Imipenem-Relebactam and Meropenem-Vaborbactam: Two Novel Carbapenem-β-Lactamase Inhibitor Combinations

Abstract

Relebactam (formerly known as MK-7655) is a non-β-lactam, bicyclic diazabicyclooctane, β-lactamase inhibitor that is structurally related to avibactam, differing by the addition of a piperidine ring to the 2-position carbonyl group. Vaborbactam (formerly known as RPX7009) is a non-β-lactam, cyclic, boronic acid-based, β-lactamase inhibitor. The structure of vaborbactam is unlike any other currently marketed β-lactamase inhibitor. Both inhibitors display activity against Ambler class A [including extended-spectrum β-lactamases (ESBLs), Klebsiella pneumoniae carbapenemases (KPCs)] and class C β-lactamases (AmpC). Little is known about the potential for relebactam or vaborbactam to select for resistance; however, inactivation of the porin protein OmpK36 in K. pneumoniae has been reported to confer resistance to both imipenem-relebactam and meropenem-vaborbactam. The addition of relebactam significantly improves the activity of imipenem against most species of Enterobacteriaceae [by lowering the minimum inhibitory concentration (MIC) by 2- to 128-fold] depending on the presence or absence of β-lactamase enzymes. Against Pseudomonas aeruginosa, the addition of relebactam also improves the activity of imipenem (MIC reduced eightfold). Based on the data available, the addition of relebactam does not improve the activity of imipenem against Acinetobacter baumannii, Stenotrophomonas maltophilia and most anaerobes. Similar to imipenem-relebactam, the addition of vaborbactam significantly (2- to > 1024-fold MIC reduction) improves the activity of meropenem against most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzymes. Limited data suggest that the addition of vaborbactam does not improve the activity of meropenem against A. baumannii, P. aeruginosa, or S. maltophilia. The pharmacokinetics of both relebactam and vaborbactam are described by a two-compartment, linear model and do not appear to be altered by the co-administration of imipenem and meropenem, respectively. Relebactam's approximate volume of distribution (V _d) and elimination half-life (t _½) of ~ 18 L and 1.2-2.1 h, respectively, are similar to imipenem. Likewise, vaborbactam's V _d and t_½ of ~ 18 L and 1.3-2.0 h, respectively, are comparable to meropenem. Like imipenem and meropenem, relebactam and vaborbactam are both primarily renally excreted, and clearance correlates with creatinine clearance. In vitro and in vivo pharmacodynamic studies have reported bactericidal activity for imipenem-relebactam and meropenem-vaborbactam against various Gram-negative β-lactamase-producing bacilli that are not inhibited by their respective carbapenems alone. These data also suggest that pharmacokinetic-pharmacodynamic parameters correlating with efficacy include time above the MIC for the carbapenems and overall exposure for their companion β-lactamase inhibitors. Phase II clinical trials to date have reported that imipenem-relebactam is as effective as imipenem alone for treatment of complicated intra-abdominal infections and complicated urinary tract infections, including acute pyelonephritis. Imipenem-relebactam is currently in two phase III clinical trials for the treatment of imipenem-resistant bacterial infections, as well as hospital-associated bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP). A phase III clinical trial has reported superiority of meropenem-vaborbactam over piperacillin-tazobactam for the treatment of complicated urinary tract infections, including acute pyelonephritis. Meropenem-vaborbactam has recently demonstrated higher clinical cure rates versus best available therapy for the treatment of carbapenem-resistant Enterobacteriaceae (CRE), as well as for HABP and VABP. The safety and tolerability of imipenem-relebactam and meropenem-vaborbactam has been reported in various phase I pharmacokinetic studies and phase II and III clinical trials. Both combinations appear to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date. In conclusion, relebactam and vaborbactam serve to broaden the spectrum of imipenem and meropenem, respectively, against β-lactamase-producing Gram-negative bacilli. The exact roles for imipenem-relebactam and meropenem-vaborbactam will be defined by efficacy and safety data from further clinical trials. Potential roles in therapy for these agents include the treatment of suspected or documented infections caused by resistant Gram-negative bacilli-producing ESBL, KPC, and/or AmpC β-lactamases. The usage of these agents in patients with CRE infections will likely become the standard of care. Finally, increased activity of imipenem-relebactam against P. aeruginosa may be of clinical benefit to patients with suspected or documented P. aeruginosa infections.