Is penicillin G (Penicillin G) acceptable for the treatment of syphilis?

Is Penicillin G Acceptable for Syphilis Treatment?

Yes, penicillin G is not only acceptable but remains the drug of choice for treating all stages of syphilis, with specific formulations and dosing regimens determined by the stage of infection. 1, 2

Why Penicillin G is the Gold Standard

Parenteral penicillin G is the preferred drug for treatment of all stages of syphilis, supported by more than 40 years of clinical experience. 1, 2 The FDA has approved penicillin G for treatment of syphilis, including congenital and neurosyphilis. 3

Key Formulations Used

Different formulations of penicillin G are used depending on the stage and location of infection:

• Benzathine penicillin G is the standard formulation for early and late latent syphilis, administered intramuscularly 2, 4
• Aqueous crystalline penicillin G is required for neurosyphilis due to superior CNS penetration, administered intravenously 1, 2
• Procaine penicillin G (with probenecid) can be used as an alternative for neurosyphilis only when combined with probenecid, as procaine penicillin alone does not achieve adequate CSF levels 2

Stage-Specific Treatment Regimens

Primary and Secondary Syphilis

• Benzathine penicillin G 2.4 million units IM as a single dose is the recommended treatment 2, 5, 4
• A recent 2025 randomized controlled trial demonstrated that one dose of 2.4 million units was noninferior to three weekly doses, with 76% achieving serologic response at 6 months in both HIV-infected and non-HIV-infected patients 6

Early Latent Syphilis

• Benzathine penicillin G 2.4 million units IM as a single dose 2
• Early latent is defined as infection acquired within the preceding year based on documented seroconversion, fourfold titer increase, recent symptoms, or exposure to a partner with documented early syphilis 2

Late Latent and Tertiary Syphilis

• Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM at weekly intervals 2, 7, 4
• Critical pitfall: Always perform CSF examination before treating tertiary syphilis to exclude neurosyphilis, which requires entirely different treatment 7, 5

Neurosyphilis

• Aqueous crystalline penicillin G 18-24 million units per day IV (administered as 3-4 million units every 4 hours or continuous infusion) for 10-14 days 1, 2
• Alternative: Procaine penicillin 2.4 million units IM daily PLUS probenecid 500 mg orally four times daily for 10-14 days (only if compliance can be ensured) 1, 2

Special Populations

HIV-Infected Patients

• Use the same treatment regimens as HIV-negative patients for all stages of syphilis 2, 5
• Available data suggest no clinical benefit to more than one dose of benzathine penicillin G for early syphilis in HIV-infected patients 1, 2
• However, closer follow-up is mandatory to detect potential treatment failure or disease progression 2, 7

Pregnant Women

• Penicillin is the ONLY therapy proven to prevent maternal transmission and treat fetal infection 2, 7, 5
• Pregnant women with penicillin allergy MUST undergo desensitization followed by penicillin treatment—no alternatives are acceptable 2, 7, 5
• All pregnant women should be screened for syphilis at first prenatal visit, during third trimester, and at delivery 2

When Penicillin Cannot Be Used

Non-Pregnant, Penicillin-Allergic Adults

• For primary, secondary, or early latent syphilis: Doxycycline 100 mg orally twice daily for 14 days 1, 2, 5
• For late latent syphilis: Doxycycline 100 mg orally twice daily for 28 days 1, 2
• A 2022 retrospective study showed doxycycline had slightly lower success rates than penicillin, particularly in late and undetermined syphilis infections, though differences were not statistically significant 8

Alternative Considerations

• Ceftriaxone 1 gram IV/IM daily for 10 days is a reasonable alternative based on randomized trial data showing comparable efficacy to benzathine penicillin 2, 5
• Azithromycin should NOT be used in the United States due to widespread macrolide resistance and documented treatment failures 2, 5

Critical Pitfalls to Avoid

• Never use oral penicillin preparations—they are completely ineffective for syphilis treatment 2, 5
• Never skip CSF examination before treating tertiary syphilis—missing neurosyphilis leads to treatment failure as the benzathine penicillin regimen is inadequate for CNS involvement 7, 5
• Never switch between different nontreponemal test methods (RPR vs VDRL) when monitoring response—results cannot be directly compared 2, 5
• Never substitute non-penicillin antibiotics in pregnancy—only penicillin prevents congenital syphilis 2, 7

Follow-Up Monitoring

• Repeat quantitative nontreponemal tests (RPR or VDRL) at 6,12, and 24 months after treatment 2, 7
• Expect a fourfold decline in titer within 6 months for primary/secondary syphilis 2, 5
• Expect a fourfold decline in titer within 12-24 months for late syphilis 2, 7
• Treatment failure is defined as persistent symptoms, sustained fourfold increase in titers, or failure of initially high titers to decline appropriately 2, 7

Jarisch-Herxheimer Reaction

• An acute febrile reaction may occur within 24 hours after any syphilis therapy, especially in early syphilis, and includes headache, myalgia, and fever 2, 7
• In pregnant women during the second half of pregnancy, this reaction may precipitate premature labor or fetal distress 2
• Patients should be counseled about this possibility and advised to seek immediate medical attention if concerning symptoms develop 2