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

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ClinicalTrials.gov Identifier: NCT03671967
Recruitment Status : Not yet recruiting
First Posted : September 14, 2018
Last Update Posted : March 15, 2019
Sponsor:
Collaborators:
Rabin Medical Center
The Baruch Padeh Medical Center, Poriya
Emek Medical Center
University of Modena and Reggio Emilia
Tel Aviv Medical Center
Meir Medical Center
Soroka University Medical Center
Laniado Hospital
The Chaim Sheba Medical Center
Hadassah Medical Organization
Università di Pisa, Cisanello Hospital
Universita di Verona
Azienda Ospedaliera Universitaria di Bologna Policlinico S. Orsola Malpighi
University of Milan
Istituti Ospitalieri di Cremona
Hospital Universitario Virgen Macarena
McGill University Health Centre/Research Institute of the McGill University Health Centre
Jewish General Hospital
Information provided by (Responsible Party):
Roni Oren MD, Rambam Health Care Campus

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.

Condition or disease Intervention/treatment Phase
Beta Lactam Resistant Bacterial Infection Enterobacteriaceae Infections Bacteremia Drug: Piperacillin/tazobactam Drug: Meropenem Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1084 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: open-label randomized controlled trial
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Piperacillin Tazobactam Versus Meropenem for Treatment of Bloodstream Infections Caused by Cephalosporin-resistant Enterobacteriaceae- a Non-inferiority Randomized Controlled Trial
Estimated Study Start Date : April 2019
Estimated Primary Completion Date : January 2024
Estimated Study Completion Date : April 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: piperacillin tazobactam Drug: Piperacillin/tazobactam
4.5 grams QID

Active Comparator: meropenem Drug: Meropenem
1 gram TID




Primary Outcome Measures :
  1. All-cause mortality [ Time Frame: 30 days from randomization ]
  2. 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


Secondary Outcome Measures :
  1. All-cause mortality [ Time Frame: 14 and 90 days from randomization ]
  2. Treatment failure [ Time Frame: 14 days and 30 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

  3. Microbiological failure [ Time Frame: 7 days and 14 days from randomization ]
    Repeat positive blood cultures with index pathogen on day 4 or later from randomization

  4. Recurrent positive blood cultures (relapse) [ Time Frame: 30 days and 90 days from randomization ]
    recurrent positive blood cultures with the index pathogen after prior sterilization of blood cultures or after end of treatment

  5. Clostridium difficile associated diarrhea [ Time Frame: 90 days from randomization ]
  6. Clinically or microbiologically documented infection other than Gram-negative bacteremia [ Time Frame: 90 days from randomization ]
  7. Number of hospital re-admissions [ Time Frame: 90 days from randomization ]
  8. Development of resistance [ Time Frame: 90 days from randomization ]
    clinical isolates resistant to piperacillin/tazobactam and meropenem and any carbapenem-resistant bacteria

  9. Carriage of carbapenemase-producing Enterobacteriaceae (CPE) and non-CPE carbapenem-resistant Enterobacteriaceae in-hospital [ Time Frame: 90 days from randomization ]
    detected by weekly rectal surveillance of carriage while in-hospital

  10. Total in-hospital days [ Time Frame: 30 days and 90 days from randomization ]
  11. Total antibiotic days [ Time Frame: 30 days and 90 days from randomization ]
  12. Adverse events [ Time Frame: 30 days from randomization ]
    diarrhea, liver function test abnormalities, antibiotic rash or other immediate-type allergy, acute kidney injury defined according to RIFLE criteria



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03671967


Contacts
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Contact: Roni Bitterman, MD 972-4-7772991 ro_oren@rambam.health.gov.il
Contact: Mical Paul, MD 972-4-7772991 m_paul@rambam.health.gov.il

Sponsors and Collaborators
Rambam Health Care Campus
Rabin Medical Center
The Baruch Padeh Medical Center, Poriya
Emek Medical Center
University of Modena and Reggio Emilia
Tel Aviv Medical Center
Meir Medical Center
Soroka University Medical Center
Laniado Hospital
The Chaim Sheba Medical Center
Hadassah Medical Organization
Università di Pisa, Cisanello Hospital
Universita di Verona
Azienda Ospedaliera Universitaria di Bologna Policlinico S. Orsola Malpighi
University of Milan
Istituti Ospitalieri di Cremona
Hospital Universitario Virgen Macarena
McGill University Health Centre/Research Institute of the McGill University Health Centre
Jewish General Hospital
Investigators
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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

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Responsible Party: Roni Oren MD, principal investigator, Rambam Health Care Campus
ClinicalTrials.gov Identifier: NCT03671967     History of Changes
Other Study ID Numbers: MOH_2018-12-25_004857
First Posted: September 14, 2018    Key Record Dates
Last Update Posted: March 15, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Roni Oren MD, Rambam Health Care Campus:
bacteremia
enterobacteriaceae
extended spectrum beta-lactamase
meropenem
piperacillin tazobactam
Additional relevant MeSH terms:
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Infection
Communicable Diseases
Bacterial Infections
Bacteremia
Enterobacteriaceae Infections
Sepsis
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Gram-Negative Bacterial Infections
Meropenem
Tazobactam
Piperacillin
Piperacillin, Tazobactam Drug Combination
Cephalosporins
Anti-Bacterial Agents
Anti-Infective Agents
beta-Lactamase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action