Syphilis Treatment Guidelines

First-Line Treatment

The Centers for Disease Control and Prevention recommends parenteral penicillin G as the preferred drug for treatment of all stages of syphilis, with the specific preparation, dosage, and duration determined by the stage of infection 1, 2
For primary and secondary syphilis, the recommended regimen is Benzathine penicillin G, 2.4 million units IM in a single dose, as suggested by the Centers for Disease Control and Prevention 1, 3
For children with acquired primary or secondary syphilis, the American Academy of Pediatrics recommends Benzathine penicillin G, 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose 3
For early latent syphilis, the recommended regimen is the same as primary and secondary syphilis - Benzathine penicillin G, 2.4 million units IM in a single dose, according to the Centers for Disease Control and Prevention 1, 4
For late latent syphilis or latent syphilis of unknown duration, the Centers for Disease Control and Prevention recommends Benzathine penicillin G, 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals 5
For tertiary syphilis, the recommended regimen is Benzathine penicillin G, 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals, as suggested by the Centers for Disease Control and Prevention 5

For primary and secondary syphilis, the Infectious Diseases Society of America recommends Doxycycline, 100 mg orally twice daily for 14 days, as an alternative treatment for penicillin-allergic patients 2, 4
For late latent syphilis or latent syphilis of unknown duration, the Centers for Disease Control and Prevention recommends Doxycycline, 100 mg orally twice daily for 28 days, as an alternative treatment for penicillin-allergic patients 2, 5

For HIV-infected patients, the Centers for Disease Control and Prevention recommends treatment regimens that are the same as for non-HIV-infected patients 2
For pregnant women, the American College of Obstetricians and Gynecologists recommends that only penicillin G is proven effective for preventing maternal transmission, and pregnant women with penicillin allergy should undergo desensitization and be treated with penicillin 1, 6

The Centers for Disease Control and Prevention recommends that quantitative nontreponemal serologic tests should be repeated at 6, 12, and 24 months, and a 4-fold decline in titer is expected within 6 months for primary/secondary syphilis and within 12-24 months for late syphilis 2, 5
CSF examination is recommended if titers increase 4-fold, an initially high titer fails to decline at least 4-fold within 12-24 months, or neurological signs or symptoms develop, as suggested by the Centers for Disease Control and Prevention 5

The Centers for Disease Control and Prevention recommends that persons exposed to a patient with primary, secondary, or early latent syphilis within the preceding 90 days should be treated presumptively, even if seronegative 1, 3
Long-term sex partners of patients with late syphilis should be evaluated clinically and serologically, according to the Centers for Disease Control and Prevention 3

The Centers for Disease Control and Prevention defines treatment failure as failure of nontreponemal test titers to decline 4-fold within 6 months after therapy for primary or secondary syphilis, and recommends re-treatment with weekly injections of benzathine penicillin G 2.4 million units IM for 3 weeks 4