Imipenem/Cilastatin/Relebactam (IMI/REL) in Treatment of CRE Infections

A Study Comparing Prospective Use of Imipenem/Cilastatin/Relebactam (IMI/REL) to Retrospective Data Using Meropenem/ Vabobactam (MVB) and Ceftazidime/Avibactam (CZA) in Treatment of Klebsiella Producing Carbapenemase Enterobacteriaceae Infections

This is an observation study comparing prospective use of Imipenem/Cilastatin/Relebactam (IMI/REL) to retrospective data using Meropenem/Vabobactam (MVB)and Ceftazidime/Avibactam CZA) in treatment of Klebsiella Producing Carbapenemase Enterobacteriaceae infections at a tertiary care hospital. The objectives of the study are to demonstrate successful treatment of KPC containing Enterobacteriaceae infections with IMI/REL including in bacteremia, and to analyze treatment outcomes in use of IMI/REL for KPC-producing infections compared to historical clinical outcome data with CZA and MVB use at the same institution.

Study Overview

• Status: Withdrawn
• Conditions: Gram-Negative Bacterial Infections; Antibiotic Resistant Infection; Carbapenem-Resistant Enterobacteriaceae Infection; KPC
• Intervention / Treatment: Drug: Imipenem+Relebactam

• Study Type: Interventional
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Christopher Polk, MD; Phone Number: 704-331-9669; Email: Christopher.Polk@atriumhealth.org
• Study Contact Backup: Name: Jessica Kearney-Bryan, MS; Phone Number: 704-355-0422; Email: Jessica.KearneyBryan@atriumhealth.org

Study Locations

• United States
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Carolinas Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Adult (>18 years of age) patients with a KPC-producing CRE infection at any site except for isolated urinary source. Patients may be initially enrolled once identified with a CRE infection defined as resistance to any carbapenem. Any carbapenem resistance will provide an initial mechanism of identifying study eligible patients in accordance with our institutions definition of CRE for infection prevention purposes. As this study is specific for KPC-producing CRE inclusion in the study analysis will require confirmation of a KPC gene by molecular analysis of the isolate and subjects enrolled may be subsequently removed from study and excluded from analysis if molecular testing reveals their CRE isolate to be a non-KPC mechanism of resistance. Polymicrobial infections at same or different sites can also be included as long as additional gram-negative active agents aside from IMI/REL are not needed for treatment.
2. Bacterial infection with Enterobacteriaceae excluding Morganellaceae
3. Ability and willingness to give informed consent. A Legal authorized representative may be used when the patient is unable to provide informed consent.
4. Be the first episode of a CRE infection to be treated with IMI/REL. Previously treatment with IMI/REL for a KPC-containing Enterobacteriaceae infection will exclude patients from enrollment.

Exclusion Criteria:

1. Receipt of more than 48 hours of effective antibiotic therapy against KPC containing infections (e.g. MVB, CZA) prior to first dose of IMI/REL being administered.
2. Infections localized to urinary source alone (bloodstream infections from urinary source will be included)
3. Infection with Morganellaceae
4. Prior serious allergic reaction to carbapenem therapy
5. Need for ongoing concomitant therapy with ganciclovir or valproic acid
6. Need for ongoing concomitant therapy with another antibiotic active against gram negative pathogens. Concomitant therapy with Vancomycin, Daptomycin, Linezolid, Clindamycin, Fidaxomicin, Nafcillin, Metronidazole, and Rifaximin will be allowed but no other antibiotic agents.
7. Pregnancy or ongoing breastfeeding. Women of childbearing age must test negative on a urine pregnancy test at time of screening for trial eligibility and remain either abstinent or use 2 forms of highly effective contraception for the duration of the IMI/REL administration during the study.
8. Inability to comply with study protocol or remain hospitalized for duration of study.
9. Life expectancy less than 72 hours in opinion of study investigators.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Observation Treatment Group; All patients observed while treated with IMI/REL.	Drug: Imipenem+Relebactam; Antibiotic treatment for KPC producing CRE-containing gram-negative infections; Other Names: Recarbrio

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical success	Clinical success defined as survival at 30 days, resolution of signs and symptoms of infection, sterilization of blood cultures within 7 days of treatment initiation in patients with bacteremia, and absence of recurrent infections.	30 days
Clinical success by site of infection	Clinical success in patients grouped by site of infection: bacteremia, respiratory, intra-abdominal infection, soft tissue, catheter associated and urinary tract. Subjects may be included in multiple groups if applicable for analysis.	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	Survival at 30 days	30 days
90 day Mortality	Survival at 90 days	90 days
Adverse effects	Incidence of nephrotoxicity, leukopenia, rash, hepatotoxicity, and seizure in treatment group	90 days
Total Length of hospital stays	Days of hospitalization for CRE infection	90 days
Recurrence of infection	Recurrence of CRE-containing infection within 90 days	90 days
Development of resistance	If recurrent CRE infection develops following index infection treated with IMI/REL, then incidence of IMI/REL resistance in subsequent bacterial cultures	90 days

Collaborators and Investigators

• Sponsor: Wake Forest University Health Sciences
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Christopher Polk, MD, Wake Forest University Health Sciences

Study record dates

Study Major Dates

• Study Start (Actual): June 7, 2021
• Primary Completion (Actual): January 12, 2023
• Study Completion (Actual): January 12, 2023

Study Registration Dates

• First Submitted: March 2, 2021
• First Submitted That Met QC Criteria: March 3, 2021
• First Posted (Actual): March 8, 2021

Study Record Updates

• Last Update Posted (Estimate): January 16, 2023
• Last Update Submitted That Met QC Criteria: January 13, 2023
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Bacterial Infections and Mycoses; Infections; Communicable Diseases; Bacterial Infections; Gram-Negative Bacterial Infections; Enterobacteriaceae Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Imipenem; Relebactam
• Other Study ID Numbers: IRB00081742; MISP 59805 (Other Identifier: Atrium)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No