What are the treatment options for Syphilis?

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From the Guidelines

Syphilis is treated primarily with antibiotics, with penicillin G being the preferred medication for all stages of infection, as supported by the most recent and highest quality study 1.

Treatment Options

The treatment options for syphilis depend on the stage and clinical manifestations of the disease.

  • For early syphilis (primary, secondary, or early latent syphilis of less than one year's duration), a single intramuscular injection of benzathine penicillin G 2.4 million units is the standard treatment, as recommended by the Centers for Disease Control and Prevention 1.
  • For late latent syphilis (infection of more than one year's duration) or syphilis of unknown duration, the recommended regimen is benzathine penicillin G 2.4 million units intramuscularly once weekly for three consecutive weeks 1.
  • For neurosyphilis, the treatment consists of aqueous crystalline penicillin G 18-24 million units daily, administered as 3-4 million units intravenously every 4 hours for 10-14 days 1.

Alternative Treatments

For patients allergic to penicillin, doxycycline 100 mg orally twice daily for 14 days (early syphilis) or 28 days (late syphilis) is an alternative, though it's less effective, as suggested by recent studies 1.

  • Azithromycin is not recommended due to resistance concerns, as highlighted by recent data 1.
  • Ceftriaxone may be a viable alternative for the treatment of early syphilis, with a recommended dose of 1 g intravenously or intramuscularly for 10 days, as suggested by a recent randomized trial 1.

Follow-up and Prevention

Patients should abstain from sexual contact until treatment is complete and follow-up testing confirms cure.

  • Follow-up blood tests are essential to ensure the infection has been successfully treated, as emphasized by the Centers for Disease Control and Prevention 1.
  • Penicillin works by interfering with bacterial cell wall synthesis, which is particularly effective against the spirochete Treponema pallidum that causes syphilis, as explained by the mechanism of action of penicillin 1.

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 options for Syphilis using doxycycline are:

  • Early Syphilis: 100 mg, by mouth, twice a day for 2 weeks
  • Syphilis of more than one year’s duration: 100 mg, by mouth, twice a day for 4 weeks 2

From the Research

Treatment Options for Syphilis

The treatment options for syphilis include:

  • Benzathine penicillin G (BPG) as the primary recommended treatment for early-stage syphilis 3, 4, 5, 6
  • Doxycycline as a second-line treatment for early syphilis, especially in cases where BPG is not available or the patient is allergic to penicillin 3, 5, 7
  • Alternative treatments such as tetracyclines and erythromycin may be considered in cases where doxycycline is not effective or suitable 4

Treatment Regimens

Different treatment regimens have been studied, including:

  • A single dose of 2.4 million units of intramuscular BPG for early syphilis 4, 6
  • A 14-day course of oral doxycycline 100 mg twice daily for early syphilis 3, 7
  • A 3-dose regimen of BPG for early syphilis in HIV-infected individuals, although studies have shown that a single dose may be sufficient 6

Efficacy of Treatment Options

Studies have shown that:

  • Doxycycline appears to be an effective agent for the treatment of early syphilis, with serological response rates comparable to BPG 3, 7
  • BPG is highly effective in treating early syphilis, with high serological response rates and low failure rates 4, 6
  • The efficacy of doxycycline and BPG may vary depending on the stage of syphilis and the presence of coinfections such as HIV 5, 6

References

Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

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

Research

Treatment of syphilis: a short critical review.

Sexually transmitted diseases, 1981

Research

Single Dose Versus 3 Doses of Intramuscular Benzathine Penicillin for Early Syphilis in HIV: A Randomized Clinical Trial.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2017

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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