A landmark randomized clinical trial has demonstrated that a single injection of benzathine penicillin G (BPG) is as effective as the standard three-dose regimen for treating early syphilis, potentially transforming treatment protocols during a period of critical antibiotic shortages and rising infection rates.
The multicenter study, led by researchers at the University of Alabama at Birmingham and funded by the National Institute of Allergy and Infectious Diseases (NIAID), enrolled 249 participants with early syphilis from October 2018 through March 2022. Results published in The New England Journal of Medicine showed that 76% of participants receiving a single 2.4 million unit intramuscular injection achieved serologic response at 6 months, compared to 70% in the three-dose group.
Trial Design and Patient Population
The study included participants with primary, secondary, and early latent syphilis stages, with or without HIV infection. Of the enrolled participants, 97% were men, 62% were Black, and 61% were living with HIV. The disease distribution included 19% with primary syphilis, 47% with secondary syphilis, and 33% with early latent syphilis.
Participants were randomly assigned to receive either a single intramuscular injection of BPG 2.4 million units or three weekly injections of the same dose. The primary endpoint was serologic response at 6 months, with a noninferiority margin of 10 percentage points.
Efficacy Results Across Patient Groups
The trial demonstrated noninferiority of single-dose treatment with a between-group difference of -6 percentage points (90% CI, -15 to 3). When stratified by HIV status, results remained consistent, with 76% of HIV-positive participants in the single-dose group achieving serologic response compared to 71% in the three-dose group.
"With no observable benefit to multiple treatments, a single treatment at a dose of 2.4 million units should be, in our opinion, the preferred treatment for early syphilis," the study authors concluded.
Safety Profile and Treatment Completion
The most common adverse events were local injection-site pain and tenderness, occurring in 76% of single-dose participants and 85% of three-dose participants. Notably, 21 participants in the three-dose group failed to complete all three treatments, potentially due to cumulative discomfort from multiple injections.
Three serious adverse events were reported but were not related to BPG treatment. One participant developed neurosyphilis three days after starting therapy and was excluded from the analysis.
Clinical Implications During Drug Shortages
The findings carry particular significance as the United States and other countries experience ongoing BPG shortages. Syphilis cases have risen 61% since 2019, with an estimated 209,000 US infections in 2023, while BPG stockouts have hampered treatment efforts globally.
"Benzathine penicillin G is highly effective against syphilis, but the three-dose regimen can be burdensome and deter people from attending follow-up visits with their healthcare providers," said Carolyn Deal, PhD, chief of NIAID's enteric and sexually transmitted infections branch. "The new findings offer welcome evidence for potentially simplifying treatment with an equally effective one-dose regimen, particularly while syphilis rates remain alarmingly high."
Addressing HIV-Related Treatment Concerns
The study specifically addressed longstanding concerns about single-dose efficacy in HIV-positive patients. Despite CDC recommendations for single-dose BPG therapy, many clinicians have historically treated HIV-positive patients with multiple doses due to theoretical concerns about treatment adequacy.
CDC scientists Lindley Barbee, MD, MPH, and Laura Bachmann, MD, MPH, wrote in an accompanying editorial that "the findings from this trial should provide reassurance to clinicians, particularly those caring for patients with HIV infection, that a single dose of benzathine penicillin G is sufficient to treat early syphilis."
Future Research Directions
Principal investigator Edward Hook, MD, noted that while BPG has been used for over 50 years, researchers continue acquiring knowledge to optimize treatment. The study authors emphasized that more research is needed to evaluate therapeutic approaches for all syphilis stages, including late syphilis, latent syphilis of unknown duration, and clinical neurosyphilis.
The editorial authors highlighted that "the question remains whether persons with late latent syphilis or syphilis of unknown duration should receive the CDC-recommended regimen of three 2.4-million-unit doses of benzathine penicillin G. The data supporting the CDC recommendation are theoretical."
