What is the recommended treatment regimen for syphilis?

Syphilis Treatment Regimens

Benzathine penicillin G is the recommended first-line treatment for all stages of syphilis, with dosing dependent on the stage of infection. 1

Treatment by Stage of Syphilis

Primary, Secondary, and Early Latent Syphilis (<1 year)

• Recommended regimen: Benzathine penicillin G 2.4 million units IM in a single dose 1
• For children: Benzathine penicillin G 50,000 units/kg IM, up to adult dose of 2.4 million units in a single dose 2

Late Latent Syphilis or Unknown Duration

• Recommended regimen: Benzathine penicillin G 2.4 million units IM weekly for 3 consecutive weeks (total 7.2 million units) 1

Neurosyphilis

• Recommended regimen: Aqueous crystalline penicillin G 18-24 million units IV daily, administered as 3-4 million units every 4 hours for 10-14 days 2, 1
• Alternative regimen: Procaine penicillin 2.4 million units IM daily PLUS Probenecid 500 mg orally four times daily, both for 10-14 days 2

Penicillin Allergic Patients

• First option: Desensitization to penicillin (preferred, especially for pregnant women and neurosyphilis) 1
• Alternative regimens (non-pregnant patients only):
  • Doxycycline 100 mg orally twice daily for 14 days (early syphilis) or 28 days (late syphilis) 1, 3
  • Tetracycline 500 mg orally four times daily for 14 days (early syphilis) or 28 days (late syphilis) 1

Special Populations

Pregnant Women

• Only recommended treatment: Benzathine penicillin G (same dosing as non-pregnant patients) 1
• Some experts recommend an additional dose one week after initial dose for pregnant women in third trimester 1
• Penicillin-allergic pregnant women should undergo desensitization followed by penicillin treatment 1

HIV-Infected Patients

• Same penicillin regimens as HIV-negative patients 1
• More frequent follow-up (every 3 months rather than every 6 months) 1

Follow-Up Recommendations

• Clinical and serologic evaluation at 3,6,9,12, and 24 months after treatment 1
• Treatment success: Resolution of clinical symptoms and ≥4-fold decrease in non-treponemal test titers within:
  • 6 months for primary/secondary syphilis
  • 12-24 months for latent syphilis 1

Treatment Failure Management

• Consider treatment failure if:

  • Clinical signs/symptoms persist or recur
  • Sustained ≥4-fold increase in non-treponemal test titer
  • Failure of titer to decrease 4-fold within appropriate timeframe 1

• If treatment failure suspected:

  1. Perform lumbar puncture to rule out neurosyphilis
  2. If no neurosyphilis: Benzathine penicillin G 2.4 million units IM weekly for 3 weeks
  3. If neurosyphilis present: Follow neurosyphilis treatment regimen 1

Important Clinical Considerations

• Warn patients about possible Jarisch-Herxheimer reaction within 24 hours after treatment (fever, headache, myalgia) 1
• Test all syphilis patients for HIV infection 2, 1
• In high HIV prevalence areas, retest patients with primary syphilis for HIV after 3 months if initial test was negative 2
• CSF examination is not recommended for routine evaluation of primary/secondary syphilis unless neurologic/ophthalmic symptoms are present 2

Partner Management

• Treat sexual contacts within 90 days prior to diagnosis presumptively, even if seronegative 2, 1
• Treat contacts >90 days before diagnosis if serologic tests aren't immediately available or follow-up is uncertain 2, 1

While some research has explored azithromycin as an alternative treatment 4, 5, benzathine penicillin G remains the gold standard therapy for all stages of syphilis due to its long history of effectiveness and prevention of late sequelae 1. Recent shortages of benzathine penicillin G have been reported 6, highlighting the importance of having alternative regimens available, though these should only be used when penicillin cannot be administered.