An Appraisal of the Pharmacokinetic and Pharmacodynamic Properties of Meropenem-Vaborbactam
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REVIEW
An Appraisal of the Pharmacokinetic and Pharmacodynamic Properties of MeropenemVaborbactam Eric Wenzler
. Patrick J. Scoble
Received: July 16, 2020 / Accepted: September 11, 2020 Ó The Author(s) 2020
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, b-lactamase inhibitor with a carbapenem backbone. Vaborbactam emanated from a discovery program specifically designed to identify candidate b-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 Digital Features To view digital features for this article go to https://doi.org/10.6084/m9.figshare.12937460. E. Wenzler (&) College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA e-mail: [email protected] P. J. Scoble PJS Pharma Consulting, Flourtown, PA, USA
typically B 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 b-lactam and b-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 meropenemvaborbactam 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.
Infect Dis Ther
PLAIN LANGUAGE SUMMARY 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 car
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