 3-month intervals (instead of 6-month intervals) to detect potential treatment failure or atypical serologic responses. 3, 1

Follow-Up and Monitoring

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

Defining Treatment Failure

Treatment failure is suspected when:

• Signs or symptoms persist or recur. 3
• There is a sustained fourfold increase in nontreponemal test titer compared with baseline. 3, 6
• Titers fail to decline fourfold within 6 months after therapy. 3, 6

When treatment failure occurs:

• Re-evaluate for HIV infection. 3, 6
• Perform CSF examination to rule out unrecognized neurosyphilis. 3, 6
• Re-treat with benzathine penicillin G 2.4 million units IM weekly for 3 weeks, unless CSF examination indicates neurosyphilis is present. 3, 5

Management of Sex Partners

• Persons exposed within 90 days preceding the diagnosis should be treated presumptively with benzathine penicillin G 2.4 million units IM, 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, 5
• Do not switch between different nontreponemal test methods (RPR vs. VDRL) when monitoring serologic response, as results cannot be directly compared. 1, 6
• Do not rely on treponemal test antibody titers to assess treatment response, as they correlate poorly with disease activity. 1
• Do not assume persistent low-titer reactivity (serofast state) necessarily indicates treatment failure—approximately 15% of patients with early syphilis will not achieve a two-dilution decline at 1 year despite adequate treatment. 3, 6

Jarisch-Herxheimer Reaction

• Warn all patients about the Jarisch-Herxheimer reaction, an acute febrile reaction that may occur within 24 hours after treatment. 1, 5
• This reaction is especially common in early syphilis and may include fever, headache, myalgia, and other flu-like symptoms. 1
• The reaction is self-limited and does not indicate treatment failure or allergy. 1