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

Study Overview
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Brief Summary
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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.

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

Conditions
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Beta Lactam Resistant Bacterial Infection, Enterobacteriaceae Infections, Bacteremia

Intervention / Treatment
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* Drug: Piperacillin/tazobactam
* Drug: Meropenem


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: open-label randomized controlled trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: piperacillin tazobactam<br> | Drug: Piperacillin/tazobactam<br>* 4.5 grams QID<br>|
| Active Comparator: meropenem<br> | Drug: Meropenem<br>* 1 gram TID<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality |  | 30 days from randomization | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality |  | 14 and 90 days from randomization | 
| 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 | 
| Microbiological failure | Repeat positive blood cultures with index pathogen on day 4 or later from randomization | 7 days and 14 days from randomization | 
| 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 | 
| 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 | clinical isolates resistant to piperacillin/tazobactam and meropenem and any carbapenem-resistant bacteria | 90 days from randomization | 
| 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 | 
| Total in-hospital days |  | 30 days and 90 days from randomization | 
| Total antibiotic days |  | 30 days and 90 days from randomization | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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bacteremia, enterobacteriaceae, extended spectrum beta-lactamase, meropenem, piperacillin tazobactam