What is the treatment for syphilis?

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From the Guidelines

The treatment for syphilis is primarily penicillin G, with the specific regimen depending on the stage of infection. For early syphilis (primary, secondary, or early latent syphilis of less than one year), a single intramuscular injection of benzathine penicillin G 2.4 million units is the recommended treatment, as supported by the most recent guidelines 1. The following are key points to consider in the treatment of syphilis:

  • For late latent syphilis (infection of more than one year) or syphilis of unknown duration, the recommended regimen is benzathine penicillin G 2.4 million units intramuscularly once weekly for three consecutive weeks, as stated in the guidelines from the U.S. Centers for Disease Control and Prevention 1.
  • Neurosyphilis requires a more intensive approach with aqueous crystalline penicillin G 18-24 million units daily, administered as 3-4 million units intravenously every 4 hours for 10-14 days.
  • For patients allergic to penicillin, doxycycline (100 mg orally twice daily for 14-28 days) or tetracycline (500 mg orally four times daily for 14-28 days) may be used, though these alternatives are less effective, as noted in the guidelines 1.
  • Pregnant women with penicillin allergies should undergo desensitization as penicillin is the only proven effective therapy during pregnancy.
  • Following treatment, patients should be monitored with blood tests to ensure the infection is clearing, as the relation between serologic and clinical response remains unclear in some cases 1. The most recent and highest quality study, published in 2009, supports the use of penicillin as the treatment of choice for syphilis, regardless of HIV status 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 for syphilis is doxycycline 100 mg, by mouth, twice a day for 2 weeks for early syphilis and for 4 weeks for syphilis of more than one year’s duration, in patients who are allergic to penicillin 2.

From the Research

Treatment Options for Syphilis

The treatment for syphilis typically involves the use of antibiotics, with the primary option being benzathine penicillin G 3, 4, 5.

  • Benzathine penicillin G is administered as a single dose of 2.4 million units intramuscularly for early syphilis 3, 5.
  • For patients who are allergic to penicillin, doxycycline is often recommended as a second-line treatment 4, 6, 7.
  • Doxycycline is typically given orally, 100 mg twice daily for 14 days for early syphilis 4, 6, 7.
  • Azithromycin has also been studied as a potential treatment for syphilis, with promising results in some studies 3, but its use is limited due to concerns about resistance 5.

Efficacy of Treatment Options

Studies have compared the efficacy of benzathine penicillin G and doxycycline in treating syphilis:

  • One study found that doxycycline was effective in treating early syphilis, with no significant difference in serological response compared to benzathine penicillin G 4.
  • Another study found that benzathine penicillin G had a slightly higher success rate than doxycycline in treating primary syphilis, but doxycycline had a lower success rate in treating late and undetermined syphilis infection 6.
  • A retrospective study found no significant difference in serological response between doxycycline and benzathine penicillin G at 6 and 12 months after treatment 7.

Special Considerations

Certain patient populations may require special consideration when treating syphilis:

  • Patients with HIV infection may be at increased risk for asymptomatic neurosyphilis, and cerebrospinal fluid examination should be considered in these cases 5.
  • Patients with late latent syphilis or undetermined infection may require longer treatment courses or closer monitoring 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

Management of adult syphilis.

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

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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