Department of Pulmonary Immunology, University of Texas Health Science Centre at Tyler, Tyler, Texas, USA.
Quantitative Preclinical & Clinical Sciences Department, Praedicare Inc., Dallas, Texas, USA.
Antimicrob Agents Chemother. 2022 Sep 20;66(9):e0068722. doi: 10.1128/aac.00687-22. Epub 2022 Aug 17.
The 12-month therapy duration for the treatment of Mycobacterium kansasii pulmonary disease calls for more efficacious drugs for better treatment outcomes and to shorten the therapy duration. We performed (i) omadacycline MIC with M. kansasii ATCC 12478 strain and 21 clinical isolates, (ii) dose-response study in the hollow fiber system model of M. kansasii (HFS-) with six human equivalent omadacycline daily doses to determine the optimal drug exposure for the maximal kill, and (iii) a second HFS- study to determine the efficacy of omadacycline (300 mg/day) plus moxifloxacin (600 mg/day) plus tedizolid (200 mg/day) combination regimen with standard regimen as comparator. GraphPad Prism was used for data analysis and graphing. MIC of the reference strain was 4 mg/L but ranged from 8 to 32 mg/L among the 21 clinical isolates. In the HFS-, the exposure required for 50% of the maximal effect (EC) was an omadacycline area under the concentration-time curve to MIC (AUC/MIC) ratio of 1.95. The optimal exposure was an AUC/MIC of 3.05, which could be achieved with 300 mg/day clinical dose. The omadacycline-moxifloxacin-tedizolid combination sterilized the HFS- in 14 days with a linear-regression based kill rate of -0.309 ± 0.044 log CFU/mL/day compared to the kill rate of -0.084 ± 0.036log CFU/mL/day with the standard regimen or 3.7-times faster. Omadacycline has efficacy against M. kansasii and could be used at 300 mg/day in combination with moxifloxacin and tedizolid for the treatment of M. kansasii pulmonary diseases with the potential to shorten the currently recommended 12-month therapy duration.
本研究旨在寻找更有效的药物来改善治疗效果并缩短治疗时间，因此开展了为期 12 个月的堪萨斯分枝杆菌肺病治疗。我们进行了以下研究：（i）使用 omadacycline 对堪萨斯分枝杆菌 ATCC 12478 株及 21 株临床分离株进行 MIC 检测；（ii）在堪萨斯分枝杆菌中空纤维系统模型（HFS-）中进行剂量反应研究，采用 6 种人类等效 omadacycline 每日剂量，以确定最大杀菌效果的最佳药物暴露水平；（iii）在第二个 HFS- 研究中，评估 omadacycline（300mg/天）+莫西沙星（600mg/天）+替加环素（200mg/天）联合方案与标准方案的疗效。GraphPad Prism 用于数据分析和绘图。参考菌株的 MIC 为 4mg/L，但 21 株临床分离株的 MIC 范围为 8-32mg/L。在 HFS- 中，达到最大效应的 50%（EC）所需的暴露量为 omadacycline 浓度时间曲线下面积与 MIC（AUC/MIC）比值为 1.95。最佳暴露量为 AUC/MIC 为 3.05，这可以通过 300mg/天的临床剂量实现。与标准方案（-0.084±0.036log CFU/mL/天）相比，omadacycline-莫西沙星-替加环素联合方案在 14 天内即可使 HFS-达到灭菌效果，基于线性回归的杀菌率为-0.309±0.044log CFU/mL/天，杀菌速度快 3.7 倍。Omadacycline 对堪萨斯分枝杆菌有效，可与莫西沙星和替加环素联合使用，以 300mg/天的剂量用于治疗堪萨斯分枝杆菌肺病，有潜力缩短目前推荐的 12 个月治疗时间。
