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

Phase 4

Recruiting

• Conditions: Beta Lactam Resistant Bacterial Infection; Enterobacteriaceae Infections; Bacteremia
• Interventions: Drug: Piperacillin/tazobactam; Drug: Meropenem

• Registration Number: NCT03671967
• Lead Sponsor: 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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2018-09-12
• Study First Submitted QC: 2018-09-12
• Study First Posted: 2018-09-14
• Study Start: 2019-05-01
• Status Verified: 2024-02
• Last Update Submitted: 2025-01-27
• Last Update Posted: 2025-01-29
• Primary Completion: 2026-01
• Study Completion: 2026-04

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 1084

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)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
piperacillin tazobactam	Piperacillin/tazobactam	-
meropenem	Meropenem	-

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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

Trial Locations

Locations (13)

Hadassah Medical Center; 🇮🇱 Jerusalem, Israel

Sourasky Medical Center; 🇮🇱 Tel Aviv, Israel

Sheba Medical Center (Tel HaShomer); 🇮🇱 Tel Aviv, Israel

University of Calgary, Cumming School of Medicine, O'Brien Institute for Public Health; 🇨🇦 Calgary, Alberta, Canada

Sanz Medical Center-Laniado Hospital; 🇮🇱 Netanya, Israel

Surrey Memorial Hospital - Fraser Health Authority; 🇨🇦 Surrey, British Columbia, Canada

Jewish Genral Hospital; 🇨🇦 Montreal, Quebec, Canada

Eastern Health; 🇨🇦 Saint John's, Newfoundland and Labrador, Canada

McGill University Health Centre; 🇨🇦 Montreal, Quebec, Canada

Soroka Medical Center; 🇮🇱 Be'er Sheva, Israel

Rambam Health Care Campus; 🇮🇱 Haifa, Israel

Meir Medical Center; 🇮🇱 Kfar Saba, Israel

Rabin Medical Center, Beilinson Campus; 🇮🇱 Petah tikva, Israel