What conditions are treated with benzathine penicillin G?

Benzathine Penicillin G: Primary Indications and Treatment Guidelines

Benzathine penicillin G is the definitive first-line treatment for all stages of syphilis except neurosyphilis, and is also used for group A streptococcal pharyngitis when single-dose intramuscular therapy is preferred. 1, 2

Primary Indications

Syphilis Treatment (All Stages Except Neurosyphilis)

Early Syphilis (Primary, Secondary, and Early Latent ≤1 year)

• A single intramuscular dose of 2.4 million units achieves 90-100% treatment success and is the standard of care. 1, 3
• Early latent syphilis is defined as infection acquired within the preceding year, documented by seroconversion, fourfold titer increase, symptoms within the past year, or a sex partner with documented early syphilis. 3
• For pediatric patients, administer 50,000 units/kg IM (maximum 2.4 million units) as a single dose after CSF examination to exclude neurosyphilis. 1, 2

Late Latent Syphilis or Syphilis of Unknown Duration (>1 year)

• Three weekly doses of 2.4 million units IM (total 7.2 million units) are required for adequate treatment. 3, 1
• CSF examination is mandatory before treatment when any of the following are present: neurologic or ophthalmic signs, evidence of tertiary syphilis, treatment failure, HIV infection with late latent disease, or nontreponemal titer ≥1:32. 3, 1
• For children, administer 50,000 units/kg IM weekly for three doses (total 150,000 units/kg, maximum 7.2 million units). 3, 2

Tertiary Syphilis (Cardiovascular or Gummatous)

• Three weekly doses of 2.4 million units IM (total 7.2 million units) with mandatory CSF examination before initiating therapy. 1, 2
• Management should involve infectious disease specialist consultation. 1

Group A Streptococcal Pharyngitis

• For adults and adolescents: 1.2 million units IM as a single dose when single-dose therapy is preferred. 2
• For children weighing <27 kg: 600,000 units IM as a single dose. 2
• This approach is particularly valuable when compliance with 10-day oral therapy is uncertain. 2

Rheumatic Fever Prevention

• Benzathine penicillin G remains the ideal drug for preventing rheumatic fever recurrences and has contributed to marked reduction in morbidity and mortality where prophylaxis programs are established. 4

Special Populations

Pregnant Women

Penicillin is the only therapy proven to prevent maternal-fetal transmission and treat fetal infection; no alternative antibiotics are acceptable. 1, 5

• All pregnant patients with penicillin allergy must undergo desensitization followed by penicillin treatment—no exceptions. 1, 5
• Treatment must be administered at least 4 weeks before delivery to optimize fetal outcomes. 1
• If a pregnant woman misses any benzathine penicillin dose, the entire course must be repeated; partial-dose exceptions are not permitted. 1
• Jarisch-Herxheimer reactions in the second half of pregnancy can precipitate preterm labor or fetal distress; obstetric monitoring for 24 hours after therapy is advised for gestations >20 weeks. 1, 5
• Routine syphilis screening is recommended at first prenatal visit, 28 weeks gestation, and at delivery. 5

HIV-Infected Patients

• HIV-infected individuals receive the same penicillin regimens as HIV-uninfected patients for all disease stages. 3, 1, 5
• Post-treatment monitoring is more intensive: clinical and serologic evaluation at 3,6,9,12, and 24 months. 3, 1
• For late latent syphilis with HIV infection, CSF examination should be performed before treatment to exclude neurosyphilis. 3, 1
• A recent 2025 randomized controlled trial demonstrated that one dose of 2.4 million units was noninferior to three doses for early syphilis, with 76% serologic response in HIV-infected patients in both groups. 6

However, an earlier 2014 observational study showed conflicting results: single-dose BPG resulted in higher serological failure rates (67.1% vs 74.8% response) and shorter time to treatment failure compared to three weekly doses in HIV-infected patients with early syphilis. 7

Given this conflicting evidence, the most recent high-quality randomized trial 6 supports single-dose therapy, but clinicians should consider three-dose regimens for HIV-infected patients when closer monitoring is not feasible.

Critical Contraindications

Benzathine penicillin G must never be used as monotherapy for neurosyphilis because it does not achieve therapeutic CSF concentrations. 1

• Neurosyphilis requires aqueous crystalline penicillin G 18-24 million units per day IV (given as 3-4 million units every 4 hours or continuous infusion) for 10-14 days. 1, 8

Penicillin-Allergic Patients (Non-Pregnant)

For early syphilis:

• Doxycycline 100 mg orally twice daily for 14 days is the preferred alternative. 1, 2
• Tetracycline 500 mg orally four times daily for 14 days is acceptable, though adherence is better with doxycycline. 1
• Ceftriaxone 1 g IM or IV daily for 10-14 days may be considered; randomized data show comparable efficacy to benzathine penicillin. 1

For late latent syphilis:

• Doxycycline 100 mg orally twice daily for 28 days. 1, 2
• Tetracycline 500 mg orally four times daily for 28 days is also acceptable. 1

Critical caveat: Patients with severe penicillin allergy (e.g., Stevens-Johnson syndrome) may cross-react with ceftriaxone because both are β-lactam antibiotics. 1

Follow-Up and Monitoring

Early Syphilis:

• Quantitative nontreponemal tests (RPR or VDRL) should be repeated at 6 and 12 months after treatment. 1, 5
• A ≥4-fold decline in titer is expected within 6 months. 1

Late Latent Syphilis:

• Quantitative nontreponemal tests should be performed at 6,12, and 24 months. 1
• A ≥4-fold decline in titer is expected within 12-24 months. 1

Treatment Failure Indicators:

• Persistent or recurrent signs/symptoms. 1
• Sustained ≥4-fold increase in nontreponemal titer. 1
• Failure of an initially high titer (≥1:32) to decline ≥4-fold within 6-12 months for early syphilis or 12-24 months for late syphilis. 1, 5

Management of Treatment Failure:

• If CSF findings are normal, retreat with benzathine penicillin G 7.2 million units (three weekly IM doses). 1, 5
• If CSF remains abnormal, manage according to neurosyphilis protocol (IV aqueous crystalline penicillin). 1, 5

Management of Sex Partners

• Presumptive treatment with benzathine penicillin G 2.4 million units IM is indicated for partners exposed within 90 days of a primary, secondary, or early latent syphilis diagnosis, even if seronegative. 1, 5
• Time windows for presumptive treatment: 3 months plus symptom duration for primary syphilis, 6 months plus symptom duration for secondary syphilis, and 1 year for early latent syphilis. 1, 5

Common Pitfalls to Avoid

• Oral penicillin preparations are ineffective for syphilis treatment and must not be used. 1
• Do not use treponemal test antibody titers alone to assess treatment response; they correlate poorly with disease activity. 1
• Do not switch between different nontreponemal test methods (e.g., VDRL vs. RPR) when monitoring serologic response; results are not directly comparable. 1
• New genital lesions after therapy do not automatically indicate treatment failure; serologic criteria define true failure. 1, 5
• Azithromycin should not be used in the United States because of widespread macrolide resistance and documented treatment failures. 1
• 15-25% of successfully treated patients remain "serofast" with low persistent titers (<1:8) that do not indicate treatment failure. 1

Additional Considerations

• All patients diagnosed with syphilis should be screened for HIV at the time of diagnosis. 3, 1, 5
• If a weekly benzathine penicillin dose is missed, an interval of 10-14 days between doses is acceptable before restarting the series (except in pregnant patients). 3, 1
• Patients should be informed that Jarisch-Herxheimer reaction (acute febrile reaction with headache, myalgia, fever) can occur within 24 hours after any syphilis therapy, especially in early disease. 1, 5