Data regarding optimal treatment for extended-spectrum beta-lactamase (ESBL) producing Enterobacterales bloodstream 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.
PeterPen-SPICE-M will expland the PeterPen trial. In PeterPen we recruit patients with bacteremia caused by 3rd generation cephalosporin-resistant E. coli or Klebsiella pneumoniae. In SPICE-M we will recruit also patients with bacteremia caused by 3rd generation cephalosporin-resistant Serratia marcescens, Providencia stuartii \& rettgeri, Indole positive Proteus spp. (Proteus vulgaris), Citrobacter freundii, Enterobacter cloacae, Klebsiella aerogenes and Morganella morganii. In both trials patients will be allocated within 72 hours of blood culture taking to piperacillin-tazobactam vs. meropenem to complete at least 7 days of covering antibiotic therapy.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
4.5 grams QID
1 gram TID
Rambam Health Care Campus
Haifa, Israel
Hadassah Medical Center
Jerusalem, Israel
Rabin Medical Center, Beilinson Hospital
Petah Tikva, Israel
Sheba Tel HaShomer Medical Campus
Ramat Gan, Israel
All-cause mortality
Primary Outcome Measure
Time frame: 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
Time frame: 7 days from randomization]
All-cause mortality
Number of deceased patients
Time frame: 14 and 90 days from randomization]
Number of participants with 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
Time frame: 14 days and 30 days from randomization
Number of participants with microbiological failure
Repeat positive blood cultures with index pathogen on day 4 or later from randomization
Time frame: 7 days and 14 days from randomization
Number of participants with recurrent positive blood cultures (relapse)
recurrent positive blood cultures with the index pathogen after prior sterilization of blood cultures or after end of treatment
Time frame: 30 days and 90 days from randomization
Number of participants with Clostridium difficile associated diarrhea
Diarrhea with positive Clostridium difficile toxin test
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Time frame: 90 days from randomization
Secondary bacterial infections
Number of participants with a new clinically-significant infection, with or without microbiological documentation. Defined using NHSN criteria for healthcare-associated infections.
Time frame: 90 days from randomization
Number of participants with hospital re-admissions
Hospital re-admission, excluding index hospitalization
Time frame: 90 days from randomization
Number of participants with development of antimicrobial resistance
clinical isolates resistant to piperacillin/tazobactam and meropenem and any carbapenem-resistant bacteria
Time frame: 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
New acquisition of carbapenemase-producing Enterobacteriaceae (CPE) and non-CPE carbapenem-resistant Enterobacteriaceae, detected through rectal surveillance or clinical cultures
Time frame: 90 days from randomization
Total in-hospital days
Total of in-hospital days per participant, including all admissions
Time frame: 30 days and 90 days from randomization
Total antibiotic days
Total antibiotic days per participant within all admissions
Time frame: 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
Time frame: 30 days