PipEracillin Tazobactam Versus mERoPENem for Treatment of Bloodstream Infections Caused by Cephalosporin-resistant Enterobacteriaceae (PETERPEN) (PETERPEN)

Piperacillin Tazobactam Versus Meropenem for Treatment of Bloodstream Infections Caused by Cephalosporin-resistant Enterobacteriaceae- a Non-inferiority Randomized Controlled Trial

Data regarding optimal treatment for extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae blood-stream infection are lacking. Observational studies show conflicting results when comparing treatment with combination beta-lactam-beta-lactamase inhibitor and carbapenems. The investigators aim to evaluate the effect of definitive treatment with meropenem vs. piperacillin-tazobactam on the outcome of patients with bacteremia due to cephalosporin-non-susceptible Enterobacteriaceae. The investigators hypothesize that piperacillin-tazobactam is non-inferior to meropenem.

Study Overview

• Status: Recruiting
• Conditions: Bacteremia; Enterobacteriaceae Infections; Beta Lactam Resistant Bacterial Infection
• Intervention / Treatment: Drug: Piperacillin/tazobactam; Drug: Meropenem

• Study Type: Interventional
• Enrollment (Estimated): 1084
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Roni Bitterman, MD; Phone Number: 972-4-7772991; Email: ro_oren@rambam.health.gov.il
• Study Contact Backup: Name: Mical Paul, MD; Phone Number: 972-4-7772991; Email: m_paul@rambam.health.gov.il

Study Locations

• Canada
  • Montreal, Quebec, Canada
    • Recruiting
    • McGill University Health Centre
    • Contact: Email: todd.lee@mcgill.ca
    • Principal Investigator: Todd Lee, MD
    • Contact: Todd Lee, MD
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
      • Recruiting
      • University of Calgary, Cumming School of Medicine, O'Brien Institute for Public Health
      • Principal Investigator: John Conly, MD
      • Contact: John Conly, MD; Email: jconly@ucalgary.ca
  • British Columbia
    • Surrey, British Columbia, Canada
      • Recruiting
      • Surrey Memorial Hospital - Fraser Health Authority
      • Contact: Kevin Afra, MD; Email: Kevin.Afra@fraserhealth.ca
      • Principal Investigator: Kevin Afra, MD
  • Newfoundland and Labrador
    • Saint John's, Newfoundland and Labrador, Canada
      • Recruiting
      • Eastern Health
      • Contact: Peter Daley, MD; Email: pkd336@mun.ca
      • Principal Investigator: Peter Daley, MD
  • Ontario
    • Kingston, Ontario, Canada
      • Recruiting
      • Kingston General Hospital
      • Contact: Tony Bai, MD; Email: tony.bai@queensu.ca
      • Contact: Barbara Antuna Puente, MD; Email: Barbarbara.antunapuente@queensu.ca
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Recruiting
      • Jewish Genral Hospital
      • Contact: Leighanne Parkes, MD
      • Contact: Leighanne Parkes; Email: leighanne.parkes@mcgill.ca
• Israel
  • Be'er Sheva, Israel
    • Recruiting
    • Soroka Medical Center
    • Contact: Lior Nesher, MD; Email: nesherke@bgu.ac.il
    • Principal Investigator: Lior Nesher
  • Haifa, Israel, 3435306
    • Recruiting
    • Rambam Health Care Campus
    • Contact: Roni Bitterman; Phone Number: 47772991; Email: ro_oren@rambam.health.gov.il
  • Jerusalem, Israel
    • Recruiting
    • Hadassah Medical Center
    • Contact: Jacob strahilevitz, MD; Email: jstrahilevitz@hadassah.org.il
    • Principal Investigator: Jacob strahilevitz, MD
  • Kfar Saba, Israel
    • Recruiting
    • Meir Medical Center
    • Contact: Michal Chowers, MD; Email: michalch@clalit.org.il
    • Principal Investigator: Michal Chowers, MD
  • Netanya, Israel, 42150
    • Recruiting
    • Sanz Medical Center-Laniado Hospital
    • Contact: Candice Datnow, MD; Email: cdatnow@laniado.org.il
    • Principal Investigator: Candice Datnow, MD
  • Petah tikva, Israel
    • Recruiting
    • Rabin Medical Center, Beilinson campus
    • Contact: Alaa Atamna, MD; Email: a.atamna86@gmail.com
    • Principal Investigator: Alaa Atamna, MD
    • Sub-Investigator: Noa Eliakim-Raz, MD
  • Tel Aviv, Israel
    • Recruiting
    • Sourasky Medical Center
    • Contact: Ronen Ben-Ami, MD; Email: ronenba@tlvmc.gov.il
    • Principal Investigator: Ronen Ben-Ami, MD
  • Tel Aviv, Israel
    • Recruiting
    • Sheba Medical Center (Tel HaShomer)
    • Contact: Dafna Yahav, MD; Email: dafna.yahav@gmail.com
    • Principal Investigator: Dafna Yahav, MD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Adults (age ≥ 18 years)
2. New onset BSI due to E. coli or Klebsiella spp. in one or more blood cultures associated with evidence of infection.
3. The microorganism will have to be non-susceptible to third generation cephalosporins (ceftriaxone and ceftazidime) and susceptible to both PTZ and meropenem (see microbiological methods).
4. Both community and hospital-acquired bacteremias will be included.
5. We will permit the inclusion of bacteremias due to E. coli or Klebsiella spp. with concomitant growth in blood of skin commensals considered as contaminants.

Exclusion Criteria:

1. More than 72 hr. elapsed since initial blood culture taken, regardless of the time covering antibiotics were started (up to 72 hrs.).
2. Polymicrobial bacteremia. Polymicrobial bacteremia will be defined as either growth of two or more different species of microorganisms in the same blood culture, or growth of different species in two or more separate blood cultures within the same episode.
3. Patients with prior bacteremia or infection that have not completed antimicrobial therapy for the previous infectious episode.
4. Patients with septic shock at the time of enrollment and randomization, defined as at least 2 measurements of systolic blood pressure < 90 mmHg and/or use of vasopressors (dopamine>15μg/kg/min, adrenalin>0.1μg/kg/min, noradrenalin>0.1μg/kg/min, vasopressin any dose) in the 12 hours prior to randomization. In the absence of the use of vasopressors, a systolic blood pressure <90 would need to represent a deviation for the patient's known normal blood pressure.

5. BSI due to specific infections known at the time of randomization:

   1. Endocarditis / endovascular infections
   2. Osteomyelitis (not resected)
   3. Central nervous system infections
6. Allergy to any of the study drugs confirmed by history taken by the investigator
7. Previous enrollment in this trial
8. Concurrent participation in another interventional clinical trial
9. Imminent death (researcher's assessment of expected death within 48 hrs. of recruitment)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: piperacillin tazobactam	Drug: Piperacillin/tazobactam; 4.5 grams QID
Active Comparator: meropenem	Drug: Meropenem; 1 gram TID

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality		30 days from randomization
Treatment failure	death OR fever > 38°C in the last 48 hours OR lack of resolution of symptoms attributed to the focus of infection OR Sequential Failure Organ Assessment (SOFA) score increasing OR positive blood cultures by the time point assessed	7 days from randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality		14 and 90 days from randomization
Treatment failure	death OR fever > 38°C in the last 48 hours OR lack of resolution of symptoms attributed to the focus of infection OR Sequential Failure Organ Assessment (SOFA) score increasing OR positive blood cultures by the time point assessed	14 days and 30 days from randomization
Microbiological failure	Repeat positive blood cultures with index pathogen on day 4 or later from randomization	7 days and 14 days from randomization
Recurrent positive blood cultures (relapse)	recurrent positive blood cultures with the index pathogen after prior sterilization of blood cultures or after end of treatment	30 days and 90 days from randomization
Clostridium difficile associated diarrhea		90 days from randomization
Clinically or microbiologically documented infection other than Gram-negative bacteremia		90 days from randomization
Number of hospital re-admissions		90 days from randomization
Development of resistance	clinical isolates resistant to piperacillin/tazobactam and meropenem and any carbapenem-resistant bacteria	90 days from randomization
Carriage of carbapenemase-producing Enterobacteriaceae (CPE) and non-CPE carbapenem-resistant Enterobacteriaceae in-hospital	detected by weekly rectal surveillance of carriage while in-hospital	90 days from randomization
Total in-hospital days		30 days and 90 days from randomization
Total antibiotic days		30 days and 90 days from randomization
Adverse events	diarrhea, liver function test abnormalities, antibiotic rash or other immediate-type allergy, acute kidney injury defined according to RIFLE criteria	30 days from randomization

Collaborators and Investigators

• Sponsor: Rambam Health Care Campus
• Collaborators: Canadian Institutes of Health Research (CIHR); Hadassah Medical Organization; McGill University Health Centre/Research Institute of the McGill University Health Centre; Rabin Medical Center; Meir Medical Center; Jewish General Hospital; Soroka University Medical Center; The Chaim Sheba Medical Center; Tel Aviv Medical Center; University of Modena and Reggio Emilia
• Investigators: Principal Investigator: Roni Bitterman, MD, Rambam Health Care Campus; Study Director: Mical Paul, MD, Rambam Health Care Campus; Study Director: Leonard Leibovici, MD, Rabin Medical Center; Study Director: Cristina Mussini, MD, University of Modena and Reggio Emilia; Study Director: Noa Eliakim-Raz, MD, Rabin Medical Center, Beilinson campus

Publications and helpful links

General Publications

• Bitterman R, Koppel F, Mussini C, Geffen Y, Chowers M, Rahav G, Nesher L, Ben-Ami R, Turjeman A, Huberman Samuel M, Cheng MP, Lee TC, Leibovici L, Yahav D, Paul M. Piperacillin-tazobactam versus meropenem for treatment of bloodstream infections caused by third-generation cephalosporin-resistant Enterobacteriaceae: a study protocol for a non-inferiority open-label randomised controlled trial (PeterPen). BMJ Open. 2021 Feb 8;11(2):e040210. doi: 10.1136/bmjopen-2020-040210.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2019
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): April 1, 2027

Study Registration Dates

• First Submitted: September 12, 2018
• First Submitted That Met QC Criteria: September 12, 2018
• First Posted (Actual): September 14, 2018

Study Record Updates

• Last Update Posted (Actual): August 1, 2025
• Last Update Submitted That Met QC Criteria: July 29, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: meropenem; bacteremia; enterobacteriaceae; extended spectrum beta-lactamase; piperacillin tazobactam
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Systemic Inflammatory Response Syndrome; Inflammation; Bacterial Infections and Mycoses; Gram-Negative Bacterial Infections; Bacteremia; Sepsis; Infections; Communicable Diseases; Bacterial Infections; Enterobacteriaceae Infections; Anti-Bacterial Agents; Anti-Infective Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; beta-Lactamase Inhibitors; Meropenem; Tazobactam; Piperacillin, Tazobactam Drug Combination; Piperacillin
• Other Study ID Numbers: MOH_2018-12-25_004857

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual patient data collected during the trial will be made available for an unlimited time period following publication of trial results. Data will be available for researchers who provide a methodologically sound proposal and contingent on both the researchers' and our ethics committee approval and the signing of a data sharing agreement.
• IPD Sharing Time Frame: following publication and for unlimited time
• IPD Sharing Access Criteria: proposals should be sent to the principal investigator at ro_oren@rambam.health.gov.il
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

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