What is the treatment of choice (TOC) for syphilis?

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From the Guidelines

The treatment of choice for syphilis is penicillin G, with the specific regimen depending on the stage of infection. For primary, secondary, or early latent syphilis (less than one year duration), a single intramuscular injection of benzathine penicillin G 2.4 million units is recommended 1. For late latent syphilis (more than one year duration) or syphilis of unknown duration, the recommended regimen is benzathine penicillin G 2.4 million units intramuscularly once weekly for three consecutive weeks. Neurosyphilis, ocular syphilis, or otosyphilis requires more intensive treatment with aqueous crystalline penicillin G 3-4 million units intravenously every 4 hours for 10-14 days.

Some key points to consider when treating syphilis include:

  • Penicillin remains the drug of choice because Treponema pallidum, the causative organism, is highly sensitive to it, and penicillin can cross the blood-brain barrier and placenta effectively 1.
  • No documented cases of penicillin resistance in T. pallidum have been reported, despite decades of use 1.
  • For penicillin-allergic patients, doxycycline 100 mg orally twice daily for 14 days (early syphilis) or 28 days (late syphilis) can be used, though desensitization to penicillin is preferred for pregnant women 1.
  • HIV-infected persons with early-stage syphilis should receive a single intramuscular injection of 2.4 million units of benzathine penicillin G, with some specialists recommending two additional weekly benzathine penicillin injections 1.

It's essential to note that the treatment regimen may vary depending on the stage of infection and the patient's HIV status. Close follow-up of persons receiving these therapies is essential to ensure effective treatment and prevent complications.

From the FDA Drug Label

Syphilis–early: Patients who are allergic to penicillin should be treated with doxycycline 100 mg, by mouth, twice a day for 2 weeks Syphilis of more than one year’s duration: Patients who are allergic to penicillin should be treated with doxycycline 100 mg, by mouth, twice a day for 4 weeks.

The treatment of choice (TOC) for syphilis when the patient is allergic to penicillin is doxycycline.

  • For early syphilis, the recommended dose is 100 mg, by mouth, twice a day for 2 weeks.
  • For syphilis of more than one year’s duration, the recommended dose is 100 mg, by mouth, twice a day for 4 weeks 2.

From the Research

Treatment of Choice (TOC) for Syphilis

The treatment of choice for syphilis depends on the stage of the disease and the patient's overall health.

  • For early syphilis, the recommended treatment is benzathine penicillin G, administered intramuscularly in a single dose of 2.4 million units 3, 4, 5.
  • For patients who are allergic to penicillin, doxycycline is a recommended alternative, administered orally at a dose of 100 mg twice daily for 14 days 6, 7.
  • Azithromycin has also been studied as a potential treatment for syphilis, with some studies suggesting it may be effective, but its use is not currently recommended due to concerns about resistance 3, 4, 5.

Special Considerations

  • For patients with late latent syphilis or syphilis of unknown duration, the treatment is also benzathine penicillin G, administered intramuscularly in three doses of 2.4 million units each, given at weekly intervals 5.
  • For patients with neurosyphilis, the treatment is aqueous crystalline penicillin G, administered intravenously in doses of 12-24 million units per day, given as 2-4 million units every 4 hours, for 10-14 days 5.
  • HIV-infected patients with syphilis may require more frequent follow-up and monitoring, as they may be at increased risk for asymptomatic neurosyphilis 5.

Efficacy of Different Treatments

  • Studies have shown that benzathine penicillin G is highly effective in treating early syphilis, with cure rates ranging from 77.6% to 94% 3, 4.
  • Doxycycline has also been shown to be effective in treating early syphilis, with cure rates ranging from 83% to 100% 6, 7.
  • Azithromycin has been shown to be effective in some studies, but its use is not currently recommended due to concerns about resistance 3, 4, 5.

References

Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

Research

Management of adult syphilis.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2011

Research

Doxycycline compared with benzathine penicillin for the treatment of early syphilis.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2006

Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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