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Beta-Lactamase Inhibitors
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Pascalis Vergidis, Matthew E. Falagas
Vaborbactam (formerly RPX7009) is a boronic acid-based beta-lactamase inhibitor that works via a novel mechanism of action compared to current clinically available beta-lactamase inhibitors (Drawz et al., 2014). In combination with a carbapenem, such as meropenem or biapenem, it exhibits strong synergistic activity against class A beta-lactamases, particularly Klebsiella pneumoniae carbapenemase (KPC) producing organisms (Hecker et al., 2015; Lapuebla et al., 2015; Livermore and Mushtaq, 2013; see Chapter 38, Meropenem and meropenem–vaborbactam).
Meropenem-vaborbactam: a critical positioning for the management of infections by Carbapenem-resistant Enterobacteriaceae
Published in Expert Review of Anti-infective Therapy, 2022
Maria Mouktaroudi, Antigone Kotsaki, Evangelos J. Giamarellos-Bourboulis
Meropenem-vaborbactam (Vaborem®) is approved by the EMA for complicated urinary tract infections including acute pyelonephritis, for complicated intra-abdominal infections and for hospital-acquired pneumonia including ventilator-associated pneumonia and for infections caused by Gram-negative bacteria where other treatments might not work [62]. The drug is approved by the FDA for complicated urinary tract infections including acute pyelonephritis. The dose regimen is 2 g/2g every 8 hours as a 3-hour intravenous infusion for patients with normal renal function and should be adjusted for lower values of creatinine clearance [63]. In the recommendations provided by both EMA and FDA is it clearly stated that vaborbactam does not inhibit class B enzymes (metallo-β-lactamases) or class D carbapenemases.
The latest advances in β-lactam/β-lactamase inhibitor combinations for the treatment of Gram-negative bacterial infections
Published in Expert Opinion on Pharmacotherapy, 2019
Meropenem is a carbapenem and vaborbactam is a novel monocyclic boronic acid-based BLI and the first BL-boronate BLI combination to reach the market, which was highly anticipated due to the decades of research by many scientists on boronic acids and serine β-lactamases (Figure 1 and Table 2) [6]. Vaborbactam is an inhibitor of many class A and C β-lactamases, including KPC carbapenemases. Intriguingly, vaborbactam also demonstrates some inhibitory activity (IC50 values = 136–631 µM) against class B metallo-β-lactamases, including all three subclasses, B1, B2, and B3 [60]. The combination of meropenem-vaborbactam demonstrates potent antimicrobial activity against CRE with an MIC90 value of 1 µg/mL for meropenem when vaborbactam is maintained at 8 µg/mL [61,62]. Against a large panel (10,426 strains) of contemporary Enterobacteriaceae, meropenem and meropenem-vaborbactam possessed an MIC90 value of 0.06 µg/mL; however, against KPC producers the MIC90 values for meropenem and meropenem-vaborbactam differentiated to >32 µg/mL and 0.5 µg/mL, respectively [63]. Unlike ceftazidime-avibactam, vaborbactam does not potentiate the activity of meropenem against P. aeruginosa in vitro [64]. However, in a neutropenic murine thigh infection model with P. aeruginosa, meropenem-vaborbactam did reduce bacterial load; thus, the combination may have some utility against other Gram negatives [65].
The antibiotic arms race: current and emerging therapy for Klebsiella pneumoniae carbapenemase (KPC) - producing bacteria
Published in Expert Opinion on Pharmacotherapy, 2018
Michael E. Plazak, Pranita D. Tamma, Emily L. Heil
Shortly following the development of avibactam, researchers discovered another novel β-lactamase inhibitor, vaborbactam. Vaborbactam is a unique boronic acid β-lactamase inhibitor, which is capable of forming a covalent bond between its boron moiety and the serine residue of KPC enzymes [70]. Like avibactam, this bond is reversible, allowing for vaborbactam to competitively inhibit the β-lactamase [70]. Addition of vaborbactam to meropenem provides potent activity against Enterobacteriaceae producing Class A carbapenemases. Meropenem-vaborbactam provides no activity against Class B and D carbapenemases [70]. The in vitro activity of the combination has been documented with two studies demonstrating activity against greater than 98% of the KPC-producing Enterobacteriaceae isolates tested [71,72]. Meropenem-vaborbactam currently is FDA-approved for the treatment of complicated UTIs based on results from the TANGO I trial [73].