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

Sponsor

Rambam Health Care Campus (Other)

Overall Status

Recruiting

CT.gov ID

NCT03671967

Collaborator

Rabin Medical Center (Other), University of Modena and Reggio Emilia (Other), Tel Aviv Medical Center (Other), Meir Medical Center (Other), Soroka University Medical Center (Other), The Chaim Sheba Medical Center (Other), McGill University Health Centre/Research Institute of the McGill University Health Centre (Other), Jewish General Hospital (Other), Canadian Institutes of Health Research (CIHR) (Other), Hadassah Medical Organization (Other)

1,084

Enrollment

Locations

Arms

Anticipated Duration (Months)

135.5

Patients Per Site

2.3

Patients Per Site Per Month

Study Details

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.

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

Study Design

Study Type:

Interventional

Anticipated Enrollment :

1084 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

open-label randomized controlled trialopen-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

Actual Study Start Date :

May 1, 2019

Anticipated Primary Completion Date :

Jan 1, 2024

Anticipated Study Completion Date :

Apr 1, 2024

Arms and Interventions

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

Arm

Intervention/Treatment

Experimental: piperacillin tazobactam

Drug: Piperacillin/tazobactam

4.5 grams QID

Active Comparator: meropenem

Drug: Meropenem

1 gram TID

Outcome Measures

Primary Outcome Measures

All-cause mortality [30 days from randomization]
Treatment failure [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

All-cause mortality [14 and 90 days from randomization]
Treatment failure [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 [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) [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 [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 [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 [90 days from randomization]
detected by weekly rectal surveillance of carriage while in-hospital
Total in-hospital days [30 days and 90 days from randomization]
Total antibiotic days [30 days and 90 days from randomization]
Adverse events [30 days from randomization]
diarrhea, liver function test abnormalities, antibiotic rash or other immediate-type allergy, acute kidney injury defined according to RIFLE criteria

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	McGill University Health Centre	Montreal, Quebec	Canada
2	Soroka Medical Center	Be'er Sheva	Israel
3	Rambam Health Care Campus	Haifa	Israel	3435306
4	Hadassah Medical Center	Jerusalem	Israel
5	Meir Medical Center	Kfar Saba	Israel
6	Rabin Medical Center, Beilinson Campus	Petah tikva	Israel
7	Sheba Medical Center (Tel HaShomer)	Tel Aviv	Israel
8	Sourasky Medical Center	Tel Aviv	Israel

Sponsors and Collaborators

Rambam Health Care Campus
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