New β-Lactam–β-Lactamase Inhibitor Combinations

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 <i>in vitro</i> 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) <i>Enterobacterales</i> and <i>Pseudomonas aeruginosa</i> Ceftazidime-avibactam is a potential drug for treating <i>Enterobacterales</i> producing extended-spectrum β-lactamase (ESBL), <i>Klebsiella pneumoniae</i> carbapenemase (KPC), AmpC, and some class D β-lactamases (OXA-48) in addition to carbapenem-resistant <i>Pseudomonas aeruginosa</i> Ceftolozane-tazobactam is a treatment option mainly for carbapenem-resistant <i>P. aeruginosa</i> (non-carbapenemase producing), with some activity against ESBL-producing <i>Enterobacterales</i> Meropenem-vaborbactam has emerged as treatment option for <i>Enterobacterales</i> producing ESBL, KPC, or AmpC, with similar activity as meropenem against <i>P. aeruginosa</i> Imipenem-relebactam has documented activity against <i>Enterobacterales</i> producing ESBL, KPC, and AmpC, with the combination having some additional activity against <i>P. aeruginosa</i> relative to imipenem. None of these drugs present <i>in vitro</i> activity against <i>Enterobacterales</i> or <i>P. aeruginosa</i> producing metallo-β-lactamase (MBL) or against carbapenemase-producing <i>Acinetobacter baumannii</i> 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 <i>in vitro</i> coverage of carbapenem-resistant <i>Enterobacterales</i>, with several drugs presenting <i>in vitro</i> activity against MBLs (cefepime-zidebactam, aztreonam-avibactam, meropenem-nacubactam, and cefepime-taniborbactam). Among these drugs, some also present <i>in vitro</i> activity against carbapenem-resistant <i>P. aeruginosa</i> (cefepime-zidebactam and cefepime-taniborbactam) and <i>A. baumannii</i> (cefepime-zidebactam and sulbactam-durlobactam).