Amoxicillin Treatment for Syphilis: Can an Old Drug Learn a New Trick?


With an increased incidence of this sexually transmitted infection, a review of an older antibiotic for treatment has shown some clinical benefits in other countries.

The CDC reports that syphilis cases have increased among males and females, in all regions of the United States, and in all age groups, including congenital syphilis. In 2021, there were 176,713 cases, representing a 28.6% increase from 2020.1

Intramuscular benzathine penicillin G (BPG) is widely recommended2-3 as the first-line treatment for primary, secondary, latent and tertiary syphilis without CNS involvement, with reported success rates of 90-100%.4 Although not mentioned by the World Health Organization (WHO) and CDC guidelines, oral amoxicillin is included in the Japanese and United Kingdom guidelines. For early syphilis, amoxicillin 500 mg three times daily is a first-line option in the Japanese guidelines5, whereas amoxicillin 500 mg four times daily plus probenecid 500 mg four times daily is an alternative in the United Kingdom guidelines.6

Ando et al conducted an open-label, randomized controlled trial to assess the non-inferiority of two amoxicillin-based regimens for the syphilis treatment at a single center in Japan. Patients with HIV, age ≥20 years, and diagnosed with syphilis by positive Treponema pallidum hemagglutination (TPHA) and a positive rapid plasma regain (RPR) test were included. Positive RPR titers were defined as the following: an RPR titer greater than 8, an RPR titer equal to 8 with clinical symptoms compatible of primary or secondary syphilis, or at least a 4-fold rise in RPR titer. Pregnant and lactating individuals and patients with neurosyphilis were excluded from the study.

Patients were randomized 1:1 to receive amoxicillin 500 mg three times daily (Japanese guideline dosage) or amoxicillin 1000 mg plus probenecid 250 mg three times daily. In both groups, patients with early syphilis received a 14-day course while patients with late syphilis received a 28-day course. Follow up visits were conducted at 3,6,9 and 12 months after treatment. The primary outcome was serological cure rate at 12 months, defined as a four-fold decrease or negative conversion in RPR titer by the conventional test, using per protocol analysis. The non-inferiority margin was 10%. Self-reported medication adherence and adverse effects including nausea, diarrhea, vomiting, drug allergy, Jarisch-Herxheimer reactions were assessed at the second visit.

Between August 2018 and February 2022, a total of 112 patients were enrolled. All study participants identified as male, the median age was 39, and 97% of participants were Asian. The majority of patients took antiretroviral therapy (91%) and had HIV viral load <200 copies/mL (84.8%). The median RPR titer at diagnosis was 64 (IQR 32-128) and the majority of patients had early syphilis. Four patients that missed follow up appointments due to COVID-19 stay-at-home orders were excluded from analysis at the applicable timepoints. Amoxicillin monotherapy did not demonstrate non-inferiority to amoxicillin/probenecid for serological cure rate at 12 months (Table). Similar trends were confirmed with automated RPR testing. No significant differences between adverse effects or medication adherence were observed; 105 participants (93.8%) reported taking more than 95% of the regimen.

This study describes the effectiveness of amoxicillin-based regimens with similar observed effectiveness to first-line syphilis therapies including BPG and doxycycline. 4.8 As a low-cost oral regimen, amoxicillin with probenecid may provide advantages for select patients. Medication adherence to a multiday amoxicillin regimen is crucial, compared to single-dose or weekly intramuscular BPG administered by a healthcare professional. Alternative treatment options are particularly vital when managing medication shortages and as of April 2023 there is an ongoing shortage of BPG in the United States due to increased demand for the medication. The CDC has issued guidance to prioritize BPG supply for patients with no alternative treatment options: pregnant people with syphilis and babies with congenital syphilis.3

Of note, the probenecid dose used in this study varies from recommendations in the UK guideline and package insert. 6,7 Probenecid inhibits tubular secretion of penicillin and subsequently increases penicillin serum concentration.7 While treponemicidal amoxicillin serum concentrations have been described6, this study did not assess medication concentration levels in participants. Further prospective studies of amoxicillin/probenecid regimens for syphilis treatment in people without HIV and women should be conducted to optimize the dosing regimen and demonstrate safety and effectiveness in a diverse patient population.

Article Citation: Ando, N., Mizushima, D., Omata, K., et al. Combination of Amoxicillin 3,000 mg and Probenecid versus 1,500 mg Amoxicillin Monotherapy for Treating Syphilis in Patients with HIV: an Open-Label, Randomized, Controlled, Non-Inferiority Trial. Clin Infect Dis. 2023 May 9;ciad278. doi: 10.1093/cid/ciad278. Online ahead of print.


  1. Centers for Disease Control and Prevention. (2023, May 16). National Overview of STDs, 2021. Centers for Disease Control and Prevention.
  2. Workowski, K. A., Bachmann, L. H., Chan, P. A., et al. Sexually Transmitted Infections Treatment Guidelines, 2021. MMWR Recomm Rep. 2021 Jul 23;70(4):1-187. doi: 10.15585/mmwr.rr7004a1
  3. Guidelines for the management of symptomatic sexually transmitted infections. (2021). World Health Organization.
  4. Clement ME, Okeke NL, and Hicks CB. Treatment of syphilis: a systematic review. JAMA. 2014 Nov 12;312(18):1905-17. doi: 10.1001/jama.2014.13259.
  5. Japanese Society for Sexually Transmitted Infections. The Japanese STI diagnosis and treatment guidelines [in Japanese]. 2016.
  6. Kingston, M., French, P., Higgins, S., et al. UK national guidelines on the management of syphilis 2015. Int J STD AIDS. 2016 May;27(6):421-46. doi:10.1177/0956462415624059. Epub 2015 Dec 31.
  7. Probenecid [package insert]. Lannett Company Inc; Philadelphia (PA): July 2012
  8. Dai T, Qu R, Liu J, Zhou P, Wang Q. Efficacy of Doxycycline in the Treatment of Syphilis. Antimicrob Agents Chemother. 2016 Dec 27;61(1):e01092-16. doi: 10.1128/AAC.01092-16.

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