A team of investigators explored the oral administration of cefixime 400 mg twice daily for 10 days to treat early syphilis and found promising results in a pilot study, the results of which were published in Clinical Infectious Diseases.

From September 2018 to January 2020, 58 participants enrolled in this randomized, open-label, noncomparative study (ClinicalTrials.gov identifier: NCT03752112) conducted at 5 primary care HIV community clinics of the AIDS Healthcare Foundation in California. In the intention-to-treat (ITT) population, 27 patients were in the cefixime arm, and 31 patients were in the penicillin arm; in the per-protocol (PP) population, an equal number of patients (15) were in each arm. The PP population was entirely men who had HIV infection, with the majority identifying as Hispanic/Latino and as men who have sex with men.

The investigators randomly assigned participants to either a single dose of benzathine penicillin G 2.4 mIU intramuscularly or oral cefixime 200 mg twice daily for 10 days. Follow-up was conducted at 3, 6, and 12 months after enrollment for clinical evaluation and rapid plasma reagin (RPR) titer testing. Participants in the cefixime arm had an additional telephone follow-up 2 weeks after enrollment for adherence evaluation.


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The primary outcome of this study was treatment response at the 3- or 6-month follow-up, defined as a 4-fold or greater decrease in RPR titer from baseline. It was noted that the primary analysis for this outcome was performed on the PP population, and another sensitivity analysis was done on the ITT population.

The investigators found that the primary outcome was achieved in 14 of 15 (93%) participants in the penicillin group (95% CI, 81-100) and 13 of 15 (87%) participants in the cefixime group (95% CI, 69-100). In the ITT sensitivity analysis, the primary outcome was achieved in 25 of 31 (81%) participants in the penicillin group (95% CI, 67-95) and 15 of 27 (56%) participants in the cefixime group (95% CI, 37-74). Three participants had no response to their respective intervention: 2 in the cefixime group and 1 in the penicillin group.

Only 1 adverse event was observed in a patient in the cefixime group who developed a mild skin rash within 4 hours of drug administration that resolved after discontinuation of the trial drug without additional treatment.

Limitations of this pilot study included the study design not being powered to observe differences between treatment groups and the limited study size, which reduced the precision of efficacy estimates.

According to the results of the PP analysis, cefixime therapy is a promising alternative treatment for HIV patients who are less responsive to standard therapy for new incident syphilis. “Larger randomized controlled studies are important next steps towards evaluating the effectiveness of cefixime,” the study authors concluded.

Reference Stafylis C, Keith K, Mehta S, et al. Clinical efficacy of cefixime for the treatment of early syphilis. Clin Infect Dis. Published online February 26, 2021. doi:10.1093