Oral Cephalosporin May Hold Potential for Early Syphilis

Oral cefixime yielded similar rates of treatment success for early syphilis when compared with penicillin, according to preliminary results of a small randomized trial.

At 3 or 6 months post-treatment, 87.5% of the 56 patients who received cefixime, 89.2% of the 49 who received benzathine penicillin G, and all seven patients who received doxycycline achieved at least a fourfold decrease from baseline in rapid plasma reagin (RPR) titers, reported Kori Keith, MPH, of the University of Southern California in Los Angeles.

“Similar to our pilot study, we are still seeing favorable results from our cefixime arm,” she told attendees at the IDWeek annual meeting in Los Angeles. “We haven’t done any in-depth analysis because these are preliminary results, but so far it’s looking favorable and we are going to continue from there.”

In that previous pilot trial, Keith and colleagues found that 87% of patients with syphilis who received oral cefixime 400 mg twice daily for 10 days were successfully treated compared with 93% of those who received penicillin.

Oral cefixime is a third-generation cephalosporin that has a similar antibacterial spectrum to ceftriaxone. Cefixime is FDA-approved, widely available, and on the World Health Organization’s list of essential medicines, Keith explained.

“Clinical use [of cefixime] has already established safety and there’s also acceptability amongst clinicians and patients,” she said.

The antibiotic may prove useful in addressing common obstacles to syphilis treatment. “Throughout the world, we’ve been seeing penicillin shortages, intolerances or allergies to penicillin, as well as fear of injections at a lot of our clinical sites,” Keith said. “And so we felt we needed alternative treatments and we also wanted something that was oral instead of an injection.”

At a post-presentation Q&A session, Alice Lehman, MD, of the University of Minnesota in Minneapolis, asked whether follow-up beyond 3 or 6 months would be required given that some people can take longer to achieve clinical cure.

Keith acknowledged that the standard is to wait a full 12 months after treatment to evaluate outcomes. However, she added that “since we’re looking at early syphilis — so that includes primary, secondary, and early-latent syphilis — we are expecting treatment outcomes by 6 months.” She noted that there is the option to add an additional follow-up evaluation at 12 months, at the discretion of the study physicians.

From 2018 through 2022, syphilis increased by nearly 77%, Keith pointed out. “We’re continuing to see rising syphilis trends here in the United States and that also goes hand-in-hand with rising congenital syphilis rates.”

She pointed to a 17.2% increase in primary and secondary syphilis among women ages 15 to 44 from 2021 to 2022. “There’s a 30.6% increase in congenital syphilis that goes along with the 17.2% increase,” said Keith.

As of May 2024, 145 participants have been enrolled in the study. Patients were included if they had early syphilis with an RPR titer of at least 1:8. Patients were excluded if they had signs of neurosyphilis, a serofast RPR, were pregnant, taking or recently took antibiotics, or if they had an allergy to the study medications.

In the modified intention-to-treat population, which includes participants who attended at least one follow-up visit, there are currently 56 participants in the cefixime group, 49 in the penicillin group, and seven in the doxycycline group. More than two-thirds of participants are people living with HIV.

Patients in the penicillin treatment group received one intramuscular injection of benzathine penicillin G 2.4 million units. In the event of penicillin shortages, patients in that group were pivoted to oral doxycycline 100 mg twice daily for 14 days. Researchers repeat RPR testing at 3-, 6-, and 9-months post-treatment and clinically evaluate patients to assess for potential reinfections, Keith said.

Adverse events (AEs) have been few, she noted. Since the trial began in 2021, there have only been three AEs in the cefixime arm and one AE in the penicillin arm — all mild skin rashes. Moreover, the cefixime adherence rate has proved to be high, at over 92% at the 10-day treatment mark.