What is the recommended treatment regimen for syphilis?

Recommended Treatment for Syphilis

For primary and secondary syphilis in adults, benzathine penicillin G 2.4 million units intramuscularly as a single dose is the definitive treatment. 1, 2, 3

Primary and Secondary Syphilis Treatment

Standard Regimen for Adults

• Benzathine penicillin G 2.4 million units IM as a single dose is the recommended treatment for primary and secondary syphilis 4, 1, 2, 3
• This regimen has been used effectively for over 50 years to achieve clinical resolution, heal lesions, prevent sexual transmission, and prevent late sequelae 4
• Parenteral penicillin G remains the preferred drug for all stages of syphilis regardless of HIV status 2

Pediatric Dosing

• Benzathine penicillin G 50,000 units/kg IM (up to adult dose of 2.4 million units) as a single dose for children with acquired primary or secondary syphilis 4, 1
• Children require CSF examination before treatment to exclude neurosyphilis 1, 3
• Birth and maternal records should be reviewed to distinguish congenital from acquired syphilis 4

Early Latent Syphilis Treatment

• Benzathine penicillin G 2.4 million units IM as a single dose for early latent syphilis (acquired within the preceding year) 1, 3
• Early latent syphilis is defined by documented seroconversion, fourfold increase in titer, history of symptoms within the past year, or having a sex partner with documented early syphilis 1

Late Latent and Tertiary Syphilis Treatment

• Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at weekly intervals for late latent syphilis, latent syphilis of unknown duration, or tertiary syphilis 1, 2, 3
• If a dose is missed, an interval of 10-14 days between doses might be acceptable before restarting the sequence 1

Neurosyphilis Treatment

• 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 is the recommended regimen for neurosyphilis 1, 2, 3
• CSF examination is indicated for patients with neurologic or ophthalmic signs/symptoms, evidence of active tertiary syphilis, treatment failure, HIV infection with late latent syphilis, or serum nontreponemal titer ≥1:32 1
• Procaine penicillin without probenecid does not achieve adequate CSF levels and is inadequate for neurosyphilis 1

Alternative Regimens for Penicillin Allergy

Non-Pregnant Adults

• Doxycycline 100 mg orally twice daily for 14 days is the preferred alternative for primary, secondary, or early latent syphilis in penicillin-allergic non-pregnant adults 1, 2, 3, 5
• Doxycycline 100 mg orally twice daily for 28 days for late latent syphilis in penicillin-allergic non-pregnant adults 1, 5
• Tetracycline 500 mg orally four times daily is an alternative (14 days for early syphilis, 28 days for late latent), though compliance is better with doxycycline due to less frequent dosing 1, 2
• Ceftriaxone 1 gram IM/IV daily for 10 days may be considered based on randomized trial data showing comparable efficacy to benzathine penicillin 1, 2

Pregnant Women

• Pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment 1, 2, 3
• Penicillin is the only therapy with documented efficacy for preventing maternal transmission and congenital syphilis 1, 2
• Alternative antibiotics are not adequately studied in pregnancy and should never be substituted 1

Special Populations

HIV-Infected Patients

• HIV-infected patients should receive the same penicillin regimen as HIV-negative patients 1, 2
• A recent 2024 study found that single-dose benzathine penicillin G plus 7-day doxycycline achieved higher serologic response rates (79.5% vs 70.3%) compared to benzathine penicillin G alone in HIV-infected patients with early syphilis 6
• However, a 2017 randomized trial showed no significant benefit of three doses versus single dose of benzathine penicillin G in HIV-infected patients (93% vs 80% success rates, P=0.17) 7
• Closer follow-up is mandatory for HIV-infected patients (every 3 months rather than every 6 months) to detect potential treatment failure 1, 2

Pregnancy

• All pregnant women should be screened for syphilis at first prenatal visit, during third trimester, and at delivery 1, 3
• Use the same stage-appropriate penicillin regimens as non-pregnant patients 3
• Jarisch-Herxheimer reaction during the 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

Follow-Up and Monitoring

• Quantitative nontreponemal serologic tests (RPR or VDRL) should be repeated at 6 and 12 months after treatment for primary/secondary syphilis 1, 2, 3
• For latent syphilis, repeat tests at 6,12, and 24 months 1
• A fourfold decline in titer is expected within 6 months for primary/secondary syphilis and within 12-24 months for late syphilis 1, 3
• Treatment failure is defined as persistent or recurring signs/symptoms, sustained fourfold increase in nontreponemal titers, or failure of initially high titer to decline at least fourfold within the expected timeframe 1, 2
• If treatment failure is suspected, re-evaluate for HIV infection and perform CSF examination 1

Management of Sex Partners

• Persons exposed within 90 days preceding diagnosis of primary, secondary, or early latent syphilis should be treated presumptively with benzathine penicillin G 2.4 million units IM, even if seronegative 4, 3
• Persons exposed >90 days before diagnosis should be treated presumptively if serologic results are not immediately available and follow-up is uncertain 4
• Time periods for identifying 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 4, 1

Additional Management Considerations

• All patients with syphilis should be tested for HIV infection at the time of diagnosis 4, 1, 3
• In high HIV prevalence areas, patients with primary syphilis should be retested for HIV after 3 months if initially negative 4
• Patients with neurologic signs/symptoms (meningitis) or ophthalmic disease (uveitis) should have CSF analysis and ocular slit-lamp examination 4
• Unless clinical signs or symptoms of neurologic or ophthalmic involvement are present, CSF analysis is not recommended for routine evaluation of primary or secondary syphilis 4

Critical Pitfalls to Avoid

• Do not use azithromycin in the United States due to widespread macrolide resistance and documented treatment failures 1, 2
• 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
• Jarisch-Herxheimer reaction (fever, headache, myalgia) may occur within 24 hours after treatment, especially in early syphilis—patients should be informed about this possible adverse reaction 1, 2, 3