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

Overview

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.

Full Title of Study: “Piperacillin Tazobactam Versus Meropenem for Treatment of Bloodstream Infections Caused by Cephalosporin-resistant Enterobacteriaceae- a Non-inferiority Randomized Controlled Trial”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: January 2026

Interventions

  • Drug: Piperacillin/tazobactam
    • 4.5 grams QID
  • Drug: Meropenem
    • 1 gram TID

Arms, Groups and Cohorts

  • Experimental: piperacillin tazobactam
  • Active Comparator: meropenem

Clinical Trial Outcome Measures

Primary Measures

  • 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

Secondary Measures

  • All-cause mortality
    • Time Frame: 14 and 90 days from randomization
  • 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
  • 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
  • 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
  • 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
    • 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
    • Time Frame: 90 days from randomization
    • detected by weekly rectal surveillance of carriage while in-hospital
  • 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
    • diarrhea, liver function test abnormalities, antibiotic rash or other immediate-type allergy, acute kidney injury defined according to RIFLE criteria

Participating in This Clinical Trial

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)

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Rambam Health Care Campus
  • Collaborator
    • Rabin Medical Center
  • Provider of Information About this Clinical Study
    • Principal Investigator: Roni Oren MD, principal investigator – Rambam Health Care Campus
  • Overall Official(s)
    • 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
    • Cristina Mussini, MD, Study Director, University of Modena and Reggio Emilia
    • Noa Eliakim-Raz, MD, Study Director, Rabin Medical Center, Beilinson Campus
  • Overall Contact(s)
    • Roni Bitterman, MD, 972-4-7772991, ro_oren@rambam.health.gov.il

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