Treatment for Acute Syphilis

First-Line Treatment

The Centers for Disease Control and Prevention recommends benzathine penicillin G 2.4 million units administered as a single intramuscular injection for the treatment of acute syphilis, including primary and secondary stages 1, 2, 3
Penicillin remains the treatment of choice for all stages of syphilis regardless of HIV status, as recommended by the Centers for Disease Control and Prevention 2, 3
The American College of Physicians notes that although some specialists recommend additional doses for HIV-infected patients with early syphilis, data suggest no significant benefit of multiple doses over a single dose in terms of serologic outcomes 1

The Centers for Disease Control and Prevention recommends doxycycline 100 mg orally twice daily for 14 days as the preferred alternative for non-pregnant patients with penicillin allergy 4, 5
Tetracycline 500 mg orally four times daily for 14 days is another alternative, though compliance is likely better with doxycycline due to less frequent dosing, as noted by the Centers for Disease Control and Prevention 4, 6, 7
Ceftriaxone 1 g daily (IM or IV) for 8-10 days may be considered as an alternative, though optimal dosing is not well established, according to the Centers for Disease Control and Prevention 6, 7

HIV-infected patients should receive the same penicillin regimen as HIV-negative patients, as recommended by the Centers for Disease Control and Prevention 2, 3
Closer follow-up is recommended for HIV-infected patients (every 3 months rather than every 6 months), according to the Centers for Disease Control and Prevention 2, 3

For patients whose compliance with therapy or follow-up cannot be ensured, desensitization and treatment with penicillin is recommended by the Centers for Disease Control and Prevention 4, 6
Pregnant patients with penicillin allergy should be desensitized and treated with penicillin, as alternatives are not adequately studied in pregnancy, as noted by the Centers for Disease Control and Prevention 4, 6

Clinical and serologic evaluation should be performed at 6 and 12 months after treatment, as recommended by the Centers for Disease Control and Prevention 6
HIV-infected patients should be monitored more frequently (every 3 months), according to the Centers for Disease Control and Prevention 2, 3
Treatment failure is defined as persistent or recurring signs/symptoms, or a sustained fourfold increase in nontreponemal test titers, as noted by the Centers for Disease Control and Prevention 4, 6

For late latent syphilis (more than one year duration) or syphilis of unknown duration, benzathine penicillin G 2.4 million units IM weekly for 3 weeks is recommended by the Centers for Disease Control and Prevention 2, 3
For neurosyphilis, aqueous crystalline penicillin G 18-24 million units daily, administered as 3-4 million units IV every 4 hours for 10-14 days is the recommended regimen, as noted by the Centers for Disease Control and Prevention 2, 8

Jarisch-Herxheimer reaction (fever, headache, myalgia) may occur within 24 hours after treatment, especially in early syphilis, as noted by the Infectious Diseases Society of America 1
Macrolide resistance in T. pallidum is widespread in the United States, making azithromycin an unsuitable alternative despite some evidence of efficacy, according to the Centers for Disease Control and Prevention 1, 3
Serologic tests may decline more slowly in patients who have had previous syphilis infections, as noted by the Centers for Disease Control and Prevention 4, 6