Is Bicillin (benzathine penicillin G) IM an acceptable treatment for syphilis?

Benzathine Penicillin G (Bicillin) IM is the Gold Standard Treatment for Syphilis

Benzathine penicillin G administered intramuscularly is not only acceptable but is the preferred and most effective treatment for all stages of syphilis, with specific dosing determined by disease stage. 1, 2, 3

Treatment Regimens by Stage

Primary and Secondary Syphilis

• Single dose of 2.4 million units IM is the recommended treatment for adults with primary or secondary syphilis 4, 1, 2
• This single-dose regimen has been validated by decades of clinical experience and recent high-quality evidence demonstrating noninferiority to multi-dose regimens 5
• A 2025 randomized controlled trial showed 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
• Pediatric dosing: 50,000 units/kg IM (maximum 2.4 million units) as a single dose 1, 2

Early Latent Syphilis

• Single dose of 2.4 million units IM for syphilis acquired within the preceding year 4, 1, 2
• Early latent syphilis is defined by documented seroconversion, fourfold increase in titer, history of symptoms within the past year, or having a sex partner with documented early syphilis 1

Late Latent Syphilis or Unknown Duration

• Total of 7.2 million units administered as three separate doses of 2.4 million units IM at weekly intervals 4, 1, 2
• Each injection must be spaced exactly 7 days apart 6
• If a dose is missed, an interval of 10-14 days between doses might be acceptable before restarting the sequence, though pregnant women who miss any dose must repeat the full course 4, 6

Tertiary Syphilis

• Same regimen as late latent: 7.2 million units total as three weekly doses of 2.4 million units IM 4

Critical Exception: Neurosyphilis

Benzathine penicillin G is NOT adequate for neurosyphilis because it does not achieve sufficient CSF levels 2. Neurosyphilis requires:

• 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
• Syphilitic eye disease should be treated as neurosyphilis with the same IV regimen 2

Special Populations

HIV-Infected Patients

• Same treatment regimens as HIV-negative patients 1, 2
• The 2025 randomized trial demonstrated equal efficacy in HIV-infected patients (76% serologic response with single dose) 5
• More frequent follow-up is required (every 3 months rather than every 6 months) 2

Pregnant Women

• Penicillin is the ONLY proven effective therapy to prevent congenital syphilis 1, 6
• Pregnant patients with penicillin allergy MUST undergo desensitization followed by penicillin treatment—no alternatives are acceptable 4, 1, 2
• Screen all pregnant women at first prenatal visit, third trimester, and at delivery 1, 2
• Up to 40% of fetuses with in-utero exposure to syphilis are stillborn or die from infection during infancy if untreated 7

Penicillin-Allergic Non-Pregnant Patients

• For primary, secondary, or early latent syphilis: Doxycycline 100 mg orally twice daily for 14 days 1, 2
• For late latent syphilis: Doxycycline 100 mg orally twice daily for 28 days 4, 1, 2
• These alternatives have limited evidence and require close serologic and clinical follow-up 4

FDA-Approved Indications

Benzathine penicillin G (Bicillin L-A) is FDA-approved for venereal infections including syphilis, yaws, bejel, and pinta 3. The drug is specifically indicated for infections due to penicillin-G-sensitive microorganisms that are susceptible to the low and very prolonged serum levels characteristic of this formulation 3.

Follow-Up and Treatment Response

• Quantitative nontreponemal serologic tests (RPR or VDRL) should be repeated at 6 and 12 months for early syphilis 1, 2
• For latent syphilis, repeat testing at 6,12, and 24 months 4
• Expected response: fourfold decline in titer within 6 months for primary/secondary syphilis 2, 6
• Treatment failure is defined by titers increasing fourfold after initial decline, or initially high titer (≥1:32) failing to decline at least fourfold within 12-24 months 4, 6

Common Pitfalls to Avoid

• Never use oral penicillin preparations—they are ineffective for syphilis treatment 1
• Do not substitute inadequate alternatives in pregnancy—only penicillin prevents congenital syphilis 6
• Do not compare titers between different test types (e.g., switching between VDRL and RPR)—results are not directly comparable 1
• Avoid azithromycin in the United States due to widespread macrolide resistance and documented treatment failures 1, 2
• Do not use procaine penicillin without probenecid for neurosyphilis—it does not achieve adequate CSF levels 1
• Be aware of the Jarisch-Herxheimer reaction, which commonly occurs within 24 hours after treatment, especially in early syphilis 4, 1

Current Supply Challenges

Recent benzathine penicillin G shortages have created treatment challenges, requiring clinicians to search multiple facilities and pharmacies or use alternative regimens like doxycycline 8. However, this does not change the fact that benzathine penicillin G remains the gold standard when available 8.