Department of Medicine, School of Medicine, University of Texas at Tyler, Tyler, TX, USA.
Quantitative Preclinical & Clinical Sciences Department, Praedicare Inc., Dallas, TX, USA; Hollow Fiber System & Experimental Therapeutics Laboratories, Praedicare Inc, Dallas, TX, USA.
Int J Antimicrob Agents. 2023 Dec;62(6):106968. doi: 10.1016/j.ijantimicag.2023.106968. Epub 2023 Sep 17.
Meropenem in combination with β-lactamase inhibitors (BLIs) and other drugs was tested to identify alternative treatment regimens for multidrug-resistant tuberculosis (MDR-TB).
The following were performed: (1) MIC experiments; (2) static time-kill studies (STKs) with different BLIs; and (3) a hollow fibre model system of TB (HFS-TB) studies with meropenem-vaborbactam combined with human equivalent daily doses of 20 mg/kg or 35 mg/kg rifampin, or moxifloxacin 400 mg, or linezolid 600 mg vs. bedaquiline-pretonamid-linezolid (BPaL) for MDR-TB. The studies were performed using Mycobacterium tuberculosis (M. tuberculosis) H37Rv and an MDR-TB clinical strain (named M. tuberculosis 16D) that underwent whole genome sequencing. Exponential decline models were used to calculate the kill rate constant (K) of different HFS-TB regimens.
Whole genome sequencing revealed mutations associated with resistance to rifampin, isoniazid, and cephalosporins. The meropenem-vaborbactam MIC of M. tuberculosis was H37Rv 2 mg/L and > 128 mg/L for M. tuberculosis 16D. Relebactam and vaborbactam improved both the potency and efficacy of meropenem in STKs. Meropenem-vaborbactam alone failed to kill M. tuberculosis 16D but killed below day 0 burden when combined with isoniazid and rifampin, with the moxifloxacin combination being the most effective and outranking bedaquiline and pretomanid. In the HFS-TB, meropenem-vaborbactam-moxifloxacin and BPaL had the highest K (log cfu/mL/day) of 0.31 (95% CI 0.17-0.58) and 0.34 (95% CI 0.21-0.56), while meropenem-vaborbactam-rifampin (35 mg/kg) had a K of 0.18 (95% CI 0.12-0.25). The K for meropenem-vaborbactam-moxifloxacin-linezolid demonstrated antagonism.
Adding meropenem-vaborbactam could potentially restore the efficacy of isoniazid and rifampin against MDR-TB. The meropenem-vaborbactam-moxifloxacin backbone regimen has implications for creating a new effective MDR-TB regimen.
为了寻找治疗耐多药结核病（MDR-TB）的替代方案，对美罗培南联合β-内酰胺酶抑制剂（BLIs）和其他药物进行了测试。
进行了以下实验：（1）微量肉汤稀释法（MIC）实验；（2）不同 BLIs 的静态时间杀伤（STK）研究；（3）使用美罗培南-沃博巴坦联合人体等效日剂量 20mg/kg 或 35mg/kg 利福平、莫西沙星 400mg 或利奈唑胺 600mg 与贝达喹啉-普托马尼-利奈唑胺（BPaL）治疗 MDR-TB 的中空纤维模型系统（HFS-TB）研究。研究使用结核分枝杆菌（M. tuberculosis）H37Rv 和经过全基因组测序的 MDR-TB 临床株（命名为 M. tuberculosis 16D）进行。使用指数衰减模型计算不同 HFS-TB 方案的杀菌率常数（K）。
全基因组测序显示与利福平、异烟肼和头孢菌素耐药相关的突变。M. tuberculosis 的美罗培南-沃博巴坦 MIC 为 H37Rv 2mg/L，M. tuberculosis 16D 为 >128mg/L。雷利巴坦和沃博巴坦提高了美罗培南在 STK 中的效力和疗效。美罗培南-沃博巴坦单独使用不能杀死 M. tuberculosis 16D，但与异烟肼和利福平联合使用时可在第 0 天之前将细菌负荷降低，其中莫西沙星联合用药的效果最为显著，优于贝达喹啉和普托马尼。在 HFS-TB 中，美罗培南-沃博巴坦-莫西沙星和 BPaL 的 K 值（log cfu/mL/天）最高，分别为 0.31（95%CI 0.17-0.58）和 0.34（95%CI 0.21-0.56），而美罗培南-沃博巴坦-利福平（35mg/kg）的 K 值为 0.18（95%CI 0.12-0.25）。美罗培南-沃博巴坦-莫西沙星-利奈唑胺的 K 值表现出拮抗作用。
添加美罗培南-沃博巴坦可能恢复异烟肼和利福平对 MDR-TB 的疗效。美罗培南-沃博巴坦-莫西沙星的骨干方案为创建新的有效 MDR-TB 方案提供了依据。
