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| Name | Class |
|---|---|
| The Chaim Sheba Medical Center | OTHER |
| Rabin Medical Center | OTHER |
| Hadassah Medical Organization | OTHER |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| piperacillin tazobactam | Experimental |
| |
| meropenem | Active Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Piperacillin / Tazobactam Injection | Drug | 4.5 grams QID |
| |
| Measure | Description | Time Frame |
|---|---|---|
| All-cause mortality | Primary Outcome Measure | 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] |
| Measure | Description | Time Frame |
|---|---|---|
| All-cause mortality | Number of deceased patients | 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 |
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Inclusion Criteria:
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:
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) or patient in palliative care
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| Name | Affiliation | Role |
|---|---|---|
| Mical Paul, MD | Rambam Health Care Campus | Principal Investigator |
| Dafna Yahav, MD | Sheba Tel HaShomer Medical Campus | Principal Investigator |
| Alaa Atamna, MD | Rabin Medical Center, Beilinson Campus | Principal Investigator |
| Roni Bitterman, MD | Rambam Health Care Campus | Study Director |
| Noa Eliakim-Raz, MD | Rabin Medical Center, Beilinson Campus | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Rambam Health Care Campus | Haifa | Israel | ||||
| Hadassah Medical Center |
De-identified individual patient data collected during the trial will be made available for an unlimited time period following publication of trial results. Data will be available for researchers who provide a methodologically sound proposal and contingent on both the researchers' and our ethics committee approval and the signing of a data sharing agreement.
following publication and for unlimited time
proposals should be sent to the principal investigator at m_paul@rambam.health.gov.il
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| Meropenem |
| Drug |
1 gram TID |
|
| 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 | 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 | 30 days and 90 days from randomization |
| Number of participants with Clostridium difficile associated diarrhea | Diarrhea with positive Clostridium difficile toxin test | 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. | 90 days from randomization |
| Number of participants with hospital re-admissions | Hospital re-admission, excluding index hospitalization | 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 | 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 | 90 days from randomization |
| Total in-hospital days | Total of in-hospital days per participant, including all admissions | 30 days and 90 days from randomization |
| Total antibiotic days | Total antibiotic days per participant within all admissions | 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 |
| Jerusalem |
| Israel |
| Rabin Medical Center, Beilinson Hospital | Petah Tikva | Israel |
| Sheba Tel HaShomer Medical Campus | Ramat Gan | Israel |
| ID | Term |
|---|---|
| D004756 | Enterobacteriaceae Infections |
| D016470 | Bacteremia |
| ID | Term |
|---|---|
| D016905 | Gram-Negative Bacterial Infections |
| D001424 | Bacterial Infections |
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |
| D018805 | Sepsis |
| D018746 | Systemic Inflammatory Response Syndrome |
| D007249 | Inflammation |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D000077725 | Piperacillin, Tazobactam Drug Combination |
| D000077731 | Meropenem |
| ID | Term |
|---|---|
| D000078142 | Tazobactam |
| D010397 | Penicillanic Acid |
| D010406 | Penicillins |
| D047090 | beta-Lactams |
| D007769 | Lactams |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D010878 | Piperacillin |
| D000667 | Ampicillin |
| D010400 | Penicillin G |
| D013457 | Sulfur Compounds |
| D013450 | Sulfones |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D004338 | Drug Combinations |
| D004364 | Pharmaceutical Preparations |
| D013845 | Thienamycins |
| D015780 | Carbapenems |
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