An Appraisal of the Pharmacokinetic and Pharmacodynamic Properties of Meropenem-Vaborbactam

Abstract

Carbapenem-resistant gram-negative pathogens remain an urgent public health threat, and safe, effective treatment options are limited. Although several agents are now available to combat these infections, meropenem-vaborbactam was the first to combine a novel, cyclic, boronic acid-based, β-lactamase inhibitor with a carbapenem backbone. Vaborbactam emanated from a discovery program specifically designed to identify candidate β-lactamase inhibitors with biochemical, microbiologic, and pharmacologic properties optimized for use in conjunction with a carbapenem. Meropenem was selected as the ideal carbapenem given its broad-spectrum in vitro activity, well established safety profile, and proven efficacy in the treatment of serious gram-negative infections. The combination has demonstrated potent in vitro activity against resistant gram-negative pathogens, particularly KPC-producing Klebsiella pneumoniae (MIC50 values typically ≤ 0.06 mg/l). Importantly, the pharmacokinetic (PK) profiles of the two agents are well matched, and the approved optimized dosing regimen of 4 g every 8 h (Q8h) as a 3-h infusion provides reliable probability of target attainment against the majority of commonly encountered carbapenem-resistant Enterobacteriaceae (CRE). Robust in vitro and in vivo PK/pharmacodynamic (PD) data support the ability of this dosing regimen to achieve specified PK/PD targets for both bactericidal activity and prevention of resistance among pathogens with MICs up to 8 mg/l. This concerted effort into optimizing the PK and PD parameters of both the β-lactam and β-lactamase inhibitor alone and in combination contributed to the clinical success of meropenem-vaborbactam demonstrated in phase 3 trials in patients with complicated urinary tract infections (cUTI), including acute pyelonephritis (AP), and serious CRE infections. As the use of meropenem-vaborbactam increases concomitantly with the prevalence of KPC-producing CRE, continued pharmacovigilance and antimicrobial stewardship efforts will be of upmost importance to ensure that these PK/PD efforts translate into improved patient outcomes. Carbapenem-resistant gram-negative pathogens, specifically, Enterobacteriaceae, remain an urgent public health threat, and safe, effective treatment options are limited. The antibiotic agents meropenem and vaborbactam were selected to be combined to leverage their individual properties for efficacy against carbapenem-resistant gram-negative pathogens, the most prevalent being Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae. Infections due to carbapenem-resistant Enterobacteriaceae (CRE) are associated with high morbidity and mortality and excess healthcare costs and have traditionally required treatment with low-efficacy, high-toxicity antimicrobials such as the polymyxins. The authors present a review of the pre-clinical, clinical, pharmacokinetic (PK), and pharmacodynamic (PD) data on meropenem-vaborbactam, and data on difficult to treat organisms, and on special patient populations obtained post-marketing. Pre-clinical in vitro and in vivo PK/PD data support this optimized combination of these agents with meropenem-vaborbactam demonstrating low MIC50/MIC90 values against KPC-producing Enterobacteriaceae. Phase 1 PK trials confirmed the PK parameters, including in subjects with renal impairment and in target extravascular body sites such as the pulmonary epithelial lining fluid. In vitro, the combination of meropenem-vaborbactam has shown potent activity against resistant gram-negative pathogens; importantly, this includes KPC-producing Klebsiella pneumoniae. The approved optimized dosing regimen [4 g every 8 h (Q8h) as a 3-h infusion] achieves the PK/PD targets to achieve both bactericidal activity and prevention of resistance among pathogens with MICs up to 8 mg/l. Phase 3 trials showed the clinical success of meropenem-vaborbactam in patients with complicated urinary tract infections (cUTI), including acute pyelonephritis (AP), and serious CRE infections.

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