Syphilis Treatment: Penicillin Dosing, Side Effects, and What to Expect

Syphilis is treated with penicillin G benzathine — a single intramuscular injection cures early-stage syphilis, and three weekly injections treat late-stage disease. Penicillin remains the only recommended therapy for pregnant women.

Syphilis is one of the few STIs where treatment is remarkably straightforward when caught early. But the protocol changes significantly depending on stage, and getting the staging wrong means getting the treatment wrong.

Treatment by Stage

According to the CDC STI Treatment Guidelines: Primary/secondary syphilis: Single IM injection of benzathine penicillin G, 2.4 million units. Cure rates exceed 95%. Early latent: Same single dose. Late latent/tertiary/unknown duration: Three doses at weekly intervals (days 1, 8, 15). Neurosyphilis: IV aqueous crystalline penicillin G, 18–24 million units/day for 10–14 days. Recognizing the symptoms of each stage is critical for correct treatment.

The Jarisch-Herxheimer Reaction

Occurs in up to 45% of primary and 75% of secondary syphilis cases within 2–8 hours of first injection. Caused by rapid death of Treponema pallidum. Self-limiting within 12–24 hours. Not an allergic reaction — it is a sign treatment is working. The syphilis rash may temporarily worsen.

Penicillin Allergy Alternatives

For non-pregnant patients: doxycycline 100 mg twice daily for 14 days (early) or 28 days (late). For pregnant women: no acceptable alternative exists. The ACOG recommends penicillin desensitization followed by standard treatment. Azithromycin is unreliable due to macrolide resistance.

Treatment During Pregnancy

Untreated syphilis causes miscarriage, stillbirth, and congenital syphilis. Treatment must be completed at least 30 days before delivery. All pregnant women should be screened at the first prenatal visit.

Test of Cure

Serial RPR/VDRL titers at 6 and 12 months (early) or 6, 12, and 24 months (late). Success = fourfold titer decline. Understanding how syphilis transmits and getting tested early is critical. Confidential testing is available nationwide.

When to Seek Urgent Care

Seek immediate attention for sudden vision changes, hearing loss, or severe headache after a syphilis diagnosis (possible neurosyphilis).

Frequently Asked Questions

Can syphilis be cured completely?

Yes, at every stage. But treatment cannot reverse damage from late-stage disease.

Why is penicillin the only option in pregnancy?

It is the only antibiotic proven to cross the placenta sufficiently to treat fetal infection.

Can syphilis come back after treatment?

Reinfection is possible — syphilis does not confer lasting immunity.