Microbiology of Meropenem-Vaborbactam: A Novel Carbapenem Beta-Lactamase Inhibitor Combination for Carbapenem-Resistant Enterobacterales Infections

Abstract

Vaborbactam is a novel boron-based beta-lactamase inhibitor developed to be effective against Klebsiella pneumoniae carbapenemase (KPC)-producing bacteria. This enzyme is a key driver in the global spread of β-lactam resistance among carbapenem-resistant Enterobacterales. Alone, vaborbactam has no antibacterial activity; however, the combination of meropenem-vaborbactam has enhanced activity against gram-negative organisms, particularly Enterobacterales with class A and C carbapenemases. Multiple in vitro studies evaluating isolates from various geographic regions, and over different time periods, have demonstrated the high potency of meropenem-vaborbactam against organisms containing KPC2 and KPC3. However, meropenem-vaborbactam does not have activity against OXA-48 or metallo-beta lactamases. This review covers the in vitro studies of meropenem-vaborbactam performed to date, which evaluated both large cohorts of clinical isolates and engineered isolates, to determine efficacy in various settings, including the presence of porin mutations and efflux pump upregulation.

Molecular Basis of AmpC β-Lactamase Induction by Avibactam in Pseudomonas aeruginosa: PBP Occupancy, Live Cell Binding Dynamics and Impact on Resistant Clinical Isolates Harboring PDC-X Variants

“…However, AmpC inhibition is out of the spectrum of most BLIs. Novel combinations such as ceftazidime/avibactam, ceftolozane/tazobactam, meropenem/vaborbactam and cefepime/zidebactam have based their activity against P. aeruginosa upon different strategies [ 7 , 8 ]. The avibactam β-lactamase inhibitor spectrum includes class C enzymes, which protect the partner β-lactam from AmpC-related hydrolysis [ 9 ].…”

“…Zidebactam, in spite of its fair inhibition capability towards class C β-lactamases, focuses its activity on β-lactam-enhancer properties derived from targeting PBP2 [ 12 , 13 ]. Finally, vaborbactam, a cyclic boronic-based narrow-spectrum BLI, does not offer additional protection against AmpC hyperproduction; however, it seems to enhance meropenem activity against P. aeruginosa [ 7 ].…”

Place in Therapy of the Newly Available Armamentarium for Multi-Drug-Resistant Gram-Negative Pathogens: Proposal of a Prescription Algorithm

“…MVB should probably be considered the preferred agent against organisms with confirmed production of KPC2 and KPC3 enzymes due to its enhanced in vitro potency and reduced emergence of resistance [ 45 ]. In the setting of empirical treatment, MVB should be taken into consideration in contexts of KPC predominance over other mechanism of carbapenem resistance [ 56 ]. This is particularly true in the aforementioned situations that underpin a risk of CZA under-exposure (severe pneumonia, RRT, septic thrombosis and delayed source control) ( Figure 1 ).…”

Challenge in the Discovery of New Drugs: Antimicrobial Peptides against WHO-List of Critical and High-Priority Bacteria

“…Other studies prioritize AMP-drug activity (synergic effect) to enhance the action of carbapenems, as recently reported, using meropenem-vaborbactam to kill high-risk bacteria with resistance to carbapenems. Vaborbactam is a boron-based inhibitor that inactivates the action of Klebsiella pneumoniae carbapenemase (KPC), which does not have antibacterial activity when used unimolecularly [ 31 ], Imipenem-cilastatin [ 32 ], and Imipenem-cilastatin-relebactam [ 32 , 33 ]. The combined activity or synergistic effect has had positive results in recent years, and its mechanisms still need to be studied in depth.…”