Back to resultsPipEracillin Tazobactam Versus mERoPENem for Treatment of Bloodstream Infections Caused by Cephalosporin-resistant Enterobacteriaceae (PETERPEN) (PETERPEN)
Primary Purpose
Beta Lactam Resistant Bacterial Infection, Enterobacteriaceae Infections, Bacteremia
Status
Recruiting
Phase
Phase 4
Locations
International
Study Type
Interventional
Intervention
Piperacillin/tazobactam
Meropenem
Sponsored by
About this trial
This is an interventional treatment trial for Beta Lactam Resistant Bacterial Infection focused on measuring bacteremia, enterobacteriaceae, extended spectrum beta-lactamase, meropenem, piperacillin tazobactam
Eligibility Criteria
Inclusion Criteria:
- Adults (age ≥ 18 years)
- New onset BSI due to E. coli or Klebsiella spp. in one or more blood cultures associated with evidence of infection.
- 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).
- Both community and hospital-acquired bacteremias will be included.
- 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:
- More than 72 hr. elapsed since initial blood culture taken, regardless of the time covering antibiotics were started (up to 72 hrs.).
- 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.
- Patients with prior bacteremia or infection that have not completed antimicrobial therapy for the previous infectious episode.
- 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.
BSI due to specific infections known at the time of randomization:
- Endocarditis / endovascular infections
- Osteomyelitis (not resected)
- Central nervous system infections
- Allergy to any of the study drugs confirmed by history taken by the investigator
- Previous enrollment in this trial
- Concurrent participation in another interventional clinical trial
- Imminent death (researcher's assessment of expected death within 48 hrs. of recruitment)
Sites / Locations
- Surrey Memorial Hospital - Fraser Health AuthorityRecruiting
- Eastern HealthRecruiting
- Centre Hospitalier Universitaire de SherbrookeRecruiting
- McGill University Health CentreRecruiting
- Soroka Medical CenterRecruiting
- Rambam Health Care CampusRecruiting
- Hadassah Medical CenterRecruiting
- Meir Medical CenterRecruiting
- Rabin Medical Center, Beilinson CampusRecruiting
- Sheba Medical Center (Tel HaShomer)Recruiting
- Sourasky Medical CenterRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
piperacillin tazobactam
meropenem
Arm Description
Outcomes
Primary Outcome Measures
All-cause mortality
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
Secondary Outcome Measures
All-cause mortality
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
Microbiological failure
Repeat positive blood cultures with index pathogen on day 4 or later 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
Clostridium difficile associated diarrhea
Clinically or microbiologically documented infection other than Gram-negative bacteremia
Number of hospital re-admissions
Development of resistance
clinical isolates resistant to piperacillin/tazobactam and meropenem and any carbapenem-resistant bacteria
Carriage of carbapenemase-producing Enterobacteriaceae (CPE) and non-CPE carbapenem-resistant Enterobacteriaceae in-hospital
detected by weekly rectal surveillance of carriage while in-hospital
Total in-hospital days
Total antibiotic days
Adverse events
diarrhea, liver function test abnormalities, antibiotic rash or other immediate-type allergy, acute kidney injury defined according to RIFLE criteria
Full Information
NCT ID
NCT03671967
First Posted
September 12, 2018
Last Updated
March 21, 2023
Sponsor
Rambam Health Care Campus
Collaborators
Rabin Medical Center, University of Modena and Reggio Emilia, Tel Aviv Medical Center, Meir Medical Center, Soroka University Medical Center, The Chaim Sheba Medical Center, McGill University Health Centre/Research Institute of the McGill University Health Centre, Jewish General Hospital, Canadian Institutes of Health Research (CIHR), Hadassah Medical Organization
1. Study Identification
Unique Protocol Identification Number
NCT03671967
Brief Title
PipEracillin Tazobactam Versus mERoPENem for Treatment of Bloodstream Infections Caused by Cephalosporin-resistant Enterobacteriaceae (PETERPEN)
Acronym
PETERPEN
Official Title
Piperacillin Tazobactam Versus Meropenem for Treatment of Bloodstream Infections Caused by Cephalosporin-resistant Enterobacteriaceae- a Non-inferiority Randomized Controlled Trial
Study Type
Interventional
2. Study Status
Record Verification Date
February 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 1, 2019 (Actual)
Primary Completion Date
January 2024 (Anticipated)
Study Completion Date
April 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Rambam Health Care Campus
Collaborators
Rabin Medical Center, University of Modena and Reggio Emilia, Tel Aviv Medical Center, Meir Medical Center, Soroka University Medical Center, The Chaim Sheba Medical Center, McGill University Health Centre/Research Institute of the McGill University Health Centre, Jewish General Hospital, Canadian Institutes of Health Research (CIHR), Hadassah Medical Organization
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Beta Lactam Resistant Bacterial Infection, Enterobacteriaceae Infections, Bacteremia
Keywords
bacteremia, enterobacteriaceae, extended spectrum beta-lactamase, meropenem, piperacillin tazobactam
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Model Description
open-label randomized controlled trial
Masking
None (Open Label)
Allocation
Randomized
Enrollment
1084 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
piperacillin tazobactam
Arm Type
Experimental
Arm Title
meropenem
Arm Type
Active Comparator
Intervention Type
Drug
Intervention Name(s)
Piperacillin/tazobactam
Intervention Description
4.5 grams QID
Intervention Type
Drug
Intervention Name(s)
Meropenem
Intervention Description
1 gram TID
Primary Outcome Measure Information:
Title
All-cause mortality
Time Frame
30 days from randomization
Title
Treatment failure
Description
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
Time Frame
7 days from randomization
Secondary Outcome Measure Information:
Title
All-cause mortality
Time Frame
14 and 90 days from randomization
Title
Treatment failure
Description
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
Time Frame
14 days and 30 days from randomization
Title
Microbiological failure
Description
Repeat positive blood cultures with index pathogen on day 4 or later from randomization
Time Frame
7 days and 14 days from randomization
Title
Recurrent positive blood cultures (relapse)
Description
recurrent positive blood cultures with the index pathogen after prior sterilization of blood cultures or after end of treatment
Time Frame
30 days and 90 days from randomization
Title
Clostridium difficile associated diarrhea
Time Frame
90 days from randomization
Title
Clinically or microbiologically documented infection other than Gram-negative bacteremia
Time Frame
90 days from randomization
Title
Number of hospital re-admissions
Time Frame
90 days from randomization
Title
Development of resistance
Description
clinical isolates resistant to piperacillin/tazobactam and meropenem and any carbapenem-resistant bacteria
Time Frame
90 days from randomization
Title
Carriage of carbapenemase-producing Enterobacteriaceae (CPE) and non-CPE carbapenem-resistant Enterobacteriaceae in-hospital
Description
detected by weekly rectal surveillance of carriage while in-hospital
Time Frame
90 days from randomization
Title
Total in-hospital days
Time Frame
30 days and 90 days from randomization
Title
Total antibiotic days
Time Frame
30 days and 90 days from randomization
Title
Adverse events
Description
diarrhea, liver function test abnormalities, antibiotic rash or other immediate-type allergy, acute kidney injury defined according to RIFLE criteria
Time Frame
30 days from randomization
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Adults (age ≥ 18 years)
New onset BSI due to E. coli or Klebsiella spp. in one or more blood cultures associated with evidence of infection.
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).
Both community and hospital-acquired bacteremias will be included.
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:
More than 72 hr. elapsed since initial blood culture taken, regardless of the time covering antibiotics were started (up to 72 hrs.).
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.
Patients with prior bacteremia or infection that have not completed antimicrobial therapy for the previous infectious episode.
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.
BSI due to specific infections known at the time of randomization:
Endocarditis / endovascular infections
Osteomyelitis (not resected)
Central nervous system infections
Allergy to any of the study drugs confirmed by history taken by the investigator
Previous enrollment in this trial
Concurrent participation in another interventional clinical trial
Imminent death (researcher's assessment of expected death within 48 hrs. of recruitment)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Roni Bitterman, MD
Phone
972-4-7772991
Email
ro_oren@rambam.health.gov.il
First Name & Middle Initial & Last Name or Official Title & Degree
Mical Paul, MD
Phone
972-4-7772991
Email
m_paul@rambam.health.gov.il
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Roni Bitterman, MD
Organizational Affiliation
Rambam Health Care Campus
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Mical Paul, MD
Organizational Affiliation
Rambam Health Care Campus
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Leonard Leibovici, MD
Organizational Affiliation
Rabin Medical Center
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Cristina Mussini, MD
Organizational Affiliation
University of Modena and Reggio Emilia
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Noa Eliakim-Raz, MD
Organizational Affiliation
Rabin Medical Center, Beilinson Campus
Official's Role
Study Director
Facility Information:
Facility Name
Surrey Memorial Hospital - Fraser Health Authority
City
Surrey
State/Province
British Columbia
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kevin Afra, MD
Email
Kevin.Afra@fraserhealth.ca
First Name & Middle Initial & Last Name & Degree
Kevin Afra, MD
Facility Name
Eastern Health
City
Saint John's
State/Province
Newfoundland and Labrador
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Peter Daley, MD
Email
pkd336@mun.ca
First Name & Middle Initial & Last Name & Degree
Peter Daley, MD
Facility Name
Centre Hospitalier Universitaire de Sherbrooke
City
Sherbrooke
State/Province
Quebec
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alex Carignan, MD
Email
alex.carignan@usherbrooke.ca
First Name & Middle Initial & Last Name & Degree
Alex Carignan, MD
Facility Name
McGill University Health Centre
City
Montreal, Quebec
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Todd Lee, MD
Email
todd.lee@mcgill.ca
First Name & Middle Initial & Last Name & Degree
Todd Lee, MD
Facility Name
Soroka Medical Center
City
Be'er Sheva
Country
Israel
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lior Nesher, MD
Email
nesherke@bgu.ac.il
First Name & Middle Initial & Last Name & Degree
Lior Nesher
Facility Name
Rambam Health Care Campus
City
Haifa
ZIP/Postal Code
3435306
Country
Israel
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Roni Bitterman
Phone
47772991
Email
ro_oren@rambam.health.gov.il
Facility Name
Hadassah Medical Center
City
Jerusalem
Country
Israel
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jacob strahilevitz, MD
Email
jstrahilevitz@hadassah.org.il
First Name & Middle Initial & Last Name & Degree
Jacob strahilevitz, MD
Facility Name
Meir Medical Center
City
Kfar Saba
Country
Israel
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michal Chowers, MD
Email
michalch@clalit.org.il
First Name & Middle Initial & Last Name & Degree
Michal Chowers, MD
Facility Name
Rabin Medical Center, Beilinson Campus
City
Petah tikva
Country
Israel
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alaa Atamna, MD
Email
a.atamna86@gmail.com
First Name & Middle Initial & Last Name & Degree
Alaa Atamna, MD
First Name & Middle Initial & Last Name & Degree
Noa Eliakim-Raz, MD
Facility Name
Sheba Medical Center (Tel HaShomer)
City
Tel Aviv
Country
Israel
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Dafna Yahav, MD
Email
dafna.yahav@gmail.com
First Name & Middle Initial & Last Name & Degree
Dafna Yahav, MD
Facility Name
Sourasky Medical Center
City
Tel Aviv
Country
Israel
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ronen Ben-Ami, MD
Email
ronenba@tlvmc.gov.il
First Name & Middle Initial & Last Name & Degree
Ronen Ben-Ami, MD
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing 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
Citations:
PubMed Identifier
33558347
Citation
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.
Results Reference
derived
Learn more about this trial
PipEracillin Tazobactam Versus mERoPENem for Treatment of Bloodstream Infections Caused by Cephalosporin-resistant Enterobacteriaceae (PETERPEN)
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