What is the dosage and frequency of benzathine penicillin G (Bicillin) injections for the treatment of syphilis?

Benzathine Penicillin G Dosing for Syphilis Treatment

For early syphilis (primary, secondary, or early latent), adults require a single intramuscular injection of 2.4 million units of benzathine penicillin G, while late latent syphilis or syphilis of unknown duration requires three weekly injections of 2.4 million units (total 7.2 million units). 1, 2

Adult Dosing by Stage

Early Syphilis (Primary, Secondary, or Early Latent <1 Year)

• Single dose of 2.4 million units IM is the standard treatment 3, 1
• This single injection achieves 90-100% treatment success rates 4
• A recent 2025 randomized controlled trial confirmed that one dose is noninferior to three doses, with 76% serologic response at 6 months regardless of HIV status 5

Late Latent Syphilis or Unknown Duration

• Three doses of 2.4 million units IM given at weekly intervals (total 7.2 million units) 3, 1, 2
• Each injection must be spaced exactly 7 days apart 1
• If a 7-day interval is missed, a 10-14 day interval may be acceptable, but optimal timing is weekly 1

Neurosyphilis

• Requires intravenous therapy: Aqueous crystalline penicillin G 18-24 million units daily (administered as 3-4 million units IV every 4 hours) for 10-14 days 2, 6
• Some specialists recommend adding a single dose of benzathine penicillin G 2.4 million units IM weekly for 3 doses after completing IV therapy 6

Pediatric Dosing

Children with Acquired Syphilis

• 50,000 units/kg IM (up to adult dose of 2.4 million units) as a single dose for early syphilis 3, 1
• For late latent syphilis: 50,000 units/kg IM administered as three doses at weekly intervals (total 150,000 units/kg up to 7.2 million units) 3
• All children require CSF examination before treatment to exclude neurosyphilis 3, 7

Congenital Syphilis (Newborns)

• Treatment depends on maternal treatment status and infant evaluation 7
• If mother inadequately treated or untreated: Aqueous crystalline penicillin G 100,000-150,000 units/kg/day IV (50,000 units/kg every 12 hours for first 7 days, then every 8 hours) for 10 days 3
• Alternative: Procaine penicillin G 50,000 units/kg IM daily for 10 days 3
• If mother adequately treated and infant evaluation normal: Benzathine penicillin G 50,000 units/kg IM as single dose 3, 7

Critical Treatment Principles

Timing and Administration

• For late latent syphilis, doses must be given weekly—if more than one day of therapy is missed, restart the entire course 7
• Injections should be deep intramuscular 1
• Most patients experience local injection-site pain and tenderness (76-85% of patients) 5

Follow-Up Monitoring

• For early syphilis: Clinical and serologic evaluation at 6 and 12 months 1, 2
• For late latent syphilis: Repeat quantitative nontreponemal tests at 6,12, and 24 months 3, 2
• A fourfold decline in titer is expected within 6 months for primary/secondary syphilis 1, 2
• Serologic response is generally slower (12-24 months) for latent syphilis 4

Treatment Failure Criteria

• Titers increasing fourfold after initial decline 1, 2
• Initially high titer (≥1:32) failing to decline at least fourfold within 12-24 months 3, 1
• Signs or symptoms persisting or recurring 3
• Treatment failures should be re-evaluated for HIV infection and CSF examination should be performed 3

Special Populations

HIV-Infected Patients

• Same single-dose regimen for early syphilis—additional doses do not enhance efficacy regardless of HIV status 1, 5
• The 2025 trial showed identical 76% serologic response rates in HIV-infected and non-infected patients with single-dose therapy 5
• All patients with syphilis should be tested for HIV 3, 2

Pregnant Women

• Same stage-appropriate penicillin dosing as non-pregnant adults 1
• Penicillin is the only proven effective treatment to prevent mother-to-fetal transmission 1, 7
• Never use tetracyclines, doxycycline, or erythromycin in pregnancy—these do not prevent congenital syphilis 1, 7
• Pregnant women allergic to penicillin should be desensitized and treated with penicillin 3

Common Pitfalls to Avoid

• Do not use umbilical cord blood for infant serologic testing—it may be contaminated with maternal blood 7
• Do not compare titers between different test types (VDRL vs RPR)—they are not directly comparable 1
• Do not consider a woman treated with non-CDC-recommended regimens as adequately treated 7
• Do not assume treatment failure based solely on persistent positive serology—many patients remain "serofast" with stable low titers after successful treatment 4
• For congenital syphilis, if any part of the infant evaluation is abnormal or not performed, a full 10-day course of penicillin is required rather than single-dose therapy 3