Since the discovery and commercialization of penicillin in 1940’s, syphilis is efficiently treatable at all stages. Despite access to testing centers, large safety campaigns and prevention tools against STIs, the WHO estimates 8 million adults acquired syphilis in 2022. One probable cause is the successive global shortages of penicillin, a consequence of supply and demand imbalances, explaining by the upsurge opposed to fewer active pharmaceutical ingredient manufacturers. Two different forms of penicillin are used for treating syphilis depending on the status of the patient and the stage of the disease: benzyl penicillin (BP) or penicillin G, an aqueous solution for intravenous injection; and the long- acting salt option benzathine BP for intramuscular route uniquely. The latter, which is the first line recommended treatment, is the most affected by the stock-outs: during 2014–2016, over 40 countries worldwide globally reported shortages in benzathine BP. The case of congenital syphilis is then crucial in a such situation. Here, we evaluate the management of the syphilis treatment in the University Hospitals of Geneva to elaborate a standard operating procedure (SOP) of penicillin uses. It will be useful to 1) mitigate strategies for potential future storages and to 2) avoid the use of inappropriate treatments leading to serious therapeutic failures. In this way, we monitor regional stock levels, the quantity of active authorized suppliers, the number and type of centers authorized to deliver. Even if Treponema pallidum resistance to penicillin has never been reported, we can notice increasing levels of general genotypic resistance thanks to recent large genomic sequencing, and clinical treatment failure to macrolides such as azithromycin (99.2 % of resistance in the USA). Nevertheless, latest in vitro studies highlighted various antibiotic classes would be potential candidates for expanding the current therapeutic repertoire for syphilis. A such SOP will be transposable to next anti-syphilis antibiotics.