Syphilis, caused by the bacterium Treponema pallidum subsp. pallidum (TPA), re-emerged as a global health problem in the twenty-first century, with a drastic increase in syphilis diagnoses reported in the past 20 years. Injection with the long-acting benzathine penicillin G is the gold-standard treatment for syphilis, but the increased number of patients combined with a limited supply chain capacity led to a global benzathine penicillin shortage. Thus, alternative therapies and vaccine development are absolute priorities in the field and have been discussed in two studies published in The New England Journal of Medicine and The Journal of Infection Diseases, respectively.

The first article is a correspondence in which the authors evaluated the current prevalence of azithromycin resistance to assess whether this macrolide antibiotic (which current Centers for Disease Control and Prevention and Canadian guidelines suggest not to use) could be included in the discussion about alternative syphilis therapies in the context of benzathine penicillin shortage. A total of 604 TPA strains were sampled between 2017 and 2023 across 13 US states, Washington DC and two Canadian states, and azithromycin resistance was assessed through the presence of A2058G or A2059G mutations in the 23S ribosomal RNA subunit gene, which both confer resistance to azithromycin. Overall, 99.2% of sampled strains (599 of 604) were genotypically resistant to azithromycin, with 584 (97.5%) and 15 (2.5%) strains carrying the A2058G and the A2059G mutations, respectively. Azithromycin resistance also drastically increased (99.3%) in women and in men who have sex with women, who historically experienced low resistance (14%, according to data obtained between 2007 and 2009). Patients in this study were shown to be representative of patients with syphilis in North America. Overall, the authors concluded that these data do not support the use of azithromycin, and clinicians should consider alternative solutions (doxycycline or ceftriaxone) in non-pregnant patients in the context of benzathine penicillin G shortage.