A single injection of penicillin may be just as effective in treating early-stage syphilis as the traditional three-dose regimen, according to a new clinical trial published in the New England Journal of Medicine.

The study, funded by the National Institute of Allergy and Infectious Diseases (NIAID), found no added benefit from administering two additional doses of benzathine penicillin G (BPG), the antibiotic widely used against syphilis.

“Benzathine penicillin G is highly effective against syphilis, but the three-dose regimen can be burdensome and deter people from attending follow-up visits,” said Carolyn Deal, chief of the Enteric and Sexually Transmitted Infections branch at NIAID. “The new findings offer welcome evidence for potentially simplifying treatment with an equally effective one-dose regimen, particularly while syphilis rates remain alarmingly high.”

Syphilis cases in the United States have surged in recent years, with more than 209,000 infections reported in 2023—an increase of 61 percent since 2019. Left untreated, the bacterial infection can lead to severe complications, including brain damage, organ failure, pregnancy-related risks, and congenital defects in newborns. It also heightens the risk of acquiring or transmitting HIV.

For the trial, 249 patients with early syphilis were enrolled across 10 U.S. medical centers. Nearly all participants were men, with 61 percent living with HIV. They were randomly assigned to receive either a single shot of BPG or the standard three-dose series at weekly intervals. Blood test results showed a similar response rate—76 percent in the single-dose group compared to 70 percent in the three-dose group, a difference researchers deemed statistically insignificant.

“Syphilis has been studied and treated for more than a century, and BPG has been in use for more than 50 years, yet we are still acquiring knowledge to help optimize treatment,” said lead researcher Dr. Edward Hook III, emeritus professor of medicine and epidemiology at the University of Alabama at Birmingham. “We hope these promising results will be complemented by scientific advances in syphilis prevention and diagnosis.”

Researchers also noted that a simplified treatment strategy could help conserve global supplies of BPG, which has faced periodic shortages in the United States and abroad. During the trial itself, limited supplies forced public health authorities to prioritize patients for treatment.

While the findings support the effectiveness of a single-dose regimen, experts caution that more studies are needed to confirm its role in treating late-stage syphilis or cases involving the nervous system.

If validated further, the simplified approach could mark a turning point in syphilis control—helping patients, easing strain on health systems, and potentially reducing the risk of antibiotic resistance.