The limited armamentarium against drug-resistant Gram-negative bacilli has led to the development of several novel β-lactam–β-lactamase inhibitor combinations (BLBLIs). In this review, we summarize their spectrum of in vitro activities, mechanisms of resistance, and pharmacokinetic-pharmacodynamic (PK-PD) characteristics. A summary of available clinical data is provided per drug. Four approved BLBLIs are discussed in detail. All are options for treating multidrug-resistant (MDR) Enterobacterales and Pseudomonas aeruginosa. Ceftazidime-avibactam is a potential drug for treating Enterobacterales producing extended-spectrum β-lactamase (ESBL), Klebsiella pneumoniae carbapenemase (KPC), AmpC, and some class D β-lactamases (OXA-48) in addition to carbapenem-resistant Pseudomonas aeruginosa. Ceftolozane-tazobactam is a treatment option mainly for carbapenem-resistant P. aeruginosa (non-carbapenemase producing), with some activity against ESBL-producing Enterobacterales. Meropenem-vaborbactam has emerged as treatment option for Enterobacterales producing ESBL, KPC, or AmpC, with similar activity as meropenem against P. aeruginosa. Imipenem-relebactam has documented activity against Enterobacterales producing ESBL, KPC, and AmpC, with the combination having some additional activity against P. aeruginosa relative to imipenem. None of these drugs present in vitro activity against Enterobacterales or P. aeruginosa producing metallo-β-lactamase (MBL) or against carbapenemase-producing Acinetobacter baumannii. Clinical data regarding the use of these drugs to treat MDR bacteria are limited and rely mostly on nonrandomized studies. An overview on eight BLBLIs in development is also provided. These drugs provide various levels of in vitro coverage of carbapenem-resistant Enterobacterales, with several drugs presenting in vitro activity against MBLs (cefepime-zidebactam, aztreonam-avibactam, meropenem-nacubactam, and cefepime-taniborbactam). Among these drugs, some also present in vitro activity against carbapenem-resistant P. aeruginosa (cefepime-zidebactam and cefepime-taniborbactam) and A. baumannii (cefepime-zidebactam and sulbactam-durlobactam).

中文翻译：

---

新的{β}-内酰胺-{β}-内酰胺酶抑制剂组合


针对耐药革兰氏阴性杆菌的有限武器导致了几种新型 β-内酰胺-β-内酰胺酶抑制剂组合 (BLBLI) 的开发。在这篇综述中，我们总结了它们的体外活性谱、耐药机制和药代动力学-药效学 (PK-PD) 特征。每种药物都提供了可用临床数据的摘要。详细讨论了四种已批准的 BLBLI。所有这些都是治疗多重耐药（MDR）肠杆菌和铜绿假单胞菌的选择。头孢他啶-阿维巴坦是一种潜在药物，可用于治疗产生超广谱 β-内酰胺酶 (ESBL)、肺炎克雷伯菌碳青霉烯酶 (KPC)、AmpC 和一些 D 类 β-内酰胺酶 (OXA-48) 的肠杆菌以及耐碳青霉烯类铜绿假单胞菌。头孢洛嗪-他唑巴坦是一种主要治疗耐碳青霉烯类铜绿假单胞菌（不产生碳青霉烯酶）的治疗选择，对产生 ESBL 的肠杆菌有一定活性。美罗培南-vaborbactam 已成为产生 ESBL、KPC 或 AmpC的肠杆菌的治疗选择，其对抗铜绿假单胞菌的活性与美罗培南相似。亚胺培南-瑞莱巴坦已被证明具有对抗产生 ESBL、KPC 和 AmpC的肠杆菌的活性，相对于亚胺培南，该组合具有一些额外的对抗铜绿假单胞菌的活性。这些药物均不具有针对肠杆菌属或丙酸杆菌的体外活性。 产生金属-β-内酰胺酶 (MBL) 的铜绿假单胞菌或对抗产生碳青霉烯酶的鲍曼不动杆菌。有关使用这些药物治疗耐多药细菌的临床数据有限，并且主要依赖于非随机研究。还概述了正在开发的八个 BLBLI。这些药物对碳青霉烯类耐药肠杆菌提供不同水平的体外覆盖，其中几种药物具有针对 MBL 的体外活性（头孢吡肟-齐德巴坦、氨曲南-阿维巴坦、美罗培南-纳库巴坦和头孢吡肟-坦尼硼巴坦）。在这些药物中，有些药物还对耐碳青霉烯类铜绿假单胞菌（头孢吡肟-齐德巴坦和头孢吡肟-坦尼硼巴坦）和鲍曼不动杆菌（头孢吡肟-齐德巴坦和舒巴坦-杜洛巴坦）具有体外活性。