What is the recommended treatment for syphilis?

Treatment for Syphilis

Benzathine penicillin G is the definitive treatment for all stages of syphilis, with dosing determined by disease stage: 2.4 million units IM as a single dose for early syphilis (primary, secondary, and early latent), or 7.2 million units total given as three weekly doses of 2.4 million units IM for late latent, latent of unknown duration, and tertiary syphilis. 1, 2

Treatment by Stage

Early Syphilis (Primary, Secondary, and Early Latent)

• Administer benzathine penicillin G 2.4 million units IM as a single injection 1, 2, 3
• Early latent syphilis is defined as infection acquired within the preceding year, documented by seroconversion, fourfold titer increase, recent symptoms, or exposure to a partner with documented early syphilis 1
• This single-dose regimen is highly effective, with expected fourfold decline in nontreponemal titers within 6 months 2, 4

Late Latent and Tertiary Syphilis

• Give benzathine penicillin G 7.2 million units total: three doses of 2.4 million units IM at weekly intervals 1, 2
• If a dose is missed, an interval of 10-14 days between doses may be acceptable before restarting the sequence 1
• Expect fourfold titer decline within 12-24 months for late syphilis 2, 4

Neurosyphilis

• Treat with aqueous crystalline penicillin G 18-24 million units per day IV (administered as 3-4 million units every 4 hours or continuous infusion) for 10-14 days 1, 4
• CSF examination is mandatory before treatment for patients with neurological signs/symptoms, tertiary syphilis, treatment failure, HIV infection with late latent syphilis, or nontreponemal titer ≥1:32 1, 2

Penicillin-Allergic Patients

Non-Pregnant Adults

• For early 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, 4
• Tetracycline 500 mg orally four times daily is an alternative (14 days for early, 28 days for late latent) 1
• Do NOT use azithromycin in the United States due to widespread macrolide resistance and documented treatment failures 1
• Ceftriaxone 1 gram IV/IM daily for 10 days is a reasonable alternative based on randomized trial data showing comparable efficacy 1

Pregnant Women and Neurosyphilis Patients

• Penicillin is the ONLY proven effective therapy—patients with penicillin allergy MUST undergo desensitization followed by penicillin treatment 1, 2, 4
• Only penicillin prevents congenital syphilis; never substitute with inadequate alternatives in pregnancy 1
• Screen all pregnant women for syphilis at first prenatal visit, during third trimester, and at delivery 1

Special Populations

HIV-Infected Patients

• Use the same treatment regimens as non-HIV-infected patients 1, 2
• Limited data suggest no benefit to multiple doses of benzathine penicillin for early syphilis in HIV patients compared to single dose 1
• Closer follow-up is mandatory to detect potential treatment failure or disease progression 1
• All patients with syphilis should be tested for HIV 2, 4

Pediatric Patients

• For acquired primary/secondary syphilis: benzathine penicillin G 50,000 units/kg IM, up to adult dose of 2.4 million units as single dose 1, 2
• For late latent syphilis: benzathine penicillin G 50,000 units/kg IM, up to adult dose of 2.4 million units, for three doses at weekly intervals (total 150,000 units/kg up to 7.2 million units) 1
• Children require CSF examination to exclude neurosyphilis before treatment 1

Follow-Up Protocol

• Perform quantitative nontreponemal serologic tests (RPR or VDRL) at 6 and 12 months for primary/secondary syphilis 1
• For latent syphilis, repeat at 6,12, and 24 months 1, 2
• Treatment failure is defined as: failure of nontreponemal titers to decline fourfold within 6 months for early syphilis, persistent/recurring symptoms, or sustained fourfold increase in titers 1, 2, 4
• If treatment failure occurs, re-evaluate for HIV infection and perform CSF examination 1

Management of Sex Partners

• Treat presumptively if exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis, even if seronegative 1, 2
• For exposures >90 days before diagnosis, treat presumptively if serologic results are not immediately available and follow-up is uncertain 1
• Time periods for at-risk partners: 3 months plus duration of symptoms for primary syphilis, 6 months plus duration of symptoms for secondary syphilis, and 1 year for early latent syphilis 1

Critical Pitfalls to Avoid

• Do NOT use oral penicillin preparations—they are ineffective for syphilis treatment 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 nontreponemal testing methods (VDRL and RPR) when monitoring serologic response, as results cannot be directly compared 1
• Warn patients about Jarisch-Herxheimer reaction, an acute febrile reaction with headache and myalgia that may occur within 24 hours after treatment, especially in early syphilis 1, 4
• In pregnant women, Jarisch-Herxheimer reaction during second half of pregnancy may precipitate premature labor or fetal distress—advise immediate medical attention for changes in fetal movements or contractions 1