Treatment Regimen for Syphilis
The recommended treatment for syphilis is benzathine penicillin G 2.4 million units IM in a single dose for adults with primary or secondary syphilis. 1
Treatment Regimens by Stage and Population
Primary and Secondary Syphilis
- Adults: Benzathine penicillin G 2.4 million units IM in a single dose 1
- Children: Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose 1
Penicillin Allergy (Non-pregnant adults)
- Doxycycline 100 mg orally twice daily for 2 weeks 1, 2
- Alternative: Tetracycline 500 mg orally 4 times daily for 2 weeks 1
Late Latent Syphilis
- Benzathine penicillin G 2.4 million units IM weekly for 3 consecutive weeks (7.2 million units total) 3
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
Congenital Syphilis
- Proven or highly probable disease: Aqueous crystalline penicillin G 100,000–150,000 units/kg/day, administered as 50,000 units/kg/dose IV every 12 hours during the first 7 days of life and every 8 hours thereafter for a total of 10 days 1
- Alternative: Procaine penicillin G 50,000 units/kg/dose IM in a single daily dose for 10 days 1
Important Clinical Considerations
Follow-Up
- Patients should be re-examined clinically and serologically at 3 months and 6 months after treatment 1
- Treatment failure is indicated by:
- Persistence or recurrence of signs/symptoms
- Sustained fourfold increase in nontreponemal test titer
- Failure of nontreponemal test titers to decline fourfold within 3-6 months after therapy 1
HIV Testing
- All patients with syphilis should be tested for HIV infection 1
- In high HIV prevalence areas, patients with primary syphilis should be retested for HIV after 3 months if initial test was negative 1
Special Situations
Neurologic Involvement
- Patients with neurologic symptoms (meningitis, cranial nerve abnormalities) or ophthalmic disease should undergo CSF analysis and appropriate evaluation 1
- Treatment should be guided by CSF results
Treatment Failure
- Re-evaluate for HIV infection
- Perform lumbar puncture unless reinfection is certain
- Re-treat with three weekly injections of benzathine penicillin G 2.4 million units IM 1
Common Pitfalls and Caveats
Jarisch-Herxheimer reaction: Patients should be warned about this potential reaction that can occur within 24 hours of treatment
Penicillin alternatives: While doxycycline is an acceptable alternative for non-pregnant penicillin-allergic patients, it has less clinical experience supporting its use 1
Recent shortages: Benzathine penicillin G shortages have been reported, potentially requiring alternative treatments in some settings 4
Serologic follow-up: Nontreponemal test titers may decline more slowly in patients with previous syphilis infections, complicating assessment of treatment response 1
Partner management: Sexual partners need to be identified, tested, and treated based on exposure timeframes (3 months plus duration of symptoms for primary syphilis, 6 months plus duration of symptoms for secondary syphilis) 1
Despite some studies showing comparable efficacy of azithromycin to benzathine penicillin G 5, 6, the CDC guidelines consistently recommend penicillin as first-line therapy due to its long history of effectiveness and the potential for resistance with other antibiotics.