Clinical trial NCT03671967: PipEracillin Tazobactam Versus MERoPENem for Treatment of Bloodstream Infections Caused by Cephalosporin-resistant Enterobacteriaceae (PETERPEN)
Official title: Piperacillin Tazobactam Versus Meropenem for Treatment of Bloodstream Infections Caused by Cephalosporin-resistant Enterobacteriaceae- a Non-inferiority Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Beta Lactam Resistant Bacterial Infection
Enterobacteriaceae Infections
Bacteremia
Keywords: bacteremia
enterobacteriaceae
extended spectrum beta-lactamase
meropenem
piperacillin tazobactam
Lead sponsor: Rambam Health Care Campus
Sponsor class: OTHER
Collaborators: name: Rabin Medical Center
name: University of Modena and Reggio Emilia
name: Tel Aviv Medical Center
name: Meir Medical Center
name: Soroka University Medical Center
name: The Chaim Sheba Medical Center
name: McGill University Health Centre/Research Institute of the McGill University Health Centre
name: Jewish General Hospital
name: Canadian Institutes of Health Research (CIHR)
name: Hadassah Medical Organization
First posted: 2018-09-14
Enrollment: 1084
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: open-label randomized controlled trial
Primary purpose: TREATMENT

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.


Eligibility 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)

Primary outcomes:
measure: All-cause mortality
timeFrame: 30 days from randomization
measure: Treatment failure
timeFrame: 7 days from randomization
Secondary outcomes:
measure: All-cause mortality
timeFrame: 14 and 90 days from randomization
measure: Treatment failure
timeFrame: 14 days and 30 days from randomization
measure: Microbiological failure
timeFrame: 7 days and 14 days from randomization
measure: Recurrent positive blood cultures (relapse)
timeFrame: 30 days and 90 days from randomization
measure: Clostridium difficile associated diarrhea
timeFrame: 90 days from randomization
measure: Clinically or microbiologically documented infection other than Gram-negative bacteremia
timeFrame: 90 days from randomization
measure: Number of hospital re-admissions
timeFrame: 90 days from randomization
measure: Development of resistance
timeFrame: 90 days from randomization
measure: Carriage of carbapenemase-producing Enterobacteriaceae (CPE) and non-CPE carbapenem-resistant Enterobacteriaceae in-hospital
timeFrame: 90 days from randomization
measure: Total in-hospital days
timeFrame: 30 days and 90 days from randomization
measure: Total antibiotic days
timeFrame: 30 days and 90 days from randomization
measure: Adverse events
timeFrame: 30 days from randomization
Other outcomes:
Locations:
city: Calgary
country: Canada
facility: University of Calgary, Cumming School of Medicine, O'Brien Institute for Public Health
state: Alberta
city: Surrey
country: Canada
facility: Surrey Memorial Hospital - Fraser Health Authority
state: British Columbia
city: Saint John's
country: Canada
facility: Eastern Health
state: Newfoundland and Labrador
city: Montreal
country: Canada
facility: Jewish Genral Hospital
state: Quebec
city: Montreal, Quebec
country: Canada
facility: McGill University Health Centre
city: Be'er Sheva
country: Israel
facility: Soroka Medical Center
city: Haifa
country: Israel
facility: Rambam Health Care Campus
city: Jerusalem
country: Israel
facility: Hadassah Medical Center
city: Kfar Saba
country: Israel
facility: Meir Medical Center
city: Netanya
country: Israel
facility: Sanz Medical Center-Laniado Hospital
city: Petah tikva
country: Israel
facility: Rabin Medical Center, Beilinson Campus
city: Tel Aviv
country: Israel
facility: Sheba Medical Center (Tel HaShomer)
city: Tel Aviv
country: Israel
facility: Sourasky Medical Center
Study officials:
affiliation: Rambam Health Care Campus
name: Roni Bitterman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Rambam Health Care Campus
name: Mical Paul, MD
role: STUDY_DIRECTOR
affiliation: Rabin Medical Center
name: Leonard Leibovici, MD
role: STUDY_DIRECTOR
affiliation: University of Modena and Reggio Emilia
name: Cristina Mussini, MD
role: STUDY_DIRECTOR
affiliation: Rabin Medical Center, Beilinson Campus
name: Noa Eliakim-Raz, MD
role: STUDY_DIRECTOR
References:
citation: Bitterman R, Koppel F, Mussini C, Geffen Y, Chowers M, Rahav G, Nesher L, Ben-Ami R, Turjeman A, Huberman Samuel M, Cheng MP, Lee TC, Leibovici L, Yahav D, Paul M. Piperacillin-tazobactam versus meropenem for treatment of bloodstream infections caused by third-generation cephalosporin-resistant Enterobacteriaceae: a study protocol for a non-inferiority open-label randomised controlled trial (PeterPen). BMJ Open. 2021 Feb 8;11(2):e040210. doi: 10.1136/bmjopen-2020-040210.