Is 2.4 Million Units in 4 mL Given in 2 Doses Effective for Syphilis?
No, a 2-dose regimen of benzathine penicillin G is not standard or recommended for syphilis treatment. The appropriate dosing depends entirely on the stage of syphilis: early syphilis (primary, secondary, or early latent) requires a single dose of 2.4 million units IM, while late latent syphilis or syphilis of unknown duration requires three weekly doses of 2.4 million units IM each 1, 2, 3.
Standard Treatment Regimens by Stage
Early Syphilis (Primary, Secondary, Early Latent)
- Single dose of 2.4 million units IM benzathine penicillin G is the definitive treatment 1, 2, 3
- This single-dose regimen is supported by over 40 years of clinical experience and recent high-quality randomized controlled trials 1
- The most recent 2025 randomized trial demonstrated that one dose was noninferior to three doses for early syphilis, with 76% serologic response in both HIV-infected and non-HIV-infected patients 4
Late Latent Syphilis or Syphilis of Unknown Duration
- Three weekly doses of 2.4 million units IM benzathine penicillin G (total 7.2 million units) 1, 2, 3
- Each dose is administered at 1-week intervals 1
Why Two Doses Is Not Recommended
There is no evidence base or guideline support for a 2-dose regimen. The treatment paradigm is binary:
- One dose for early disease (infection within the past year) 1, 2, 3
- Three doses for late or unknown duration disease (infection beyond one year or timing uncertain) 1, 3
A 2-dose regimen falls into a therapeutic gap with no supporting data and would represent both overtreatment for early syphilis and undertreatment for late latent syphilis 1.
Evidence Against Multiple Doses for Early Syphilis
Recent high-quality evidence demonstrates that additional doses beyond one do not enhance efficacy in early syphilis:
- A 2025 multicenter randomized controlled trial showed noninferiority of single-dose versus three-dose therapy for early syphilis, with serologic response rates of 76% versus 70% respectively (difference -6 percentage points, demonstrating noninferiority) 4
- The 2010 CDC guidelines explicitly state that "additional doses of benzathine penicillin G in early syphilis do not enhance efficacy, regardless of HIV status" 1
- A 2022 systematic review confirmed limited data suggest no benefit to more than one dose of benzathine penicillin G for early syphilis in HIV-infected patients 1
Critical Pitfall: Proper Staging Is Essential
The most common error is failing to properly stage syphilis before treatment. You must determine:
- Timing of infection: Can the patient be definitively classified as having acquired syphilis within the past year? 1
- Clinical manifestations: Are there signs of primary (chancre) or secondary (rash, mucocutaneous lesions) syphilis? 2, 5
- Serologic titers: While titers alone cannot distinguish early from late latent syphilis, they provide supporting information 1
If any doubt exists about timing or if the infection is of unknown duration, treat as late latent syphilis with three weekly doses 1, 3.
Special Considerations for HIV-Infected Patients
- HIV-infected patients with early syphilis should receive the same single-dose regimen as HIV-negative patients 1, 3, 6
- Some specialists historically recommended three doses for HIV-infected patients, but this is not supported by current evidence 1, 6, 4
- The 2017 randomized trial in HIV-infected patients showed no significant difference between one and three doses (80% vs 93% success rates, P=0.17) 6
- The 2025 trial confirmed equivalent serologic responses in HIV-infected participants (76% for both one and three doses) 4
When Three Doses Are Absolutely Required
Late latent syphilis or syphilis of unknown duration mandates three weekly doses 1, 3:
- Total dose: 7.2 million units (2.4 million units IM weekly × 3 weeks) 1, 3
- This applies regardless of HIV status 1, 3
- CSF examination should be considered before treatment in HIV-infected patients with late latent syphilis 1, 3