A shortage of benzathine penicillin G in Italy, as reported by the Italian Medicines Agency, highlights the relevance of recent research published in The New England Journal of Medicine.

The trial found that a single dose of benzathine penicillin G was as effective as the standard three-dose regimen for early syphilis, including in patients with HIV infection.

At 6 months, serologic response rates were comparable in both groups, with no relapses or treatment failures.

These results could change clinical practice in Italy, particularly given the unavailability of benzathine penicillin G in the country and “for which the drug has been authorized for importation from abroad,” according to a press release published by the Italian Medicines Agency.

Trial Design

The multicenter, randomized controlled study, led by researchers from The University of Alabama at Birmingham and nine other US centers, enrolled 249 adults with early syphilis (primary, secondary, or early latent, confirmed serologically) from 2018 to 2022.

Pregnant women, patients allergic to penicillin, those with recent antibiotic use for Treponema pallidum, and those with suspected neurosyphilis were excluded.

Participants were randomly assigned to receive either a single intramuscular injection of 2.4 million units of benzathine penicillin G or three weekly injections at the same dose.

Most participants were men (97%), and 61% were HIV positive and on antiretroviral therapy.

The primary endpoint was serologic response at 6 months, defined as a negative rapid plasma reagin (RPR) test or at least a fourfold decline in RPR titer.

In intention-to-treat analyses, 76% of patients treated with a single dose achieved a favorable serologic response at 6 months (95% CI, 68%-82%) compared with 70% in the three-dose group (95% CI, 61%-77%), within the predetermined noninferiority margin. Among patients with HIV, the response rates were comparable: 76% with the single-dose regimen and 71% with the three-dose regimen.

No clinical relapse or treatment failures were observed. Side effects were mild. Local pain was more common with the three-injection regimen (85% vs 76%).

Patients who developed a Jarisch-Herxheimer reaction — characterized by fever, chills, malaise, or worsening of syphilitic skin rash that occurs within 24-48 hours after the first injection — were more likely to achieve a positive serologic response, regardless of the treatment regimen.

These findings support a simplified approach to early syphilis treatment, with a single injection of benzathine penicillin G being effective in most patients.

Rising Incidence

Syphilis cases have risen steadily in recent years in Italy. According to the 2025 Annual Epidemiological Report from the European Centre for Disease Prevention and Control, 41,051 confirmed cases were reported in 2023 across 29 countries in the European Economic Area.

This represents a 13% increase compared with 2022 (8.8 per 100,000) and is double the total reported in 2014. Italy also reported an increase in cases from 2019 (1826 cases; 3.1 per 100,000 inhabitants) to 2023 (2538 cases; 4.3 per 100,000 inhabitants).

If inadequately treated, syphilis can lead to neurologic and cardiovascular complications, adverse pregnancy outcomes, and HIV transmission.

“A single treatment with BB for early syphilis is appealing for several reasons, including antimicrobial stewardship and patient comfort. During our trial, as on several occasions over the past several decades, BB was in short supply in the United States. This shortage led public health authorities to prioritize which patients receive BB and which should be treated with alternative therapies,” the authors wrote. This shortage is a global issue, including in Italy.

A single-dose benzathine penicillin G regimen offers various advantages for early syphilis, such as simplifying care and treatment planning, improving adherence, reducing injection-related pain, and increasing the likelihood of treatment completion.

The healthcare system supports more efficient stock management and reserves drugs for vulnerable patients. Evidence of effectiveness in patients who are HIV positive addresses long-standing concerns and supports the use of a simpler regimen in outpatient clinics and prevention services.

This story was translated from Univadis Italy.