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

Plain Language Summary Meropenem-vaborbactam is a new combination antibiotic that was designed specifically for efficacy against bacteria that produce the Klebsiella pneumoniae carbapenemase (KPC) enzyme, which enables resistance to beta-lactam antibiotics. The global spread and increase of difficult-to-treat infections caused by carbapenem-resistant Enterobacterales (CRE) is in part because they produce KPC enzymes. The authors review the in vitro studies of meropenem-vaborbactam activity, which have included isolates from different geographic regions, time periods, and settings, showing that it has high potency against organisms containing KPC enzymes-KPC2 and KPC3. Meropenem-vaborbactam was tested against globally sourced isolates that carried different resistance mechanisms, including carbapenem resistance, multidrug resistant (MDR), and resistance to colistin and/or tigecycline; it inhibited activity of 99.1% Enterobacterales isolates tested at <= 1 mu g/ml, and at <= 8 mu g/ml it inhibited 96.5% of MDR isolates and 82% of XDR isolates. Against OXA-48 or metallo-beta lactamase enzymes, meropenem-vaborbactam has limited or no activity, so in the Asia-Pacific region where MLBs are prevalent it was least effective, but and was most effective against US strains where KPC is prevalent. In multiple studies, meropenem-vaborbactam showed strong in vitro activity against E. coli, Enterobacter spp., and K. pneumoniae. Compared to available antibiotics, against both clinical and engineered isolates, as well as engineered E. coli strains with KPC, SHV, and TEM enzymes, meropenem-vaborbactam demonstrated lower MIC values. Overall, in vitro studies of meropenem-vaborbactam have shown enhanced activity against CRE and KPC producers compared to other antibiotics, which is needed in the current CRE environment where KPC is dominant. Vaborbactam is a novel boron-based beta-lactamase inhibitor developed to be effective againstKlebsiella pneumoniaecarbapenemase (KPC)-producing bacteria. This enzyme is a key driver in the global spread of beta-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.