What is the recommended treatment for syphilis?

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Last updated: July 2, 2025View editorial policy

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From the Guidelines

The recommended treatment for syphilis is penicillin G, specifically benzathine penicillin G administered as an intramuscular injection, as supported by the most recent and highest quality study 1.

Treatment Regimens

For primary, secondary, or early latent syphilis (less than one year duration), a single dose of 2.4 million units of benzathine penicillin G is the standard treatment.

  • This regimen is based on expert opinion reinforced by case series, clinical trials, and 50 years of clinical experience 1.
  • For late latent syphilis (more than one year duration) or syphilis of unknown duration, the recommended regimen is 2.4 million units of benzathine penicillin G administered intramuscularly once weekly for three consecutive weeks.

Alternative Treatments

For patients with penicillin allergy, alternative treatments include doxycycline (100 mg orally twice daily for 14 days) or tetracycline (500 mg orally four times daily for 14 days) 1.

  • However, these alternatives are less effective, and penicillin desensitization should be considered for pregnant women with penicillin allergy, as penicillin is the only proven effective therapy for preventing congenital syphilis.

Additional Considerations

After treatment, follow-up blood tests are necessary to confirm the infection is resolving 1.

  • Penicillin works by interfering with the cell wall synthesis of Treponema pallidum, the bacterium that causes syphilis, leading to its destruction.
  • Sexual partners should also be notified, tested, and treated if necessary to prevent reinfection.

Recent Findings

Recent studies suggest that azithromycin may not be a recommended treatment for syphilis in the United States due to concerns regarding macrolide resistance 1.

  • However, ceftriaxone may be an acceptable alternative regimen for neurosyphilis, with a recommended dose of 2 g daily IV for 10-14 days 1.

From the FDA Drug Label

All cases of penicillin treated syphilis should receive adequate follow-up including clinical and serological examinations. The recommended follow-up varies with the stage of syphilis being treated. The recommended treatment for syphilis is penicillin G.

  • The specific dosage and administration route may vary depending on the stage of syphilis and patient factors.
  • Penicillin G is the preferred treatment for syphilis, and patients should receive adequate follow-up, including clinical and serological examinations, after treatment 2.
  • It is essential to note that the treatment of syphilis with penicillin G should be done under the guidance of a healthcare professional, and the patient should be monitored for any potential adverse effects or interactions with other medications 3.

From the Research

Treatment Options for Syphilis

The recommended treatment for syphilis is primarily based on the stage of the disease. According to various studies, the following are key points regarding treatment options:

  • Benzathine penicillin G is the first-line treatment for early syphilis in non-penicillin-allergic patients 4, 5, 6, 7.
  • Azithromycin has been studied as an alternative treatment for early syphilis, with some studies showing equivalent efficacy to benzathine penicillin G 4, 6, 7.
  • Doxycycline is considered a second-line treatment for syphilis and has been shown to be effective in some studies 5, 8.
  • Tetracycline is also a second-line treatment option, with similar efficacy to doxycycline in some studies 8.

Efficacy of Treatment Options

The efficacy of these treatment options can be summarized as follows:

  • Benzathine penicillin G: 86% to 95% cure rate in early syphilis patients 4, 5, 6, 7.
  • Azithromycin: 77.6% to 97.7% cure rate in early syphilis patients 4, 6, 7.
  • Doxycycline: 82.9% to 100% cure rate in early syphilis patients 5, 8.
  • Tetracycline: similar efficacy to doxycycline in some studies 8.

Considerations for Treatment

When considering treatment options for syphilis, the following factors should be taken into account:

  • Penicillin allergy: alternative treatments such as azithromycin or doxycycline may be necessary 4, 5, 6, 7.
  • HIV status: some studies suggest that HIV-positive patients may require alternative treatments or longer treatment courses 6, 7.
  • Pregnancy: benzathine penicillin G is the recommended treatment for syphilis in pregnant women, but alternative treatments may be necessary in cases of penicillin allergy 4, 5, 6, 7.

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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