TOPLINE:

Single-dose benzathine penicillin G was as effective as three weekly doses in achieving a 6-month serologic response among patients with early syphilis — including those with HIV — while simplifying treatment and reducing the burden of multiple injections and clinic visits.

METHODOLOGY:

• Researchers conducted a randomized, noninferiority trial at 10 sites in the US, comparing a single 2.4 million-unit injection of benzathine penicillin G with a three-dose regimen (2.4 million units each) in patients with early (ie, primary, secondary, or early latent) syphilis.
• Adult patients (mean age, 35 years; 97% men; 61% having HIV infection) with reactive rapid plasma reagin test results for Treponema pallidum were randomly assigned to receive either a single-dose intramuscular injection (n = 124) or three weekly doses (n = 125) of benzathine penicillin G.
• The primary endpoint was seroreversion to nonreactive status or a decrease in the rapid plasma reagin titer by two or more dilutions at 6 months. The noninferiority margin was prespecified at 10 percentage points.
• The key secondary endpoint was a 6-month serologic response based on HIV status.

TAKEAWAY:

• At 6 months, 76% of patients in the single-dose group and 70% of those in the three-dose group achieved a serologic response (between-group difference, -6 percentage points; 90% CI, -15 to 3), meeting the prespecified noninferiority margin.
• Among patients with one or more follow-up visits between 6 and 24 days post-enrollment, 72% achieved a complete resolution of symptoms, whereas 28% had reduced ulcers or rash; these findings were consistent across dose groups and syphilis stages.
• Serologic response rates were comparable between patients with and without HIV infection in both the single-dose and three-dose groups.
• Three serious adverse events were reported (one case each of proctocolitis, psychiatric care-specific hospitalization, and facial paralysis), all deemed unrelated to benzathine penicillin G. Among solicited systemic symptoms, more events occurred in the three-dose group than in the single-dose group.

IN PRACTICE:

“The elimination of unnecessary doses of benzathine penicillin G reduces the cost of treatment, aligns with the principles of antimicrobial stewardship, and is more convenient for patients in that the numbers of clinic visits and painful intramuscular injections are decreased,” the authors wrote.

“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,” the authors of a linked editorial added.

SOURCE:

The study was led by Edward W. Hook III, MD, The University of Alabama at Birmingham. It was published online on September 3, 2025, in The New England Journal of Medicine.

LIMITATIONS:

The number of female participants was notably low. The study excluded people with latent syphilis of unknown duration, which represents a significant patient population. Additionally, the trial produced limited data on people with advanced or untreated HIV infection.

DISCLOSURES:

The study was supported by the National Institute of Allergy and Infectious Diseases, Sexually Transmitted Infections Clinical Trials Group. One of the authors disclosed being employed by the Bill and Melinda Gates Foundation. Some authors reported receiving financial aid from and having other ties with companies including Entasis, Hologic Inc., Cepheid, and Mayne Pharma Inc.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.