What is the recommended treatment for syphilis?

Treatment for Syphilis

Parenteral penicillin G is the preferred drug for all stages of syphilis, with benzathine penicillin G 2.4 million units IM as a single dose for early syphilis (primary, secondary, and early latent) and 7.2 million units total (three weekly doses of 2.4 million units) for late latent or tertiary syphilis. 1, 2

Treatment by Stage

Early Syphilis (Primary, Secondary, and Early Latent)

• Benzathine penicillin G 2.4 million units IM in a single dose is the recommended regimen 1, 2, 3
• Early latent syphilis is defined as infection acquired within the preceding year based on documented seroconversion, fourfold increase in titer, history of symptoms, or having a sex partner with documented early syphilis 1
• A fourfold decline in nontreponemal test titers is expected within 6 months after treatment 2, 4

Late Latent Syphilis or Latent Syphilis of Unknown Duration

• Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals 1, 2
• If a dose is missed, an interval of 10-14 days between doses might be acceptable before restarting the sequence 1
• A fourfold decline in titers is expected within 12-24 months for late syphilis 2

Tertiary Syphilis

• Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals 1, 2

Neurosyphilis

• Aqueous crystalline penicillin G 18-24 million units per day, administered as 3-4 million units IV every 4 hours for 10-14 days 1, 4
• CSF examination is recommended for patients with neurological signs/symptoms, tertiary syphilis, or those whose serological titers fail to decline appropriately 1

Alternative Treatments for Penicillin-Allergic Patients

Non-Pregnant Adults

• For primary and secondary syphilis: Doxycycline 100 mg orally twice daily for 14 days 1, 2, 4
• For late latent syphilis: Doxycycline 100 mg orally twice daily for 28 days 1, 2
• Ceftriaxone 1 gram IV/IM daily for 10 days is a reasonable alternative based on randomized trial data showing comparable efficacy to benzathine penicillin 1

Critical Caveat: Azithromycin

• Azithromycin should NOT be used in the United States due to widespread macrolide resistance and documented treatment failures 1

Pregnant Women and Neurosyphilis Patients

• Penicillin remains the only proven effective therapy 1, 2
• All pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment 1, 2
• Only penicillin prevents congenital syphilis; never substitute with inadequate alternatives in pregnancy 1

Special Populations

HIV-Infected Patients

• Treatment regimens are the same as for non-HIV-infected patients 1, 2
• HIV-infected patients may have atypical serologic responses but generally respond well to standard treatment 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
• Closer follow-up is mandatory to detect potential treatment failure or disease progression 1

Pregnant Women

• Screen all pregnant women for syphilis at first prenatal visit, during third trimester, and at delivery 1
• Jarisch-Herxheimer reaction during second half of pregnancy may precipitate premature labor or fetal distress 1
• Women should seek immediate medical attention if they notice changes in fetal movements or contractions after treatment 1

Pediatric Patients

• For children with acquired primary or secondary syphilis: Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose 2

Follow-Up and Monitoring

Serologic Testing Schedule

• Quantitative nontreponemal serologic tests (RPR or VDRL) should be repeated at 3,6,12, and 24 months 1, 4
• A fourfold change in nontreponemal test titer is considered clinically significant 4

Treatment Failure Criteria

• Failure of nontreponemal test titers to decline fourfold within 6 months after therapy for primary or secondary syphilis 1, 4
• If treatment failure is suspected, patients should be re-evaluated for HIV infection and undergo CSF examination 1
• Re-treatment with weekly injections of benzathine penicillin G 2.4 million units IM for 3 weeks is recommended 2

Management of Sex Partners

Exposure Within 90 Days

• Persons exposed within 90 days preceding the diagnosis of primary, secondary, or early latent syphilis should be treated presumptively even if seronegative 1, 2

Exposure Beyond 90 Days

• Persons exposed >90 days before diagnosis should be treated presumptively if serologic test results are not immediately available and follow-up is uncertain 1
• Long-term sex partners of patients with late syphilis should be evaluated clinically and serologically 2

Important Clinical Considerations

Jarisch-Herxheimer Reaction

• An acute febrile reaction may occur within 24 hours after any syphilis therapy, especially in early syphilis 1
• Patients should be informed about this possible adverse reaction, which may include headache, myalgia, and fever 1

Critical Pitfalls to Avoid

• Do not use oral penicillin preparations for syphilis treatment as they are ineffective 1
• Do not rely solely on treponemal test antibody titers to assess treatment response, as they correlate poorly with disease activity 1
• Do not switch between different testing methods (e.g., VDRL and RPR) when monitoring serologic response, as results cannot be directly compared 1
• All patients with syphilis should be tested for HIV 4