What is the treatment for Syphilis?

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From the Guidelines

Syphilis should be treated with penicillin, specifically benzathine penicillin G, as it is the preferred drug for all stages of the disease. The preparation, dosage, and length of treatment depend on the stage and clinical manifestations of the disease 1. For primary, secondary, or early latent syphilis, a single intramuscular injection of benzathine penicillin G 2.4 million units is recommended. For late latent syphilis or syphilis of unknown duration, the recommended regimen is benzathine penicillin G 2.4 million units intramuscularly once weekly for three consecutive weeks.

Some key points to consider when treating syphilis include:

  • The use of penicillin is crucial in treating syphilis, as it effectively kills the Treponema pallidum bacteria that causes the disease
  • Patients with penicillin allergy may be treated with alternative antibiotics, such as doxycycline, but penicillin desensitization is preferred for pregnant women
  • Follow-up blood tests are necessary to ensure the infection is resolving after treatment
  • Sexual partners should also be evaluated and treated to prevent further transmission of the disease

It's also important to note that while alternative treatments, such as ceftriaxone and azithromycin, may be effective in some cases, their use is not as well-established as penicillin, and more research is needed to determine their efficacy 1. Therefore, penicillin remains the first-line treatment for syphilis, and alternative treatments should only be used in cases where penicillin is not suitable.

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.

  • Doxycycline dosage for syphilis treatment:
    • 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

Syphilis Treatment Options

  • The recommended treatment for early syphilis is a single dose of 2.4 million units of benzathine penicillin G 3, 4, 5.
  • Alternative treatments, such as azithromycin, have been studied, but its use is limited due to concerns about resistance 6, 3.
  • Ceftriaxone and doxycycline have also been shown to be effective in treating early syphilis, particularly in HIV-infected patients 7.
  • Doxycycline is an acceptable alternative to penicillin for treating early and late latent syphilis if penicillin cannot be used 4.

Treatment Efficacy

  • A study comparing azithromycin to benzathine penicillin G found that azithromycin had a cumulative response rate of 94% compared to 86% for benzathine penicillin G 6.
  • Another study found that ceftriaxone and doxycycline had similar efficacy to benzathine penicillin G in treating early syphilis in HIV-infected patients 7.
  • A randomized clinical trial found that a 3-dose regimen of benzathine penicillin G did not improve syphilis serological outcomes compared to a single dose in HIV-infected patients 5.

Special Considerations

  • HIV-infected patients with syphilis may require closer monitoring and more frequent serological testing due to the increased risk of treatment failure and neurosyphilis 3, 4.
  • Pregnant women with syphilis should be treated with penicillin, and missed doses are not acceptable due to the risk of congenital syphilis 4.
  • Cerebrospinal fluid examination is recommended in certain cases, such as in patients with neurological symptoms or those who do not respond to treatment 3, 4.

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

Management of Adult Syphilis: Key Questions to Inform the 2015 Centers for Disease Control and Prevention Sexually Transmitted Diseases Treatment Guidelines.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2015

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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