Is penicillin G (potassium) effective for treating syphilis?

Penicillin G Potassium for Syphilis Treatment

Yes, penicillin G potassium is highly effective for treating syphilis and is FDA-approved for this indication, serving as the preferred drug for all stages of syphilis including congenital and neurosyphilis. 1

FDA-Approved Indication

Penicillin G potassium injection is specifically FDA-approved for treating syphilis, including both congenital syphilis and neurosyphilis caused by Treponema pallidum. 1 This represents the gold standard treatment with over 50 years of clinical experience demonstrating efficacy. 2

Treatment Regimens by Stage

The specific formulation and dosing of penicillin G varies by stage of infection:

Early Syphilis (Primary, Secondary, Early Latent)

• Benzathine penicillin G 2.4 million units IM as a single dose is the standard treatment for early syphilis. 3, 4
• A recent 2025 randomized controlled trial demonstrated that one dose of 2.4 million units was noninferior to three weekly doses, with 76% serologic response at 6 months in both HIV-infected and non-HIV-infected patients. 5
• This single-dose regimen showed no clinical relapse or treatment failure in either group. 5

Late Latent Syphilis or Unknown Duration

• Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at weekly intervals is recommended. 3, 4
• This extended regimen is intended to prevent progression of late complications rather than affect transmission. 2

Neurosyphilis

• Aqueous crystalline penicillin G 18-24 million units IV daily (administered as 3-4 million units every 4 hours or continuous infusion) for 10-14 days is required for neurosyphilis. 3, 4
• This parenteral formulation achieves adequate CSF concentrations necessary for treating CNS infection. 2
• One study demonstrated that high-dose IV penicillin G (10 MIU every 6 hours) achieved CSF concentrations far exceeding the minimally treponemacidal level. 6

Critical Considerations

Pregnancy

• Parenteral penicillin G is the only therapy with documented efficacy for preventing maternal transmission to the fetus and treating fetal infection. 3, 7
• Pregnant women with penicillin allergy must undergo desensitization followed by penicillin treatment—no exceptions. 3, 7
• Up to 40% of fetuses with in-utero syphilis exposure are stillborn or die from infection during infancy if untreated. 8
• Some experts recommend a second dose of benzathine penicillin 2.4 million units IM one week after the initial dose for pregnant women with primary, secondary, or early latent syphilis. 3

HIV-Infected Patients

• HIV-infected patients receive the same penicillin regimens as non-HIV-infected patients. 3
• Treatment response is comparable between HIV-infected and non-infected individuals (76% vs 76% serologic response at 6 months with single-dose therapy). 5
• Closer follow-up is mandatory to detect potential treatment failure or disease progression. 3

Penicillin Allergy

• Patients with penicillin allergy should undergo skin testing and desensitization, then be treated with penicillin. 2, 3
• For non-pregnant adults with early syphilis who cannot receive penicillin, doxycycline 100 mg orally twice daily for 14 days is the guideline-endorsed alternative. 3, 4
• For late latent syphilis in penicillin-allergic non-pregnant adults, doxycycline 100 mg orally twice daily for 28 days is recommended. 3, 4
• Ceftriaxone 1 gram IM/IV daily for 10 days is another alternative with randomized trial data showing comparable efficacy to benzathine penicillin, though patients with severe penicillin allergy may also react to ceftriaxone as both are beta-lactam antibiotics. 3, 7

Important Clinical Pitfalls

Jarisch-Herxheimer Reaction

• An acute febrile reaction with headache, myalgia, and other symptoms may occur within 24 hours after any syphilis therapy, particularly in early syphilis. 2, 3
• In pregnant women treated during the second half of pregnancy, this reaction may precipitate premature labor or fetal distress. 3
• Women should seek immediate medical attention if they notice contractions or changes in fetal movements after treatment. 3

Formulation Matters

• Do not use oral penicillin preparations for syphilis treatment—they are ineffective. 3
• Procaine penicillin without probenecid does not achieve adequate CSF levels and is inadequate for neurosyphilis treatment. 3
• Benzathine penicillin G (long-acting IM formulation) differs from aqueous crystalline penicillin G (IV formulation used for neurosyphilis). 3, 4

Monitoring and Follow-Up

• Quantitative nontreponemal serologic tests (RPR or VDRL) should be repeated at 6 and 12 months for primary/secondary syphilis, and at 6,12, and 24 months for latent syphilis. 3, 4
• A fourfold decline in titer is expected within 6 months for primary/secondary syphilis and within 12-24 months for late syphilis. 3, 4
• Use the same nontreponemal test method throughout follow-up, as VDRL and RPR results cannot be directly compared. 2, 3
• Treatment failure is defined as failure of nontreponemal test titers to decline fourfold within 6 months after therapy for primary or secondary syphilis. 3, 4

Supply Challenges

• Recent benzathine penicillin G shortages have created treatment challenges, requiring searches across multiple facilities and pharmacies. 9
• Alternative subcutaneous infusion formulations are being studied for late-latent syphilis to reduce pain and improve treatment completion. 10

What NOT to Use

• Azithromycin should NOT be used in the United States due to widespread macrolide resistance and documented treatment failures. 3, 7
• Erythromycin does not reliably cure fetal infection and is inadequate for pregnancy. 3
• Enhanced penicillin therapy (standard benzathine penicillin combined with high-dose oral amoxicillin and probenecid) did not improve clinical outcomes and is not recommended. 7