An Update on Existing and Emerging Data for Meropenem-Vaborbactam

• Published in: Clinical therapeutics Vol. 42; no. 4; pp. 692 - 702
• Main Authors: Shoulders, Bethany R., Casapao, Anthony M., Venugopalan, Veena
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-04-2020; Elsevier Limited
• Subjects: Acids; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - adverse effects; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacokinetics; Antibiotics; Bacteremia; Bacteria; Bacterial diseases; Boronic Acids - administration & dosage; Boronic Acids - adverse effects; Boronic Acids - chemistry; Boronic Acids - pharmacokinetics; Carbapenemase; carbapenemase-producing organisms; Chemotherapy; Chloride; Clinical trials; Drug Combinations; Drug dosages; Drug Interactions; E coli; Efflux; Enterobacter cloacae; Enterobacteriaceae; Enzymes; FDA approval; Gram-negative bacteria; Hemodialysis; Heterocyclic Compounds, 1-Ring - administration & dosage; Heterocyclic Compounds, 1-Ring - adverse effects; Heterocyclic Compounds, 1-Ring - chemistry; Heterocyclic Compounds, 1-Ring - pharmacokinetics; Humans; Infections; Klebsiella; Klebsiella pneumonia carbapenemase; Klebsiella pneumoniae; Meropenem; Meropenem - administration & dosage; Meropenem - adverse effects; Meropenem - chemistry; Meropenem - pharmacokinetics; meropenem-vaborbactam; Minimum inhibitory concentration; Multidrug resistance; Multidrug resistant organisms; multidrug-resistant gram-negative organisms; Organisms; Permeability; Pharmacodynamics; Pharmacokinetics; Pharmacology; Piperacillin; Piperacillin-tazobactam; Pneumonia; Pseudomonas aeruginosa; Pyelonephritis; Renal replacement therapy; Skin; Tazobactam; Urinary tract; vaborbactam; United States > US; carbapenemase-producing organisms; Klebsiella pneumonia carbapenemase; meropenem-vaborbactam; vaborbactam; multidrug-resistant gram-negative organisms
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2020.01.023

The search for new agents to treat multidrug-resistant gram-negative bacterial infections has been ongoing. Specifically, carbapenem-resistant Enterobacteriaceae (CRE) infections often exhibit multiple resistance mechanisms, including alterations in drug structure, bacterial efflux pumps, and drug permeability. Vaborbactam, a cyclic boronic acid pharmacophore, has the highest potency in vitro with meropenem as an inhibitor of class A carbapenemases, including Klebsiella pneumoniae carbapenemase (KPC). This combination product was approved by the US Food and Drug Administration for complicated urinary tract infections (cUTIs) in August 2017, and recent Phase III trial data have expanded the literature available. This article aimed to describe the literature regarding spectrum of activity, dosing and administration, including pharmacokinetic and pharmacodynamics properties, safety profile, and efficacy end points.
The terms meropenem, vaborbactam, RPX7009, and meropenem-vaborbactam were used to search for literature via PubMed, ClinicalTrials.gov, and published abstracts from 2013 to July 2019. Abstracts from IDWeek 2019 were also searched via these terms. Results were limited to availability in English.
Meropenem-vaborbactam covers a spectrum of gram-negative bacterial pathogens, including K pneumoniae, Escherichia coli, and Enterobacter cloacae complex. Although the addition of vaborbactam to meropenem results in MIC lowering for KPC-positive Enterobacteriaceae, in vitro data reveal limited activity against resistant strains of Acinetobacter species and Pseudomonas aeruginosa. Data from 2 Phase III studies compare the drug with available therapies for the following indications: cUTIs, acute pyelonephritis, hospital-acquired and ventilator-acquired bacterial pneumonia, bacteremia, and complicated intra-abdominal infections. Outcomes include an improvement in clinical success when compared with piperacillin-tazobactam (98.4% vs 94%; 95% CI, 0.7%–9.1%; P < 0.001 for noninferiority) for overall treatment of cUTIs and acute pyelonephritis and clinical cure (64.3% vs 33.3%; P = 0.04) when compared with best available therapy for CRE infections in various sites of infection. Adverse events have been described as mild to moderate, with few events requiring discontinuation of the drug therapy.
Currently, meropenem-vaborbactam is approved for treatment of cUTIs and acute pyelonephritis; however, off-label use, in particular for CRE infections, appears beneficial. Clinical trials to date have found an improvement in clinical cure and potentially an improved tolerability compared with standard therapies. Most of the evidence for meropenem-vaborbactam activity and the role in therapy focuses on KPC-producing organisms; however, because in vitro activity has been found with some non–KPC-producing CRE, its role may be further described from upcoming in vivo cases and postmarketing research.