Repurposing antibiotics to treat syphilis
Authors: Chrysovalantis Stafylis, Jeffrey D Klausner
Journal: The Lancet Infectious Diseases (2024)

In The Lancet Infectious Diseases, Maria Ubals and colleagues1Ubals M Nadal-Baron P Arando M et al.Oral linezolid compared with benzathine penicillin G for treatment of early syphilis in adults (Trep-AB Study) in Spain: a prospective, open-label, non-inferiority, randomised controlled trial.Lancet Infect Dis. 2024; (published online Jan 8.)https://doi.org/10.1016/S1473-3099(23)00683-7Summary Full Text Full Text PDF Scopus (2) Google Scholar showed that linezolid 600 mg, taken orally once per day for 5 days was not effective in treating syphilis. Syphilis, a sexually transmitted disease caused by the bacterium Treponema pallidum subspecies pallidum, is a growing public health problem globally.2Peeling RW Mabey D Chen XS Garcia PJ Syphilis.Lancet. 2023; 402: 336-346Summary Full Text Full Text PDF PubMed Scopus (16) Google Scholar According to WHO, there were 7·1 million new cases worldwide among adults in 2020. The prevalence of congenital syphilis is also rising (425 cases per 100 000 live births) making the WHO's goal of elimination increasingly unattainable.3Moseley P Bamford A Eisen S et al.Resurgence of congenital syphilis: new strategies against an old foe.Lancet Infect Dis. 2023; (published online Aug 8.)https://doi.org/10.1016/S1473-3099(23)00314-6Summary Full Text Full Text PDF PubMed Scopus (6) Google Scholar Syphilis can cause serious medical complications and increases the risk of acquiring and transmitting HIV infection by two to five times.4Fleming DT Wasserheit JN From epidemiological synergy to public health policy and practice: the contribution of other sexually transmitted diseases to sexual transmission of HIV infection.Sex Transm Infect. 1999; 75: 3-17Crossref PubMed Scopus (1869) Google Scholar The current recommendation for the treatment of all early stages of syphilis by both WHO and the US Centers for Disease Control and Prevention (CDC) is injectable benzathine penicillin G (BPG) administered intramuscularly as a single dose of 2·4 million units.5US Centers for Disease Control and PreventionSexually transmitted infections treatment guidelines, 2021. US Centers for Disease Control and Prevention, Atlanta2021Google Scholar More importantly, penicillin is the only recommended treatment for pregnant women, and if given to an infected mother early in pregnancy, prevents mother-to-child transmission. Current shortages of benzathine penicillin are a public health crisis and underline the urgency for identifying alternative treatment options.6Nurse-Findlay S Taylor MM Savage M et al.Shortages of benzathine penicillin for prevention of mother-to-child transmission of syphilis: an evaluation from multi-country surveys and stakeholder interviews.PLoS Med. 2017; 141002473 Crossref PubMed Scopus (109) Google Scholar Some alternative treatments to penicillin exist, but unfortunately each has limitations.5US Centers for Disease Control and PreventionSexually transmitted infections treatment guidelines, 2021. US Centers for Disease Control and Prevention, Atlanta2021Google Scholar Oral doxycycline administered twice per day for 14 days is the CDC-recommended alternative when penicillin is contraindicated or unavailable, but it is not recommended during pregnancy and in young children. Oral azithromycin has been proven effective in treating early syphilis, but resistance has limited its use. Ceftriaxone, a third-generation cephalosporin, requires daily intramuscular or intravenous injections for 10–14 days, making this regimen inconvenient and impractical in most clinical settings. In pregnancy, because there are limited data concerning the efficacy and safety of those alternative regimens, pregnant women with penicillin allergy must undergo penicillin desensitisation. Ubals and colleagues did a multicentre, prospective, open-label, non-inferiority, randomised controlled trial to assess the efficacy of linezolid in primary, secondary, and early syphilis. This was the first human study evaluating linezolid for the treatment of syphilis. The investigational treatment regimen was oral linezolid 600 mg, once per day for 5 days. Linezolid was compared to one intramuscular injection of 2·4 million units BPG. Among the 59 analysed participants randomly assigned to linezolid (n=29) or BPG (n=30), the treatment success rate 48 weeks after treatment was substantially worse, with 19 (70%) of 27 participants (95% CI 49·8 to 86·2) in the linezolid group compared with 28 (100%) of 28 participants (87·7 to 100·0) in the BPG group. The authors used a composite measure of clinical, serological, and microbiological criteria to ensure accurate classification of the primary outcome. They were also able to differentiate between cases of linezolid failure and reinfection through T pallidum genomic analysis. The trial was halted early because of the 30% difference between the linezolid and the BPG group. As a safety precaution, the study team will follow up participants treated with linezolid up to 24 months after enrolment to ensure adequate treatment and absence of recurrence of infection. Despite the negative outcome, there are some important points that need to be made. Linezolid has been shown to be effective against T pallidum both in vitro and in in-vivo studies in rabbits using an equivalent duration and dosage.7Haynes AM Giacani L Mayans MV et al.Efficacy of linezolid on Treponema pallidum, the syphilis agent: a preclinical study.EBioMed. 2021; 65103281 Summary Full Text Full Text PDF PubMed Scopus (15) Google Scholar Despite those encouraging preclinical results, in the Ubal trial1Ubals M Nadal-Baron P Arando M et al.Oral linezolid compared with benzathine penicillin G for treatment of early syphilis in adults (Trep-AB Study) in Spain: a prospective, open-label, non-inferiority, randomised controlled trial.Lancet Infect Dis. 2024; (published online Jan 8.)https://doi.org/10.1016/S1473-3099(23)00683-7Summary Full Text Full Text PDF Scopus (2) Google Scholar only 70% of study participants were successfully treated. Considering that T pallidum is a slow-growing bacterium that spreads systematically, a longer duration of treatment and more frequent dosing is probably necessary, as pharmacokinetic simulations show. Additionally, in the animal study,7Haynes AM Giacani L Mayans MV et al.Efficacy of linezolid on Treponema pallidum, the syphilis agent: a preclinical study.EBioMed. 2021; 65103281 Summary Full Text Full Text PDF PubMed Scopus (15) Google Scholar only a single strain (SS14) was used to evaluate the efficacy of the linezolid, but in the trial only 12 of 28 isolated clinical strains belonged to the SS14 clade. More research is needed to evaluate linezolid at higher doses for longer duration and in additional strains of T pallidum. The negative trial result should not discourage researchers, public health authorities, or regulatory authorities from continuing to undertake and support studies to repurpose older, widely available antibiotics for syphilis. This could be a fast, low-cost strategy, leveraging the known clinical profile and safety of antibiotics in use, thus simplifying regulatory approval and clinical adoption. Minocycline8Wu H Qi M Wang H Liu Q Liu Y Efficacy of minocycline in the treatment of early syphilis.Int J STD AIDS. 2021; 32: 648-653Crossref PubMed Scopus (4) Google Scholar and amoxicillin in combination with probenecid9Ando N Mizushima D Omata K et al.Combination of amoxicillin 3000 mg and probenecid versus 1500 mg amoxicillin monotherapy for treating syphilis in patients with human immunodeficiency virus: an open-label, randomized, controlled, non-inferiority trial.Clin Infect Dis. 2023; 77: 779-787Crossref PubMed Scopus (6) Google Scholar have shown efficacy against syphilis. Presently, three additional treatment regimens (oral cefixime for 10 days, combination of ceftriaxone and doxycycline, and oral linezolid for 10 days) are under evaluation. Identifying safer and alternative treatment options for syphilis must continue to be a high priority. We declare no competing interests. Oral linezolid compared with benzathine penicillin G for treatment of early syphilis in adults (Trep-AB Study) in Spain: a prospective, open-label, non-inferiority, randomised controlled trialThe efficacy of linezolid at a daily dose of 600 mg for 5 days did not meet the non-inferiority criteria compared with BPG and, as a result, this treatment regimen should not be used to treat patients with early syphilis. Full-Text PDF Open Access