Abstract:
Recently, several β-lactam (BL)/β-lactamase inhibitor (BLI) combinations have entered clinical testing or have been marketed for use, but limited direct comparative studies of their in vitro activity exist. Xeruborbactam (XER, also known as QPX7728), which is undergoing clinical development, is a cyclic boronate BLI with potent inhibitory activity against serine (serine β-lactamase) and metallo-β-lactamases (MBLs). The objectives of this study were (i) to compare the potency and spectrum of β-lactamase inhibition by various BLIs in biochemical assays using purified β-lactamases and in microbiological assays using the panel of laboratory strains expressing diverse serine and metallo-β-lactamases and (ii) to compare the in vitro potency of XER in combination with multiple β-lactam antibiotics to that of other BL/BLI combinations in head-to-head testing against recent isolates of carbapenem-resistant Enterobacterales (CRE). Minimal inhibitory concentrations (MICs) of XER combinations were tested with XER at fixed 4 or 8 µg/mL, and MIC testing was conducted in a blinded fashion using Clinical and Laboratory Standards Institute reference methods. Xeruborbactam and taniborbactam (TAN) were the only BLIs that inhibited clinically important MBLs. The spectrum of activity of xeruborbactam included several MBLs identified in Enterobacterales, e.g., and various IMP enzymes and NDM-9 that were not inhibited by taniborbactam. Xeruborbactam potency against the majority of purified β-lactamases was the highest in comparison with other BLIs. Meropenem-xeruborbactam (MEM-XER, fixed 8 µg/mL) was the most potent combination against MBL-negative CRE with MIC90 values of 0.125 µg/mL. MEM-XER and cefepime-taniborbactam (FEP-TAN) were the only BL/BLIs with activity against MBL-producing CREs; with MEM-XER (MIC90 of 1 µg/mL) being at least 16-fold more potent than FEP-TAN (MIC90 of 16 µg/mL). MEM-XER MIC values were ≤8 µg/mL for >90% of CRE, including both MBL-negative and MBL-positive isolates, with FEP-TAN MIC of >8 µg/mL. Xeruborbactam also significantly enhanced potency of other β-lactam antibiotics, including cefepime, ceftolozane, ceftriaxone, aztreonam, piperacillin, and ertapenem, against clinical isolates of Enterobacterales that carried various class A, class C, and class D extended-spectrum β-lactamases and carbapenem-resistant Enterobacterales, including metallo-β-lactamase-producing isolates. These results strongly support further clinical development of xeruborbactam combinations.
摘要:
最近,几种β-内酰胺(BL)/β-内酰胺酶抑制剂(BLI)组合已进入临床试验或已上市使用,但对其体外活性的直接比较研究有限。Xeruborbactam(XER,也称为QPX7728),正在进行临床开发,是对丝氨酸(丝氨酸β-内酰胺酶)和金属β-内酰胺酶(MBL)具有有效抑制活性的环状硼酸BLI。这项研究的目的是(i)在使用纯化的β-内酰胺酶的生化测定中,以及在使用表达多种丝氨酸和金属的实验室菌株组的微生物学测定中,比较各种BLI对β-内酰胺酶的抑制作用和谱-β-内酰胺酶和(ii)比较XER与多种β-内酰胺抗生素组合的体外效力,与其他BL/BLI组合的体外效力在耐肠杆菌头对肠原酶XER组合的最小抑制浓度(MIC)用固定的4或8µg/mL的XER测试,使用临床和实验室标准协会参考方法以盲法进行MIC测试。Xeruborbaptam和taniborbaptam(TAN)是唯一抑制临床上重要的MBL的BLI。沙鲁巴坦的活性谱包括在肠杆菌中鉴定的几种MBL,例如,和各种IMP酶和NDM-9未被坦尼博巴坦抑制。与其他BLI相比,克鲁巴坦对大多数纯化的β-内酰胺酶的效力最高。美罗培南-克鲁巴坦(MEM-XER,固定8µg/mL)是针对MBL阴性CRE的最有效组合,MIC90值为0.125µg/mL。MEM-XER和头孢吡肟-坦尼博巴坦(FEP-TAN)是唯一具有抗产MBL的CRE活性的BL/BLIs;MEM-XER(MIC90为1µg/mL)比FEP-TAN(MIC90为16µg/mL)至少高16倍。对于>90%的CRE,MEM-XERMIC值≤8µg/mL,包括MBL阴性和MBL阳性分离株,FEP-TANMIC>8µg/mL。Xeruborbactam还显着增强了其他β-内酰胺抗生素的效力,包括头孢吡肟,头孢洛赞,头孢曲松,氨曲南,哌拉西林,和厄他培南,针对携带各种A类的肠杆菌的临床分离株,C类,和D类超广谱β-内酰胺酶和耐碳青霉烯类肠杆菌,包括产生金属-β-内酰胺酶的分离株。这些结果有力地支持了沙鲁伯巴坦组合的进一步临床开发。