Department of Pulmonary Immunology, University of Texas Health Science Center, Tyler, Texas, USA.
Department of Immunology, UT Southwestern Medical Center, Dallas, Texas, USA.
Antimicrob Agents Chemother. 2022 Apr 19;66(4):e0232021. doi: 10.1128/aac.02320-21. Epub 2022 Mar 22.
There is limited high-quality evidence to guide the optimal treatment of Mycobacterium kansasii pulmonary disease. We retrospectively collected clinical data from 33 patients with M. kansasii pulmonary disease to determine the time-to-sputum culture conversion (SCC) upon treatment with a standard combination regimen consist of isoniazid-rifampin-ethambutol. Next, MIC experiments with 20 clinical isolates were performed, followed by a dose-response study with the standard laboratory strain using the hollow-fiber system model of M. kansasii infection (HFS-). The inhibitory sigmoid maximum effect () model was used to describe the relationship between the bacterial burden and rifampin concentrations. Finally, clinical trial simulations were performed to determine the clinical dose to achieve the optimal rifampin exposure in patients. The SCC rate in patients treated with combination regimen containing rifampin at 10 mg/kg of body weight/day was 73%, the mean time to SSC was 108 days, and the mean duration of therapy was 382 days. The MIC of the M. kansasii laboratory strain was 0.125 mg/L, whereas the MICs of the clinical isolates ranged between 0.5 and 4 mg/L. In the HFS- model, a maximum kill () of 7.82 log CFU/mL was recorded on study day 21. The effective concentration mediating 80% of the (EC) was calculated as the ratio of the maximum concentration of drug in serum for the free, unbound fraction () to MIC of 34.22. The target attainment probability of the standard 10-mg/kg/day dose fell below 90% even at the MIC of 0.0625 mg/L. Despite the initial kill, there was M. kansasii regrowth with the standard rifampin dose in the HFS- model. Doses higher than 10 mg/kg/day, in combination with other drugs, need to be evaluated for better treatment outcome.
针对堪萨斯分枝杆菌肺病的最佳治疗方法，目前仅有有限的高质量证据可以指导。我们回顾性地收集了 33 例堪萨斯分枝杆菌肺病患者的临床数据，以确定标准联合方案（包括异烟肼-利福平-乙胺丁醇）治疗后痰培养转换（SCC）的时间。接着，我们进行了 20 株临床分离株的 MIC 实验，然后使用堪萨斯分枝杆菌感染的中空纤维系统模型（HFS-）对标准实验室菌株进行了剂量反应研究。采用细菌负荷与利福平浓度的抑制型最大效应（）模型来描述两者之间的关系。最后，我们进行了临床试验模拟，以确定实现患者最佳利福平暴露的临床剂量。每天给予 10mg/kg 体重的利福平的联合方案治疗患者的 SCC 率为 73%，SCC 平均时间为 108 天，平均治疗时间为 382 天。堪萨斯分枝杆菌实验室菌株的 MIC 为 0.125mg/L，而临床分离株的 MIC 范围在 0.5 至 4mg/L 之间。在 HFS-模型中，第 21 天记录到 7.82log CFU/mL 的最大杀伤（）。EC 被计算为游离未结合部分的药物血清最大浓度（）与 MIC 的比值，为 34.22。即使在 MIC 为 0.0625mg/L 时，标准 10mg/kg/天剂量的达标概率也低于 90%。尽管初始杀菌效果显著，但在 HFS-模型中，使用标准利福平剂量仍会出现堪萨斯分枝杆菌的再次生长。需要评估高于 10mg/kg/天的剂量，与其他药物联合使用，以获得更好的治疗效果。
