Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Infectious Diseases Unit, Department of Internal Medicine, University of Groningen, Groningen, The Netherlands.
Antimicrob Agents Chemother. 2019 Jan 29;63(2). doi: 10.1128/AAC.01478-18. Print 2019 Feb.
Buruli ulcer (BU), caused by , is a neglected tropical skin and soft tissue infection that is associated with disability and social stigma. The mainstay of BU treatment is an 8-week course of rifampin (RIF) at 10 mg/kg of body weight and 150 mg/kg streptomycin (STR). Recently, the injectable STR has been shown to be replaceable with oral clarithromycin (CLR) for smaller lesions for the last 4 weeks of treatment. A shorter, all-oral, highly efficient regimen for BU is needed, as the long treatment duration and indirect costs currently burden patients and health systems. Increasing the dose of RIF or replacing it with the more potent rifamycin drug rifapentine (RPT) could provide such a regimen. Here, we performed a dose-ranging experiment of RIF and RPT in combination with CLR over 4 weeks of treatment in a mouse model of disease. A clear dose-dependent effect of RIF on both clinical and microbiological outcomes was found, with no ceiling effect observed with tested doses up to 40 mg/kg. RPT-containing regimens were more effective on All RPT-containing regimens achieved culture negativity after only 4 weeks, while only the regimen with the highest RIF dose (40 mg/kg) did so. We conclude that there is dose-dependent efficacy of both RIF and RPT and that a ceiling effect is not reached with the current standard regimen used in the clinic. A regimen based on higher rifamycin doses than are currently being evaluated against tuberculosis in clinical trials could shorten and improve therapy of Buruli ulcer.
布鲁里溃疡（BU）由 引起，是一种被忽视的热带皮肤和软组织感染，可导致残疾和社会耻辱。BU 治疗的主要方法是 8 周疗程的利福平（RIF），剂量为 10mg/kg 体重和 150mg/kg 链霉素（STR）。最近，研究表明，对于治疗的最后 4 周，较小的病变可以用口服克拉霉素（CLR）替代注射用 STR。需要一种更短、全口服、高效的 BU 治疗方案，因为目前较长的治疗时间和间接费用给患者和卫生系统带来了负担。增加 RIF 剂量或用更有效的利福霉素药物利福喷汀（RPT）替代它可以提供这样的方案。在这里，我们在 疾病的小鼠模型中进行了为期 4 周的 RIF 和 RPT 与 CLR 联合治疗的剂量范围实验。结果发现 RIF 对临床和微生物学结果均有明显的剂量依赖性效应，在测试剂量高达 40mg/kg 时未观察到上限效应。含 RPT 的方案在所有含 RPT 的方案在仅 4 周后均实现了培养阴性，而只有最高 RIF 剂量（40mg/kg）的方案如此。我们得出结论，RIF 和 RPT 均有剂量依赖性疗效，目前在临床上使用的标准方案并未达到上限。基于比目前在临床试验中用于结核病的更高利福霉素剂量的方案可能会缩短和改善布鲁里溃疡的治疗。
