Jo Jinhee, Carlson Travis J, Hu Chenlin, Williamson John C, Belin Yolanda T, Horvath Thomas D, Haidacher Sigmund J, Bassères Eugénie, Begum Khurshida, Alam M Jahangir, Garey Kevin W
Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX, USA.
Division of Pharmacotherapy and Translational Sciences, The University of Texas at Austin College of Pharmacy, San Antonio, TX, USA.
J Antimicrob Chemother. 2025 Aug 12. doi: 10.1093/jac/dkaf278.
There is an urgent need to develop new antimicrobials effective intravenously for Clostridioides difficile infection (CDI). Omadacycline is an aminomethylcycline tetracycline available orally and intravenously with potent in vitro activity against C. difficile and a low propensity to cause CDI. The purpose of this study was to assess the safety, faecal pharmacokinetics, microbiome and bile acid changes in healthy subjects given a course of intravenous omadacycline with oral omadacycline step down after 5 days.
This Phase 1, open-label study was conducted in healthy volunteers 18-40 years. Subjects received a 5-day course of omadacycline given intravenously followed by 5 days of oral omadacycline. Stool samples were analysed for omadacycline concentrations, gut microbiome changes and bile acid changes from baseline.
Eight healthy volunteers aged 30 ± 4 years (50% Female) were recruited and all completed therapy. All subjects had detectable omadacycline stool concentrations after 48 hours of intravenous dosing and averaged 195 ± 97 µg/g (mean ± SD) by day 5. Omadacycline concentrations increased rapidly after the start of oral therapy on day 6 with average concentrations of 854 ± 404 µg/g of stool by day 10. Microbiome and bile acid evaluations showed preservation of key microbiome taxa that confer health benefit and preservation of bile acid homeostasis.
Intravenous omadacycline followed by oral step-down administration in healthy adults achieved high faecal concentrations while preserving key bacterial species and bile acid homeostasis in the gut. These findings support Phase 2 studies directed towards the development of omadacycline as a CDI-targeted antibiotic.
迫切需要开发对艰难梭菌感染（CDI）有效的新型静脉用抗菌药物。奥马环素是一种氨基甲基环素类四环素，有口服和静脉注射剂型，对艰难梭菌具有强大的体外活性，且引起CDI的可能性较低。本研究的目的是评估健康受试者接受5天静脉注射奥马环素后改为口服奥马环素逐步减量治疗过程中的安全性、粪便药代动力学、微生物组和胆汁酸变化。
这项1期开放标签研究在18至40岁的健康志愿者中进行。受试者接受为期5天的静脉注射奥马环素治疗，随后5天口服奥马环素。分析粪便样本中奥马环素浓度、肠道微生物组变化以及与基线相比的胆汁酸变化。
招募了8名年龄为30±4岁（50%为女性）的健康志愿者，所有受试者均完成治疗。静脉给药48小时后，所有受试者的粪便中均可检测到奥马环素浓度，到第5天平均浓度为195±97μg/g（均值±标准差）。第6天开始口服治疗后，奥马环素浓度迅速升高，到第10天粪便平均浓度为854±404μg/g。微生物组和胆汁酸评估显示，对健康有益的关键微生物类群得以保留，胆汁酸稳态也得以维持。
健康成年人先静脉注射奥马环素，然后改为口服逐步减量给药，可在肠道中达到较高的粪便浓度，同时保留关键细菌种类和胆汁酸稳态。这些发现支持开展2期研究，以开发奥马环素作为一种针对CDI的抗生素。
