Avery Lindsay M, Edwards Mitchell, Yi Fan, Moeck Greg, Uehara Tsuyoshi, Pevear Daniel C
Department of Biology, Venatorx Pharmaceuticals, Inc., Malvern, Pennsylvania, USA.
Antimicrob Agents Chemother. 2025 Sep 3;69(9):e0001725. doi: 10.1128/aac.00017-25. Epub 2025 Jul 31.
Taniborbactam is a novel cyclic boronate β-lactamase inhibitor that potentiates the activity of cefepime against Enterobacterales and strains harboring serine and metallo-β-lactamases. Taniborbactam lacks intrinsic antibacterial activity. An hollow fiber infection model (HFIM) was used to evaluate bacterial kill and the potential for treatment-emergent resistance associated with the clinical cefepime-taniborbactam dose of 2-0.5 g every 8 h, administered as a 2 h infusion, for 7 days. Nine cefepime-resistant bacterial strains were studied among one , five , and three that harbored a variety of cephalosporinases, extended-spectrum β-lactamases, and carbapenemases with cefepime-taniborbactam MIC values that ranged from 0.25 to 8 µg/mL. All nine strains grew rapidly when treated with cefepime alone, consistent with phenotypic resistance. Human plasma concentration-time profiles for cefepime and taniborbactam were simulated in the HFIM systems and resulted in bactericidal activity (≥3 log CFU/mL reduction) against eight of nine strains when assessed 8 h after initiation of the first dose, and against all nine strains by day 7. Treatment-emergent resistance, defined as bacterial subpopulations with ≥4 times the baseline MIC, was not detected in any cefepime-taniborbactam model from days 1 to 7. Therefore, human cefepime-taniborbactam exposures demonstrated sustained bactericidal activity and suppressed the emergence of resistance in a 7-day HFIM among serine and metallo-β-lactamase-positive Enterobacterales and strains. These observations support the clinical development of cefepime-taniborbactam and inform understanding of its potential role in treating serine and/or metallo-β-lactamase-positive Gram-negative bacterial infections.
他尼硼巴坦是一种新型环状硼酸酯β-内酰胺酶抑制剂，可增强头孢吡肟对肠杆菌科细菌以及携带丝氨酸和金属β-内酰胺酶菌株的活性。他尼硼巴坦缺乏内在抗菌活性。采用中空纤维感染模型（HFIM）评估每8小时给予2 - 0.5 g临床剂量头孢吡肟 - 他尼硼巴坦（以2小时输注方式给药，持续7天）的细菌杀灭效果以及治疗中出现耐药性的可能性。研究了9株头孢吡肟耐药菌株，其中1株阴沟肠杆菌、5株肺炎克雷伯菌和3株鲍曼不动杆菌，这些菌株携带多种头孢菌素酶、超广谱β-内酰胺酶和碳青霉烯酶，头孢吡肟 - 他尼硼巴坦的最低抑菌浓度（MIC）值范围为0.25至8 μg/mL。单独用头孢吡肟治疗时，所有9株菌株均快速生长，符合表型耐药特征。在HFIM系统中模拟了头孢吡肟和他尼硼巴坦的人血浆浓度 - 时间曲线，结果显示在首剂给药8小时后评估时，对9株菌株中的8株具有杀菌活性（≥3 log CFU/mL降低），到第7天时对所有9株菌株均有杀菌活性。在第1天至第7天的任何头孢吡肟 - 他尼硼巴坦模型中均未检测到治疗中出现的耐药性，即细菌亚群的MIC比基线高≥4倍。因此，人头孢吡肟 - 他尼硼巴坦暴露在7天的HFIM中显示出持续的杀菌活性，并抑制了丝氨酸和金属β-内酰胺酶阳性肠杆菌科细菌及鲍曼不动杆菌菌株中耐药性的出现。这些观察结果支持头孢吡肟 - 他尼硼巴坦的临床开发，并有助于了解其在治疗丝氨酸和/或金属β-内酰胺酶阳性革兰氏阴性菌感染中的潜在作用。
