Imipenem‐Cilastatin‐Relebactam: A Novel β‐Lactam–β‐Lactamase Inhibitor Combination for the Treatment of Multidrug‐Resistant Gram‐Negative Infections

Abstract

Imipenem‐cilastatin‐relebactam (IMI‐REL) is a novel β‐lactam–β‐lactamase inhibitor combination recently approved for the treatment of complicated urinary tract infections (cUTIs) and complicated intraabdominal infections (cIAIs). Relebactam is a β‐lactamase inhibitor with the ability to inhibit a broad spectrum of β‐lactamases such as class A and class C β‐lactamases, including carbapenemases. The addition of relebactam to imipenem restores imipenem activity against several imipenem‐resistant bacteria, including Enterobacteriaceae and Pseudomonas aeruginosa. Clinical data demonstrate that IMI‐REL is well tolerated and effective in the treatment of cUTIs and cIAIs due to imipenem‐resistant bacteria. In a phase III trial comparing IMI‐REL with imipenem plus colistin, favorable clinical response was achieved in 71% and 70% of patients, respectively. Available clinical and pharmacokinetic data support the approved dosage of a 30‐minute infusion of imipenem 500 mg–cilastatin 500 mg–relebactam 250 mg every 6 hours, along with dosage adjustments based on renal function. In this review, we describe the chemistry, mechanism of action, spectrum of activity, pharmacokinetics and pharmacodynamics, and clinical efficacy, and safety and tolerability of this new agent. The approval of IMI‐REL represents another important step in the ongoing fight against multidrug‐resistant gram‐negative pathogens.

Antibiotic Resistance inBacillus-based Biopesticide Products

“…Both B. thuringiensis products demonstrated complete resistance to ceftazidime, a third-generation cephalosporin. Resistance to third-generation broad spectrum cephalosporins are of special concern, the WHO has categorized this drug class as “highest priority critically important antimicrobials.”(26) Resistance to imipenem, a broad spectrum beta lactamase usually reserved for multi-drug resistant infections,(37) was found in one B. thuringiensis product, and in some replicates of the other B. thuringiensis product, as well as in B. amyloliquefaciens replicates.…”

Microbial Resistance Movements: An Overview of Global Public Health Threats Posed by Antimicrobial Resistance, and How Best to Counter

“…The addition of relebactam, a novel beta-lactamase inhibitor in the diazabicyclooctane class, was the innovation in this combination ( 141 , 142 ), conferring advantage by overcoming the resistance issue of several imipenem-resistant microorganisms, including Enterobacteriaceae and Pseudomonas aeruginosa ( 144 ). Relebactam impedes bacterial synthesis of class A and C β-lactamases, consequently, lowering the minimum inhibitory concentration (MIC) and improving imipenem sensitivity activity against P aeruginosa ( 144 ). The approval of imipenem-cilastatin/relebactam brings new hope for enduring combat against MDR pathogenic microbes ( 144 – 146 ).…”

“…Relebactam impedes bacterial synthesis of class A and C β-lactamases, consequently, lowering the minimum inhibitory concentration (MIC) and improving imipenem sensitivity activity against P aeruginosa ( 144 ). The approval of imipenem-cilastatin/relebactam brings new hope for enduring combat against MDR pathogenic microbes ( 144 – 146 ).…”

1,3‐Diazepine: A privileged scaffold in medicinal chemistry

“…A 12 step‐synthesis of MK‐7655 with an overall yield of 10% on a multi‐kilograms preparation was reported by a Merck team in 2011 127 . The relebactam/imipenem/cilastatin association was accepted by the FDA in February 2019 and marketed as Recarbrio® for the treatment of complicated urinary tract infections and complicated intra‐abdominal infections caused by Gram‐negative bacteria 128 …”