Delving into the Latest Updates on Relebactam with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Relebactam (USAN), Relebactam anhydrous, Relebactam hydrate (JAN)

+ [1]

Target

β-lactamase

Mechanism

β-lactamase inhibitors(Beta Lactamase inhibitors)

Therapeutic Areas

Infectious DiseasesRespiratory DiseasesUrogenital Diseases+ [1]

Active Indication-

Inactive Indication

Complicated intra-abdominal infectionComplicated urinary tract infectionHospital acquired bacterial pneumonia+ [3]

Originator Organization

Merck Sharp & Dohme Corp.

Active Organization-

Inactive Organization

Merck Sharp & Dohme Corp.Merck Sharp & Dohme LLC

Drug Highest PhasePendingPhase 3

First Approval Date-

RegulationFast Track (US), Qualified Infectious Disease Product (US)

Structure

Molecular FormulaC12H20N4O6S

InChIKeySMOBCLHAZXOKDQ-ZJUUUORDSA-N

CAS Registry1174018-99-5

Critically ill patients with sepsis undergo several physiological alterations that can alter the distribution, metabolism, and elimination of drugs. Some patients with sepsis may realize enhanced cardiac output leading to increases in glomerular filtration that result in increasing drug clearance. This clinical state is referred as Augmented Renal Clearance (ARC). Importantly, many beta-lactam antibiotics can be adversely affected by ARC, and some of these agents required increasing dosage to compensate for enhanced clearance. Imipenem-relebactam is a new broad spectrum antibiotic. This study is designed to assess the pharmacokinetics of both components, imipenem and relebactam, in critically ill patients with ARC.

Start Date10 Feb 2020

Sponsor / Collaborator

Hartford Hospital

[+1]

NCT04196608 / Unknown statusNot ApplicableIIT

In Vitro Activity of Ceftolozane/Tazobactam and Imipenem/Relebactam in Clinical Isolates of Pseudomonas Aeruginosa and Enterobacterales Collected From Hematology and Oncology Patients

The purpose of the ACTHEON Study is to evaluate the in vitro activity of ceftolozane-tazobactam, imipenem-relebactam and comparator agents (amoxicillin- clavulanate, piperacillin-tazobactam, ceftazidime, cefotaxime, cefepime, imipenem, meropenem, levofloxacin and amikacin; see list more details on page 7) against clinical isolates of P. aeruginosa and Enterobacterales prospectively collected from hematology and oncology patients with complicated intra-abdominal infections (cIAIs), complicated urinary infections (cUTIs), lower respiratory tract infections (LRTIs), and blood stream infections (BSIs) from 15 participating centers in Spain

Start Date01 Nov 2019

Sponsor / Collaborator

Merck Sharp & Dohme Corp.

NCT02493764 / CompletedPhase 3

A Phase III, Randomized, Double-Blind, Active Comparator-Controlled Clinical Trial to Study the Safety, Tolerability, and Efficacy of Imipenem/Cilastatin/Relebactam (MK-7655A) Versus Piperacillin/Tazobactam in Subjects With Hospital-Acquired Bacterial Pneumonia or Ventilator-Associated Bacterial Pneumonia

This study aims to compare treatment with a fixed-dose combination (FDC) of imipenem/relebactam/cilastatin (IMI/REL) with a FDC of piperacillin/tazobactam (PIP/TAZ) in participants with hospital-acquired or ventilator-associated bacterial pneumonia (HABP or VAPB, respectively). The primary hypothesis is that IMI/REL is non-inferior to PIP/TAZ in the incidence rate of all-cause mortality.

Start Date24 Nov 2015

Sponsor / Collaborator

Merck Sharp & Dohme Corp.

100 Clinical Results associated with Relebactam

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100 Translational Medicine associated with Relebactam

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100 Patents (Medical) associated with Relebactam

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340

Literatures (Medical) associated with Relebactam

01 Mar 2024·Journal of global antimicrobial resistance

The occurrence of the carbapenemase gene, blaNDM-5, on a transmissible IncX3 plasmid in multidrug-resistant Escherichia coli isolated from a farm dog

Article

Author: Kassem, Issmat I ; Oueslati, Saoussen ; Osman, Marwan ; Naas, Thierry ; Daaboul, Dina ; Dabboussi, Fouad ; El Omari, Khaled

OBJECTIVES:

In-depth phenotypic and genomic analyses on a carbapenem-resistant Escherichia coli isolate, recovered from the faeces of a farm dog in Lebanon, focusing on its antimicrobial resistance (AMR) patterns and the underlying resistome.

METHODS:

E. coli strain EC-106 was identified using MALDI-TOF-MS. Analyses using Carba NP, immunochromatographic assay NG Carba5, and other antimicrobial susceptibility testing were performed. Whole-genome sequencing (WGS) using the Illumina technology and different software available at the Center of Genomic Epidemiology wwere used to predict the resistome, sequence type (ST), plasmid types, and virulence genes.

RESULTS:

Susceptibility testing revealed that E. coli EC-106 was multi-drug resistant, including against newer antimicrobials such as imipenem-relebactam (MIC = 16 µg/mL), meropenem-vaborbactam (MIC = 16 µg/mL), and ceftazidime-avibactam (MIC > 32 µg/mL), but remained susceptible to aztreonam (MIC = 0.12 µg/mL), aztreonam-avibactam (MIC = 0.06 µg/mL), and cefiderocol (MIC = 0.5 µg/mL). WGS analyses showed that E. coli EC-106 carried 13 acquired resistance genes associated with resistance to β-lactams (bla_NDM-5 and bla_TEM-1B), aminoglycosides (aac(3)-IId, aph(3')-Ia, aadA1, and aadA2), tetracyclines (tetA), amphenicols (partial catA1), macrolides (mphA), sulphonamides (sul1 and sul3), trimethoprim (dfrA12), and quaternary ammonium compounds (partial qacE). The bla_NDM-5 was located on an IncX3 plasmid. The isolate was predicted to be a human pathogen (92.9%) and belonged to ST1011.

CONCLUSION:

To our knowledge, this is the first report of the detection of an IncX3 plasmid carrying the bla_NDM-5 gene in animals in Lebanon, highlighting the severe AMR challenges in the country. Taken together, our current and previous findings suggest that bla_NDM-5 might be spreading in different hosts and genetic backgrounds across clinical and non-clinical settings.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

Non-KPC Attributes of Newer β-lactam/β-lactamase Inhibitors, Part 1: Enterobacterales and Pseudomonas aeruginosa

Article

Author: Fratoni, Andrew J ; Nicolau, David P ; Kuti, Joseph L ; Gethers, Matthew L

Abstract:

Gram-negative antibiotic resistance continues to grow as a global problem due to the evolution and spread of β-lactamases. The early β-lactamase inhibitors (BLIs) are characterized by spectra limited to class A β-lactamases and ineffective against carbapenemases and most extended spectrum β-lactamases. In order to address this therapeutic need, newer BLIs were developed with the goal of treating carbapenemase producing, carbapenem resistant organisms (CRO), specifically targeting the Klebsiella pneumoniae carbapenemase (KPC). These BL/BLI combination drugs, avibactam/avibactam, meropenem/vaborbactam, and imipenem/relebactam, have proven to be indispensable tools in this effort. However, non-KPC mechanisms of resistance are rising in prevalence and increasingly challenging to treat. It is critical for clinicians to understand the unique spectra of these BL/BLIs with respect to non-KPC CRO. In Part 1of this 2-part series, we describe the non-KPC attributes of the newer BL/BLIs with a focus on utility against Enterobacterales and Pseudomonas aeruginosa.

01 Feb 2024·Diagnostic microbiology and infectious disease

Moving towards a standardized definition of antimicrobial resistance: a comparison of the antimicrobial susceptibility profile of difficult-to-treat resistance (DTR) versus multidrug-resistant (MDR) Pseudomonas aeruginosa clinical isolates (CANWARD, 2016-2021)

Article

Author: Adam, H J ; Karlowsky, J A ; Lagacé-Wiens, P R S ; Zhanel, G G ; Baxter, M R ; Bay, D C ; Walkty, A

Pseudomonas aeruginosa clinical isolates demonstrating difficult-to-treat resistance (DTR) and multidrug-resistant (MDR) phenotypes were evaluated by broth microdilution. Susceptibility was lower for all antimicrobials versus DTR relative to MDR isolates. Ceftazidime-avibactam, ceftolozane-tazobactam, and imipenem-relebactam susceptibility was 35.9%, 64.5%, and 47.0% for DTR isolates and 60.5%, 80.6%, and 71.5% for MDR isolates.

1

News (Medical) associated with Relebactam

17 May 2023

·endpts.com

Merck defends antibiotic's approval from 2019 as BMJ investigation points to 'decline' in FDA standards

A new BMJ investigation and companion editorial published earlier this week is raising questions on if the FDA lowered its standards to approve Merck’s antibiotic Recarbrio (imipenem/cilastatin/relebactam) in 2019 to treat complicated intra-abdominal and complicated urinary tract infections (cIAI and cUTI) for patients who have few or no other treatment options. The BMJ article raises questions cited in the FDA’s review memorandum, released as part of Recarbrio’s approval, which noted that the agency generally accepts 10% worse efficacy for non-inferiority studies in cUTI. However, Merck chose a 15% worse efficacy cut-off and didn’t hit that target, meaning it would allow “as many as one in seven patients to potentially have a worse outcome and still declare the trial a success.”

Drug ApprovalQualified Infectious Disease Product

100 Deals associated with Relebactam

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External Link

KEGG	Wiki	ATC	Drug Bank
D10726	-	-	DB12377

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Hospital acquired bacterial pneumonia	Phase 3	-	Merck Sharp & Dohme Corp.	24 Nov 2015
VABP	Phase 3	-	Merck Sharp & Dohme Corp.	24 Nov 2015
Complicated intra-abdominal infection	Phase 2	-	Merck Sharp & Dohme LLC	01 Jun 2012
Complicated urinary tract infection	Phase 2	-	Merck Sharp & Dohme Corp.	16 May 2012
Pyelonephritis	Phase 2	-	Merck Sharp & Dohme Corp.	16 May 2012
Sepsis	Phase 1	US	Merck Sharp & Dohme LLC	10 Feb 2020

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02493764 (RESTORE-IMI 2 \| MK-7655A-014 \| 7655A-014, CTgov)	Phase 3	Hospital acquired bacterial pneumonia \| VABP	537	Imipenem+Relebactam+Cilastatin+Linezolid (IMI/REL)	nhnpqjqnem(pglxssgpya) = oqwqtgjuky knawnxiqla (fpryyosdiv, jtbegnrenm - hzfbwqshho) View more	-	16 Apr 2020
				Linezolid+Piperacillin+Tazobactam (PIP/TAZ)	nhnpqjqnem(pglxssgpya) = bxnehqpsvg knawnxiqla (fpryyosdiv, xcsbkupusy - mlbsquwrfh) View more
NCT01506271 (MK-7655-004 \| 7655-004, CTgov)	Phase 2	Complicated intra-abdominal infection	351	Relebactam 250 mg+Imipenem/cilastatin (Relebactam 250 mg With Imipenem/Cilastatin)	qxcveawctt(vqackudxtt) = feuhkwjigy dawqnsuotj (pkntnrywnb, bggymidxfy - cipinbeleh) View more	-	10 Jun 2019
				Relebactam 125 mg+Imipenem/cilastatin (Relebactam 125 mg With Imipenem/Cilastatin)	qxcveawctt(vqackudxtt) = ekvaoktzhu dawqnsuotj (pkntnrywnb, ylthqkebuz - xcfwpsyqna) View more
NCT01505634 (MK-7655-003 \| 7655-003, CTgov)	Phase 2	Pyelonephritis \| Complicated urinary tract infection	302	Relebactam 250 mg+Ciprofloxacin+imipenem/cilastatin 500 mg (Relebactam 250 mg With Imipenem/Cilastatin)	vltmhqlblm(ywkluvelcx) = zieowdixoh wxgkemngxt (omidjfeicz, exaktebncr - xlzvfbyqcc) View more	-	24 May 2019
				Relebactam 125 mg+Ciprofloxacin+imipenem/cilastatin 500 mg (Relebactam 125 mg With Imipenem/Cilastatin)	vltmhqlblm(ywkluvelcx) = qdqfcffaux wxgkemngxt (omidjfeicz, hopimzwppe - urrvmedpeq) View more