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

Bacteremia Clinical Trial

— PETERPEN  

Official title:

Piperacillin Tazobactam Versus Meropenem for Treatment of Bloodstream Infections Caused by Cephalosporin-resistant Enterobacteriaceae- a Non-inferiority Randomized Controlled Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03671967
• Other study ID #: MOH_2018-12-25_004857
• Status: Recruiting
• Phase: Phase 4
• Start date: May 1, 2019
• Est. completion date: April 2026

Study information

• Verified date: February 2024
• Source: Rambam Health Care Campus
• Contact: Roni Bitterman, MD
• Phone: 972-4-7772991
• Email: ro_oren[@]rambam.health.gov.il
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1084
• Est. completion date: April 2026
• Est. primary completion date: January 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Bacteremia
• Bacterial Infections
• Beta Lactam Resistant Bacterial Infection
• Communicable Diseases
• Enterobacteriaceae Infections
• Infections
• Sepsis

Intervention

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

Locations

Country	Name	City	State
Canada	Jewish Genral Hospital	Montreal	Quebec
Canada	McGill University Health Centre	Montreal, Quebec
Canada	Eastern Health	Saint John's	Newfoundland and Labrador
Canada	Surrey Memorial Hospital - Fraser Health Authority	Surrey	British Columbia
Israel	Soroka Medical Center	Be'er Sheva
Israel	Rambam Health Care Campus	Haifa
Israel	Hadassah Medical Center	Jerusalem
Israel	Meir Medical Center	Kfar Saba
Israel	Rabin Medical Center, Beilinson Campus	Petah tikva
Israel	Sheba Medical Center (Tel HaShomer)	Tel Aviv
Israel	Sourasky Medical Center	Tel Aviv

Sponsors (11)

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

Countries where clinical trial is conducted

Canada,  Israel, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	All-cause mortality		30 days from randomization
Primary	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	7 days from randomization
Secondary	All-cause mortality		14 and 90 days from randomization
Secondary	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	14 days and 30 days from randomization
Secondary	Microbiological failure	Repeat positive blood cultures with index pathogen on day 4 or later from randomization	7 days and 14 days from randomization
Secondary	Recurrent positive blood cultures (relapse)	recurrent positive blood cultures with the index pathogen after prior sterilization of blood cultures or after end of treatment	30 days and 90 days from randomization
Secondary	Clostridium difficile associated diarrhea		90 days from randomization
Secondary	Clinically or microbiologically documented infection other than Gram-negative bacteremia		90 days from randomization
Secondary	Number of hospital re-admissions		90 days from randomization
Secondary	Development of resistance	clinical isolates resistant to piperacillin/tazobactam and meropenem and any carbapenem-resistant bacteria	90 days from randomization
Secondary	Carriage of carbapenemase-producing Enterobacteriaceae (CPE) and non-CPE carbapenem-resistant Enterobacteriaceae in-hospital	detected by weekly rectal surveillance of carriage while in-hospital	90 days from randomization
Secondary	Total in-hospital days		30 days and 90 days from randomization
Secondary	Total antibiotic days		30 days and 90 days from randomization
Secondary	Adverse events	diarrhea, liver function test abnormalities, antibiotic rash or other immediate-type allergy, acute kidney injury defined according to RIFLE criteria	30 days from randomization