• Posted September 4, 2025

Single-Dose Penicillin Effective Against Early Syphilis

A single dose of penicillin works just as well to cure early syphilis as the three-injection regimen now used by many doctors, a new clinical trial says.

Second and third doses of benzathine penicillin G (BPG) don’t provide any additional benefit in treating early-stage syphilis, researchers reported in the New England Journal of Medicine.

“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 health care providers,” said Carolyn Deal, chief of the enteric and sexually transmitted infections branch of the National Institute of Allergy and Infectious Diseases (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,” Deal said in a news release. She was not involved in the research, which NIAID funded.

Syphilis continues to be a health threat for sexually active Americans, researchers said in background notes. In 2023, the nation saw more than 209,000 syphilis cases, up 61% from 2019 levels.

Without treatment, syphilis can cause brain damage, organ failure, pregnancy complications and birth defects, researchers said. The bacterial infection also increases a person’s likelihood of acquiring or transmitting HIV.

BPG is one of the few antibiotics known to be effective against syphilis. It’s imported into the U.S. now to resolve a nationwide shortage, researchers noted.

For the new study, 249 people with early syphilis were recruited at 10 U.S. medical centers, nearly all men and 61% living with HIV.

Participants were randomly chosen to receive either one shot of BPG or the three-dose series at weekly intervals.

About 76% of people in the single-dose group responded to the penicillin, based on blood tests, compared to 70% of those in the three-dose group. Overall, the difference between the groups was not statistically significant, researchers said.

“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 us optimize treatment,” said lead researcher Dr. Edward Hook III, an 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,” he added in a news release.

Limiting syphilis treatment to a single dose could help prevent the bacteria from developing antibiotic resistance, researchers said, as well as helping limit the impact of drug shortages.

“During our trial, as on several occasions over the past several decades, benzathine penicillin G was in short supply in the United States,” researchers wrote in their paper.

“This shortage led public health authorities to prioritize which patients receive benzathine penicillin G and which should be treated with alternative therapies,” researchers wrote. “Global shortages of benzathine penicillin G are also common and undermine syphilis-control efforts in many countries.”

Although the trial provides evidence that a single dose of BPG is as effective as three doses, more research is needed to fully understand the potential of a shorter treatment strategy, researchers noted.

It’s also not clear whether a one-dose approach would work in people with late-stage syphilis or syphilis that has already invaded the nervous system, researchers added.

More information

Yale Medicine has more on syphilis.

SOURCES: National Institutes of Health, news release, Sept. 3, 2025; The New England Journal of Medicine, Sept. 3, 2025