LB-4 - Cefepime-Enmetazobactam Demonstrates Superiority to Piperacillin-Tazobactam in a Subgroup of Patients with Complicated Urinary Tract Infections/Acute Pyelonephritis Caused by Extended Spectrum β-Lactamase-Producing Enterobacterales

Background: There is a critical need for carbapenem-sparing therapies for infections caused by extended spectrum β-lactamase (ESBL)-producing Enterobacterales.  Enmetazobactam is a novel ESBL inhibitor combined with the cephalosporin cefepime.  Treatment outcomes of cefepime-enmetazobactam (FPE) versus piperacillin-tazobactam (PTZ) were assessed in subgroups of patients with ESBL-producing baseline uropathogens (ESBL-BU) in the ALLIUM phase 3 trial of complicated urinary tract infections (cUTI)/acute pyelonephritis (AP).

Methods: 1034 cUTI/AP patients randomized 1:1 in a double-blind, multicenter trial received either 2 g cefepime/0.5 g enmetazobactam or 4 g piperacillin/0.5 g tazobactam q8h by 2h infusion for 7 to 14 days.  Enterobacterales with MICs ≥1 µg/ml to ceftazidime, ceftriaxone, cefepime, meropenem, or FPE were genotyped for β-lactamases.  In addition to the primary analysis (by stratified Newcombe) of overall success (combination of clinical cure and microbiological eradication) in the microbiological modified intent to treat population (mMITT) at test-of-cure (TOC), subgroup analyses were performed on patients with ESBL-BU non-resistant to FPE (MIC≤8 µg/ml) and PTZ (MIC≤64 µg/ml) and a subgroup (mMITT+R) that also included the ESBL-BU resistant to either agent (FPE MIC ≥16 µg/ml or PTZ MIC≥128 µg/ml).

Results: In mMITT, FPE (273/345, 79.1%) demonstrated superiority to PTZ (196/333, 58.9%) at TOC (difference, 21.2%; 95% CI: 14.3, 27.9).  The prevalence rate of ESBL-BU was 20.9% (142/678), with 99.3% (141/142) expressing a CTX-M-type (-1, -3, -9, -14, -15, -27, -55, -91, -169) and 3.5% (5/142) co-expressing AmpC (CMY-2/-59).  FPE (56/76, 73.7%) demonstrated superiority to PTZ (34/66, 51.5%) in this subgroup at TOC (difference 30.2%; 95% CI: 13.4, 45.1; Table).  In mMITT+R, the ESBL-BU prevalence rate was 22.3% (172/771), with 6.4% (11/172) co-expressing AmpC (CMY-2/-4/-59/-99), 4.7% (8/172) co-expressing a metallo-β-lactamase (VIM-1, NDM-1), and 2.3% (4/172) co-expressing OXA-48.  Superiority of FPE (67/91, 73.6%) compared to PTZ (41/81, 50.6%) was also observed at TOC despite inclusion of ESBL-BU resistant to either agent (difference 30.0%; 95% CI: 14.9, 43.3).Table


Conclusion: FPE may represent a new empiric carbapenem-sparing option in settings where ESBL are endemic.

Presenter and Author(s)

• 

  Keith S. Kaye, MD, MPH

  Professor of Internal Medicine, Director of Research, Division of Infectious Diseases
  University of Michigan Medical School
  Ann Arbor, MI

  Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.

  Slides

Co-Author(s)

• AB

  Adam Belley, PHD

  Allecra Therapeutics
  Beaconsfield, QC, Canada

  Disclosure: Allecra Therapeutics SAS (Consultant)
• PB

  Philip Barth, MD

  Sr. Consultant, Clinical Operations
  Allecra Therapeutics SAS
  St. Louis, Alsace, France

  Disclosure: Allecra Therapeutics SAS (Consultant)
• SK

  Shikhar Kashyap, n/a

  Clinical Project Manager
  Allecra Therapeutics SAS
  St. Louis, Alsace, France

  Disclosure: Allecra Therapeutics SAS (Consultant)Allecra Therapeutics SAS (Consultant)
• OL

  Omar Lahlou, PhD

  Director, Regulatory Affairs
  Allecra Therapeutics SAS
  St. Louis, Alsace, France

  Disclosure: Allecra Therapeutics SAS (Employee)
• PM

  Paola Motta, PhD

  Director, DMPK
  Allecra Therapeutics SAS
  St. Louis, Alsace, France

  Disclosure: Allecra Therapeutics SAS (Employee)
• PK

  Philipp Knechtle, PhD

  Chief Scientific Officer
  discoveric bio beta Ltd
  Pfaeffikon, Zurich, Switzerland

  Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
• PV

  Patrick Velicitat, MD

  Chief Medical Officer
  Allecra Therapeutics SAS
  St. Louis, Alsace, France

  Disclosure: Allecra Therapeutics SAS (Employee)