What is the recommended dose of benzathine penicillin G (Bicillin) for the treatment of syphilis, administered one dose every week?

Benzathine Penicillin G Dosing for Syphilis

For early syphilis (primary, secondary, or early latent), administer benzathine penicillin G 2.4 million units IM as a single dose; for late latent syphilis or syphilis of unknown duration, administer 2.4 million units IM weekly for three consecutive weeks (total 7.2 million units). 1, 2

Dosing by Syphilis Stage

Early Syphilis (Primary, Secondary, or Early Latent)

• Single dose of 2.4 million units IM is the standard treatment for adults 1, 2
• This applies to patients with documented infection acquired within the preceding year 1
• The most recent high-quality randomized trial (2025) confirmed that one dose is noninferior to three doses, with 76% serologic response at 6 months in both HIV-infected and HIV-uninfected patients 3

Late Latent Syphilis or Unknown Duration

• Three doses of 2.4 million units IM administered at 1-week intervals (total 7.2 million units) 1, 2
• Each injection must be spaced exactly 7 days apart 2
• If a dose is missed, pharmacologic considerations suggest a 10-14 day interval may be acceptable before restarting the sequence, though this should not be considered acceptable for pregnant patients 1, 2

Special Population Considerations

HIV-Infected Patients

• Use the same single-dose regimen for early syphilis as HIV-uninfected patients 2, 4, 3
• A 2017 randomized trial found no benefit to three doses versus one dose in HIV-infected patients with early syphilis (80% vs 93% success rates, not statistically significant) 4
• The 2025 NEJM trial definitively established noninferiority of single-dose therapy regardless of HIV status 3
• While one older observational study from 2014 suggested higher failure rates with single-dose therapy in HIV-infected patients 5, the more recent and higher-quality randomized controlled trials 4, 3 support single-dose treatment

Pediatric Dosing

• 50,000 units/kg IM (up to adult dose of 2.4 million units) as a single dose for early latent syphilis 1, 2
• For late latent syphilis: 50,000 units/kg IM administered as three doses at 1-week intervals (total 150,000 units/kg, up to adult total of 7.2 million units) 1, 2
• All children require CSF examination to exclude neurosyphilis before treatment 1, 2

Pregnant Patients

• Use the same stage-appropriate penicillin dosing as non-pregnant adults 2, 6
• Penicillin is the only proven effective treatment to prevent mother-to-fetal transmission 2
• Pregnant women who miss any dose during three-dose therapy must repeat the full course 1
• Penicillin-allergic pregnant women must be desensitized, as alternatives like doxycycline and tetracyclines do not prevent congenital syphilis 2, 6

Critical Clinical Pitfalls

Staging Accuracy

• Patients must meet specific criteria to be classified as early latent syphilis: documented seroconversion within the past year, unequivocal symptoms of primary/secondary syphilis within the past year, or a sex partner with documented early syphilis 1
• When in doubt, treat as late latent syphilis (three doses) rather than risk undertreatment 1
• Nontreponemal titers alone cannot reliably distinguish early from late latent syphilis 1

Neurosyphilis Exclusion

• Perform CSF examination before treating with standard benzathine penicillin regimens if patients have: neurologic/ophthalmic symptoms, evidence of tertiary syphilis, treatment failure, or HIV infection with late latent syphilis 1
• If neurosyphilis is confirmed, benzathine penicillin is inadequate; use aqueous crystalline penicillin G 18-24 million units/day IV for 10-14 days instead 6, 7

Follow-Up and Treatment Response

• Monitor quantitative nontreponemal tests (RPR/VDRL) at 6,12, and 24 months 1
• Expect a fourfold (two-dilution) decline in titer within 6 months for primary/secondary syphilis 2, 6
• Treatment failure is defined as: titers increasing fourfold after initial decline, or initially high titer (≥1:32) failing to decline fourfold within 12-24 months 1, 2

HIV Testing

• All patients with syphilis should be tested for HIV infection 1, 6