New Perspectives on Antimicrobial Agents: Imipenem-Relebactam

O'Donnell, J. Nicholas; Lodise, Thomas

doi:10.1128/aac.00256-22

Cited by 21 publications

(9 citation statements)

References 81 publications

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“…One of these combinations, imipenem/relebactam, unites imipenem/cilastatin with relebactam, a bicyclic diazabicyclooctane inhibitor of class A and C β-lactamases. 1 Imipenem/relebactam is approved by the EMA and the FDA for hospital-acquired and ventilator-associated bacterial pneumonia (HAP and VAP), bacteraemia associated with HAP and VAP (EMA only), and infections due to aerobic Gram-negative bacilli in adults with limited treatment options [e.g. complicated urinary tract infection (UTI), complicated intra-abdominal infection].…”

Section: Introductionmentioning

confidence: 99%

Susceptibility of Gram-negative isolates collected in South Korea to imipenem/relebactam and comparator agents—SMART 2018–21

Karlowsky,

Wise,

Chen

et al. 2023

JAC-Antimicrobial Resistance

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Objectives To evaluate the in vitro susceptibility of recent Gram-negative pathogens collected in South Korean medical centres to imipenem/relebactam and comparator agents. Methods From 2018 to 2021, six hospitals in South Korea each collected up to 250 consecutive, aerobic or facultative Gram-negative pathogens per year from patients with bloodstream, intra-abdominal, lower respiratory tract and urinary tract infections. MICs were determined using CLSI broth microdilution and interpreted by 2023 CLSI breakpoints. Most isolates that were imipenem/relebactam, imipenem or ceftolozane/tazobactam non-susceptible were screened for β-lactamase genes by PCR or WGS. Results Of all non-Morganellaceae Enterobacterales (NME) isolates (n = 4100), 98.8% were imipenem/relebactam susceptible. Most NME were also susceptible to imipenem alone (94.7%) and meropenem (97.3%); percent susceptible values for non-carbapenem β-lactam comparators were lower (68%–80%). Imipenem/relebactam retained activity against 96.4%, 70.8% and 70.6% of MDR, difficult-to-treat resistant (DTR) and meropenem-non-susceptible NME, respectively, and inhibited 93.1% of KPC-carrying and 95.5% of ESBL-carrying NME. Of imipenem/relebactam-resistant NME, 21/25 (84.0%) carried an MBL or an OXA-48-like carbapenemase. Of all Pseudomonas aeruginosa isolates (n = 738), 82.8% were imipenem/relebactam susceptible; percent susceptible values for all β-lactam comparators, including carbapenems (imipenem, meropenem) were 61.5%–74.7%. Less than 20% of MDR and DTR isolates, and 41% of meropenem-non-susceptible P. aeruginosa isolates were imipenem/relebactam susceptible. Of imipenem/relebactam-resistant P. aeruginosa isolates, 61.6% carried an MBL and 37.0% did not possess any acquired β-lactamase genes. Conclusions Based on in vitro data, imipenem/relebactam, if licensed in South Korea, may be a viable treatment option for many hospitalized patients infected with common Gram-negative pathogens including NME exhibiting MDR, DTR and carbapenem resistance and many β-lactam-resistant phenotypes of P. aeruginosa.

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Section: Introductionmentioning

confidence: 99%

Susceptibility of Gram-negative isolates collected in South Korea to imipenem/relebactam and comparator agents—SMART 2018–21

Karlowsky,

Wise,

Chen

et al. 2023

JAC-Antimicrobial Resistance

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“… 19 , 20 Relebactam is a chemical compound used with imipenem to take role as a β-lactamase inhibitor and it blocks the ability of bacteria to destroy the β-lactam ring. 21 Unfortunately, several studies have shown a concerning uprising in resistance toward this antibiotic resistance. 12 , 13 , 22 …”

Section: Discussionmentioning

confidence: 99%

Global Resistance of Imipenem/Relebactam against Gram-Negative Bacilli: Systematic Review and Meta-Analysis

Abniki,

Tashakor,

Masoudi

et al. 2024

Current Therapeutic Research

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“…PK/PD targets were 30% fT>MIC for imipenem and free AUC normalized to MIC (at 2 mcg/mL) of ≥8.0 (equivalent to AUC 0–∞ ≥20.52 mcg·h/mL) for relebactam, which is associated with a 2‐log kill in preclinical models; the relebactam concentration is fixed because it does not have intrinsic antibacterial activity. This has been previously described 15,20,23,26–28 …”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics, Safety, and Tolerability of Imipenem/Cilastatin/Relebactam in Children with Confirmed or Suspected Gram‐Negative Bacterial Infections: A Phase 1b, Open‐Label, Single‐Dose Clinical Trial

Bradley

Makieieva

Tøndel

et al. 2023

The Journal of Clinical Pharma

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Imipenem/cilastatin/relebactam is approved for treatment of serious gram‐negative bacterial infections in adults. This study assessed pharmacokinetics (PK), safety, and tolerability of a single dose of imipenem/cilastatin/relebactam (fixed 2:1 ratio of imipenem/cilastatin to relebactam, with a maximum dose of 15 mg/kg imipenem and 15 mg/kg cilastatin [≤500 mg imipenem and ≤500 mg cilastatin] and 7.5 mg/kg relebactam [≤250 mg relebactam]) in children with confirmed/suspected gram‐negative bacterial infections receiving standard‐of‐care antibacterial therapy. In this phase 1, noncomparative study (ClinicalTrials.gov identifier, NCT03230916), the PK/pharmacodynamic (PD) target for imipenem was percent time of the dosing interval that unbound plasma concentration exceeded the minimum inhibitory concentration (%ƒT>MIC) of ≥30% (MIC = 2 μg/mL). For relebactam, the PK/PD target was free area under the concentration–time curve (AUC) normalized to MIC (at 2 μg/mL) ≥8.0 (equivalent to AUC from 0 extrapolated to infinity ≥20.52 μg∙h/mL), respectively. Safety was assessed up to 14 days after drug infusion. For imipenem, the ranges of geometric mean %fT>MIC and maximum concentration (Cmax) across age cohorts were 56.5%‐93.7% and 32.2‐38.2 μg/mL, respectively. For relebactam, the ranges of geometric mean Cmax and AUC from 0 to 6 hours across age cohorts were 16.9‐21.3 μg/mL and 26.1‐55.3 μg·h/mL, respectively. 8/46 (17%) children experienced ≥1 adverse events and 2/46 (4%) children experienced nonserious adverse events that were deemed drug related by the investigator. Imipenem and relebactam exceeded plasma PK/PD targets; single doses of imipenem/cilastatin/relebactam were well tolerated with no significant safety concerns identified. These results informed imipenem/cilastatin/relebactam dose selection for further pediatric clinical evaluation.This article is protected by copyright. All rights reserved

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New Perspectives on Antimicrobial Agents: Imipenem-Relebactam

Cited by 21 publications

References 81 publications

Susceptibility of Gram-negative isolates collected in South Korea to imipenem/relebactam and comparator agents—SMART 2018–21

Susceptibility of Gram-negative isolates collected in South Korea to imipenem/relebactam and comparator agents—SMART 2018–21

Global Resistance of Imipenem/Relebactam against Gram-Negative Bacilli: Systematic Review and Meta-Analysis

Pharmacokinetics, Safety, and Tolerability of Imipenem/Cilastatin/Relebactam in Children with Confirmed or Suspected Gram‐Negative Bacterial Infections: A Phase 1b, Open‐Label, Single‐Dose Clinical Trial

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