The resurgence of syphilis cases in the United States has captured the attention of public health officials and researchers alike, prompting renewed efforts to refine and optimize treatment protocols for this enduring sexually transmitted infection. Recently published research from the University of Alabama at Birmingham (UAB) offers groundbreaking evidence that challenges long-standing treatment regimens, specifically regarding the dosage of benzathine penicillin G (BPG) required to effectively cure early syphilis. This pivotal study, featured in the prestigious New England Journal of Medicine, could reshape clinical guidelines while addressing significant concerns over drug supply and patient compliance.
Syphilis, caused by the bacterium Treponema pallidum, remains a formidable public health challenge despite the availability of effective antibiotic treatment. The disease’s capacity to cause both acute and chronic infections leads to serious complications, including neurological damage and congenital abnormalities if left untreated. Health authorities reported more than 209,000 syphilis cases in 2023 across the United States, marking the highest incidence since 1950, coupled with nearly 4,000 cases of congenital syphilis. The infection’s bidirectional relationship with HIV – enhancing transmission and acquisition – further complicates control efforts in affected populations.
For decades, the Centers for Disease Control and Prevention (CDC) has recommended a single intramuscular dose of benzathine penicillin G as the standard treatment for early syphilis. However, clinical practices have often varied, with some clinicians administering three weekly doses, particularly for patients co-infected with HIV, based on concerns about treatment failure and relapse. This divergence reflects lingering uncertainty about the optimal treatment regimen capable of achieving sustained serological cure, especially in populations with compromised immune function.
The randomized controlled trial conducted by UAB researchers directly addressed this clinical dilemma by enrolling 249 individuals diagnosed with early syphilis at 10 sites throughout the United States. The cohort was predominantly composed of men (97%), with a majority identifying as Black (62%) and living with HIV (64%). This demographic representation holds critical significance, as these groups bear a disproportionate burden of syphilis and HIV co-infection, providing robust applicability to real-world patient populations.
Participants were randomly assigned to receive either the conventional single dose of BPG or the extended three-dose regimen administered weekly. The trial meticulously monitored serological and clinical outcomes over a designated follow-up period, employing stringent criteria to define treatment success. The results were remarkable: the efficacy of the single-dose regimen was statistically indistinguishable from that of the three-dose protocol, offering compelling evidence that fewer injections are sufficient to eradicate early syphilitic infection.
One of the key implications arising from these findings is the potential to simplify syphilis treatment. Dr. Edward Hook III, the study’s lead author and professor of medicine and epidemiology at UAB, emphasized that reducing the number of injections could alleviate patient burden and healthcare system challenges. This simplification not only enhances patient adherence but also reduces the logistical complexities associated with multiple clinic visits and administration of intramuscular injections, which often impede completion of therapy.
Beyond clinical convenience, the study’s outcomes hold substantial importance in the context of nationwide shortages of benzathine penicillin G. The drug’s supply chain has been historically unstable, marked by intermittent stock-outs that hamper treatment availability. Dr. Jodie Dionne, associate professor of medicine and co-author of the study, highlighted that validating the single-dose regimen could significantly extend the existing drug supply. This conservation of resources has profound public health ramifications, enabling broader access to treatment amidst supply constraints.
Syphilis’s pathophysiology underscores the criticality of timely and effective intervention. The spirochetal bacterium Treponema pallidum possesses the ability to invade multiple organ systems, including the central nervous system, resulting in neurosyphilis if untreated. The infection’s insidious progression through primary, secondary, and latent stages can culminate in devastating clinical sequelae. Congenital syphilis remains particularly alarming, as maternal infection transmitted to the fetus can cause miscarriage, stillbirth, or severe neonatal morbidity, underscoring the urgency of adequate treatment protocols.
The battle against syphilis is further complicated by its interaction with HIV. Co-infection exacerbates immunologic challenges, potentially impacting treatment efficacy and disease progression. This complexity has historically justified more aggressive treatment approaches for syphilis in individuals with HIV. However, the UAB study’s inclusion of a substantial proportion of HIV-positive participants provides reassurance that the single-dose BPG regimen maintains its effectiveness within this vulnerable subgroup, potentially redefining treatment stratification.
These landmark findings are poised to influence future clinical practice guidelines issued by key public health agencies, including the CDC. By substantiating that one intramuscular injection of benzathine penicillin G is sufficient to cure early syphilis, the study offers a scientific basis for streamlining treatment protocols. Improved adherence, reduced healthcare resource utilization, and enhanced drug availability emerge as tangible benefits, potentially mitigating the surge in syphilis cases which have posed significant public health concerns.
Importantly, this research aligns with ongoing efforts to mitigate antibiotic shortages, a recurring problem with BPG that partially stems from its limited manufacturing sources and complex supply chains. By validating reduced dosing, the study encourages better stewardship of this essential antibiotic, ensuring more equitable distribution and availability across different healthcare settings, including resource-limited environments.
Lastly, the randomized controlled trial methodology provides high-quality evidence due to its rigorous design, controlling for confounding variables and enabling causal inference between the intervention and outcomes. The multicenter nature of the study, encompassing diverse geographic and demographic populations, strengthens the generalizability of the results, addressing previous gaps in treatment research for syphilis, particularly among marginalized communities disproportionately affected by the epidemic.
In conclusion, the University of Alabama at Birmingham’s recent research offers a scientifically robust reevaluation of established syphilis treatment, highlighting that a single dose of benzathine penicillin G suffices to cure early-stage disease, including in persons living with HIV. This advancement heralds a new era in the management of syphilis, promising enhanced patient adherence, optimized use of limited drug supplies, and simplified clinical care. As syphilis continues its alarming resurgence, these findings equip healthcare providers and public health officials with vital tools to curb this persistent infectious threat more effectively.
Subject of Research: People
Article Title: One Dose versus Three Doses of Benzathine Penicillin G in Early Syphilis
News Publication Date: 3-Sep-2025
Web References:
- https://www.nejm.org/doi/full/10.1056/NEJMoa2401802
- https://www.cdc.gov/sti-statistics/data-vis/table-syph-total-state-abc.html
- https://www.uab.edu/home/
References:
New England Journal of Medicine, DOI: 10.1056/NEJMoa2401802
Keywords:
Sexually transmitted diseases, Syphilis, Infectious diseases, Human immunodeficiency virus
