Bacteremia, Beta Lactam Resistant Bacterial Infection, Enterobacteriaceae Infections
Conditions
Keywords
bacteremia, enterobacteriaceae, extended spectrum beta-lactamase, meropenem, piperacillin tazobactam
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.
Interventions
DRUGPiperacillin/tazobactam
4.5 grams QID
DRUGMeropenem
1 gram TID
Sponsors
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
Rambam Health Care Campus
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
open-label randomized controlled trial
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| All-cause mortality | 14 and 90 days from randomization | — |
| 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 |
| Development of resistance | 90 days from randomization | clinical isolates resistant to piperacillin/tazobactam and meropenem and any carbapenem-resistant bacteria |
| 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 |
Countries
Canada, Israel
Contacts
Primary ContactMical Paul, MD
Backup ContactRoni Bitterman, MD
Outcome results
None listed