Single vs. Multiple Doses: Optimizing Penicillin Regimens for Early Syphilis

The debate is continuing to simmer regarding the optimal dosing strategy for early syphilis treatment, a matter not just of clinical preferences but with significant implications for patient outcomes and healthcare logistics. With recent research reinforcing rather than overturning traditional guidance, the question is arising: can a single injection suffice where three were once considered?

Recent multicenter research is underscoring that a single intramuscular injection of benzathine penicillin G aligns with current clinical guidance for early syphilis—CDC recommendations call for 2.4 million units IM once for primary, secondary, and early latent disease, while three weekly doses are reserved for late latent or unknown duration—so the new data is reinforcing existing practice rather than overturning it.

This finding from a multicenter analysis is reinforcing guideline-recommended single-dose therapy for early syphilis and is questioning the practice of prescribing extra doses in early disease.

Beyond the headlines, the implications for patient care are remaining profound. Equally pragmatic is the evidence indicating that in early syphilis— including among people with HIV—available observational and trial data are showing no added benefit from additional weekly doses compared with a single 2.4 million unit injection when follow-up is ensured, while ongoing research is continuing to refine subgroup estimates. This research is steering clinical decisions toward more accessible care modalities.

By exploring these findings, healthcare providers are witnessing an evidence-informed shift where enhanced adherence and treatment completion rates are becoming feasible under constrained resource settings. This shift in protocol, supported by an NIH-supported multicenter study, is enabling a reduction in healthcare burden and is aligning with modern syphilis management strategies.

What are these findings meaning for the patient experience? Humanizing this data, the patient experience lens is suggesting higher satisfaction due to fewer clinic visits and reduced healthcare interactions, while also recognizing trade-offs such as fewer touchpoints for counseling, partner services, and repeat STI/HIV testing—making it important to book follow-up and offer bundled counseling at the time of treatment.

Addressing the clinical challenge faced in resource-limited settings, single-dose regimens are presenting a logical strategy, especially amid ongoing penicillin shortages (during such periods, public health advisories are prioritizing guideline-indicated single-dose therapy for early syphilis and discouraging extra doses). It is cleverly balancing resource constraints while meeting efficacy standards, ensuring that patients are not facing unnecessary treatment barriers.

Reinforcing this is evidence from a Clinical Infectious Diseases 2015 cohort analysis reporting similar serologic response rates at 6–12 months in early syphilis, while noting that subgroup analyses are limited and direct head-to-head comparisons across all groups are not definitive.

Building on the guideline-consistent evidence above, clinics are reshaping workflows by defaulting to single-dose therapy for early syphilis, scheduling serologic follow-up at 6 and 12 months at the time of injection, and integrating brief counseling and partner services referrals into that same visit to maintain quality while simplifying care.

Key Takeaways:

• Recent studies are validating that a single-dose penicillin regimen for early syphilis is matching the traditional three-dose approach in efficacy.
• Implementing a single-dose regimen can improve patient adherence and satisfaction by minimizing clinic visits, provided follow-up testing and counseling are proactively scheduled.
• Adapting standard treatment protocols to incorporate single-dose regimens can optimize resource utilization, particularly in areas with penicillin shortages.
• Syphilis management is leveraging new research findings to refine therapeutic strategies, enhancing both patient care and clinical efficiency.