Beta Lactam Resistant Bacterial InfectionPhase 4PETERPENNCT03671967
PipEracillin Tazobactam Versus mERoPENem for Treatment of Bloodstream Infections Caused by Cephalosporin-resistant Enterobacteriaceae (PETERPEN)
A Phase 4 study testing Piperacillin/tazobactam and Meropenem in people with Beta Lactam Resistant Bacterial Infection and Enterobacteriaceae Infections, run by Rambam Health Care Campus at 14 sites in 2 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Beta Lactam Resistant Bacterial Infection, Enterobacteriaceae Infections, Bacteremia
- What is being tested?
- Piperacillin/tazobactam and Meropenem
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 1,084 participants
- Where
- 14 sitesin 2 countries
- Study dates
- 1 May 2019to 1 Apr 2027
- Phase
- Phase 4
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
Show all 12Show fewer
- 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)
Trial locations and contacts
14 sites in 2 countries. Contact the study team or a site near you to ask about taking part.
14 sites in 2 countries
Israel8 sites, 8 recruiting
- Recruiting
Soroka Medical Center
Beersheba
Lior Nesher, MD, nesherke@bgu.ac.il
Lior Nesher
- Recruiting
Rambam Health Care Campus
Haifa, Israel, 3435306
Roni Bitterman, 47772991, ro_oren@rambam.health.gov.il
- Recruiting
Hadassah Medical Center
Jerusalem
Jacob strahilevitz, MD, jstrahilevitz@hadassah.org.il
Jacob strahilevitz, MD
- Recruiting
Meir Medical Center
Kfar Saba
Michal Chowers, MD, michalch@clalit.org.il
Michal Chowers, MD
- Recruiting
Sanz Medical Center-Laniado Hospital
Netanya, 42150
Candice Datnow, MD, cdatnow@laniado.org.il
Candice Datnow, MD
- Recruiting
Rabin Medical Center, Beilinson Campus
Petah Tikva
Alaa Atamna, MD, a.atamna86@gmail.com
Alaa Atamna, MD
- Recruiting
Sheba Medical Center (Tel HaShomer)
Tel Aviv
Dafna Yahav, MD, dafna.yahav@gmail.com
Dafna Yahav, MD
- Recruiting
Sourasky Medical Center
Tel Aviv
Ronen Ben-Ami, MD, ronenba@tlvmc.gov.il
Ronen Ben-Ami, MD
Canada6 sites, 6 recruiting
- Recruiting
University of Calgary, Cumming School of Medicine, O'Brien Institute for Public Health
Calgary, Alberta, T2N 4Z6
John Conly, MD, jconly@ucalgary.ca
John Conly, MD
- Recruiting
Kingston General Hospital
Kingston, Ontario
Tony Bai, MD, tony.bai@queensu.ca
Barbara Antuna Puente, MD, Barbarbara.antunapuente@queensu.ca
- Recruiting
Jewish Genral Hospital
Montreal, Quebec, H3T 1E2
Leighanne Parkes, MD
Leighanne Parkes, leighanne.parkes@mcgill.ca
- Recruiting
McGill University Health Centre
Montreal, Quebec
Todd Lee, MD
todd.lee@mcgill.ca
- Recruiting
Eastern Health
St. John's, Newfoundland and Labrador
Peter Daley, MD, pkd336@mun.ca
Peter Daley, MD
- Recruiting
Surrey Memorial Hospital - Fraser Health Authority
Surrey, British Columbia
Kevin Afra, MD, Kevin.Afra@fraserhealth.ca
Kevin Afra, MD
About this study
Official title: 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.
- Being tested
- Piperacillin/tazobactam, Meropenem
- Keywords
- bacteremia, enterobacteriaceae, extended spectrum beta-lactamase, meropenem, piperacillin tazobactam
- Medical subject headings
- Enterobacteriaceae Infections, Bacteremia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Piperacillin/tazobactamDrug
4.5 grams QID
MeropenemDrug
1 gram TID
| Study group | Role | What they receive |
|---|---|---|
| piperacillin tazobactam | Experimental | Not described Receives: Drug: Piperacillin/tazobactam |
| meropenem | Active comparator | Not described Receives: Drug: Meropenem |
What is being measured
The primary outcome is the main question the study is designed to answer.
All-cause mortality
Measured: 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
Measured: 7 days from randomization
Secondary outcomes (12)
All-cause mortality
Measured: 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
Measured: 14 days and 30 days from randomization
Microbiological failure
Repeat positive blood cultures with index pathogen on day 4 or later from randomization
Measured: 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
Measured: 30 days and 90 days from randomization
Clostridium difficile associated diarrhea
Measured: 90 days from randomization
Clinically or microbiologically documented infection other than Gram-negative bacteremia
Measured: 90 days from randomization
Number of hospital re-admissions
Measured: 90 days from randomization
Development of resistance
clinical isolates resistant to piperacillin/tazobactam and meropenem and any carbapenem-resistant bacteria
Measured: 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
Measured: 90 days from randomization
Total in-hospital days
Measured: 30 days and 90 days from randomization
Total antibiotic days
Measured: 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
Measured: 30 days from randomization
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Sep 2018
- Study start1 May 2019
- Primary completion1 Jan 2027 (estimated)
- Study completion1 Apr 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Beta Lactam Resistant Bacterial InfectionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- open-label randomized controlled trial
- Masking
- None (open label)
- Enrolment
- 1,084 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Rambam Health Care Campus
- Sponsor type
- University, hospital or other
- 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
- Responsible party
- Sponsor
- Investigators
- Roni Bitterman, MD, Principal investigator, Rambam Health Care CampusMical Paul, MD, Study director, Rambam Health Care CampusLeonard Leibovici, MD, Study director, Rabin Medical CenterCristina Mussini, MD, Study director, University of Modena and Reggio EmiliaNoa Eliakim-Raz, MD, Study director, Rabin Medical Center, Beilinson Campus
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03671967
- Sponsor's protocol ID
- MOH_2018-12-25_004857
- Acronym
- PETERPEN
- Status last verified
- Jul 2025
- First submitted
- 12 Sep 2018
- Last updated
- 1 Aug 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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.
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.
PubMed 33558347
Study at a glance
From the registry record, last updated by the sponsor on 1 Aug 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Piperacillin Tazobactam Versus Meropenem for Treatment of Bloodstream Infections Caused by Cephalosporin-resistant Enterobacteriaceae- a Non-inferiority Randomized Controlled Trial
- ClinicalTrials.gov ID
- NCT03671967
- Acronym / sponsor ID
- PETERPEN / MOH_2018-12-25_004857
- Keywords
- bacteremia, enterobacteriaceae, extended spectrum beta-lactamase, meropenem, piperacillin tazobactam
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 1,084 participants (estimated)
- Lead sponsor
- Rambam Health Care CampusUniversity, hospital or other
- 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
- Study start
- 1 May 2019 (actual)
- Primary completion
- 1 Jan 2027 (estimated)
- Study completion
- 1 Apr 2027 (estimated)
- First posted
- 14 Sep 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- open-label randomized controlled trial
| Arm | Type | Receives |
|---|---|---|
| piperacillin tazobactam | Experimental | Drug: Piperacillin/tazobactam |
| meropenem | Active comparator | Drug: Meropenem |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (12 listed)
- 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:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Piperacillin/tazobactam4.5 grams QID | Drug | piperacillin tazobactam |
| Meropenem1 gram TID | Drug | meropenem |
Primary outcome
All-cause mortality
Time frame: 30 days from randomization
Treatment failure
Time frame: 7 days from randomization
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
12 secondary outcomes
All-cause mortality
Time frame: 14 and 90 days from randomization
Treatment failure
Time frame: 14 days and 30 days from randomization
Microbiological failure
Time frame: 7 days and 14 days from randomization
Recurrent positive blood cultures (relapse)
Time frame: 30 days and 90 days from randomization
Clostridium difficile associated diarrhea
Time frame: 90 days from randomization
Clinically or microbiologically documented infection other than Gram-negative bacteremia
Time frame: 90 days from randomization
Number of hospital re-admissions
Time frame: 90 days from randomization
Development of resistance
Time frame: 90 days from randomization
Carriage of carbapenemase-producing Enterobacteriaceae (CPE) and non-CPE carbapenem-resistant Enterobacteriaceae in-hospital
Time frame: 90 days from randomization
Total in-hospital days
Time frame: 30 days and 90 days from randomization
Total antibiotic days
Time frame: 30 days and 90 days from randomization
Adverse events
Time frame: 30 days from randomization
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Aug 2025.
- Derived from this study: PubMed 33558347Bitterman 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.
- Individual participant dataSharing planned: Yes. 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.
Related trials for Beta Lactam Resistant Bacterial Infection
Active, not recruiting
Diagnostic Performance and Acceptability of Rectal Swab for Screening of ESBL Enterobacterales
Enterobacteriaceae, Swabs
RecruitingObservational study
Antimicrobial Therapy for Difficult-to-treat Pseudomonas Aeruginosa
Pseudomonas Infections, Pseudomonas Aeruginosa
Not yet recruitingObservational study
Prevalence of Carriage of Extended-Spectrum Beta-Lactamase (ESBL)-Producing Enterobacteria in Preterm Premature Rupture of Membranes : A French Multicenter Cohort Study
Premature Rupture of Membranes, Enterobacteriaceae
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Roni Bitterman, MD principal investigator
Rambam Health Care Campus
Mical Paul, MD study director
Rambam Health Care Campus
Leonard Leibovici, MD study director
Rabin Medical Center
14 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Piperacillin/tazobactam and Meropenem in people with Beta Lactam Resistant Bacterial Infection and Enterobacteriaceae Infections, run by Rambam Health Care Campus at 14 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 1 Aug 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 14 sites in Israel, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Mical Paul, MD (972-4-7772991, m_paul@rambam.health.gov.il), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
All-cause mortality (time frame: 30 days from randomization). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03671967, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Aug 2025.