Back to resultsPipEracillin/Tazobactam Versus mERoPENem for Treatment of AmpC Producing Blood Stream Infections (SPICE-M)
Primary Purpose
Beta Lactam Resistant Bacterial Infection, Enterobacteriaceae Infections, Bacteremia
Status
Recruiting
Phase
Phase 4
Locations
Israel
Study Type
Interventional
Intervention
Piperacillin / Tazobactam Injection
Meropenem
Sponsored by
About this trial
This is an interventional treatment trial for Beta Lactam Resistant Bacterial Infection focused on measuring bacteremia, enterobacteriaceae, extended spectrum beta-lactamase, meropenem, piperacillin tazobactam
Eligibility Criteria
Inclusion Criteria:
- Adults (age ≥ 18 years)
- New onset BSI due to Serratia marcescens, Providencia spp., Morganella morganii, Citrobacter freundii, and Enterobacter 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 study pathogens 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) or patient in palliative care
Sites / Locations
- Rambam Health Care CampusRecruiting
- Hadassah Medical CenterRecruiting
- Rabin Medical Center, Beilinson HospitalRecruiting
- Sheba Tel HaShomer Medical CampusRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
piperacillin tazobactam
meropenem
Arm Description
Outcomes
Primary Outcome Measures
All-cause mortality
Primary Outcome Measure
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
Secondary Outcome Measures
All-cause mortality
Number of deceased patients
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
Number of participants with microbiological failure
Repeat positive blood cultures with index pathogen on day 4 or later 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
Number of participants with Clostridium difficile associated diarrhea
Diarrhea with positive Clostridium difficile toxin test
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.
Number of participants with hospital re-admissions
Hospital re-admission, excluding index hospitalization
Number of participants with development of antimicrobial resistance
clinical isolates resistant to piperacillin/tazobactam and meropenem and any carbapenem-resistant bacteria
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
Total in-hospital days
Total of in-hospital days per participant, including all admissions
Total antibiotic days
Total antibiotic days per participant within all admissions
Adverse events
diarrhea, liver function test abnormalities, antibiotic rash or other immediate-type allergy, acute kidney injury defined according to RIFLE criteria
Full Information
NCT ID
NCT05355350
First Posted
April 4, 2022
Last Updated
July 25, 2022
Sponsor
Rambam Health Care Campus
Collaborators
The Chaim Sheba Medical Center, Rabin Medical Center, Hadassah Medical Organization
1. Study Identification
Unique Protocol Identification Number
NCT05355350
Brief Title
PipEracillin/Tazobactam Versus mERoPENem for Treatment of AmpC Producing Blood Stream Infections
Acronym
SPICE-M
Official Title
PipEracillin/Tazobactam vs mERoPENem for Treatment of AmpC-producing Bloodstream Infections: an Extension of the Original PETERPEN Trial
Study Type
Interventional
2. Study Status
Record Verification Date
July 2022
Overall Recruitment Status
Recruiting
Study Start Date
July 1, 2022 (Actual)
Primary Completion Date
January 1, 2026 (Anticipated)
Study Completion Date
June 1, 2026 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Rambam Health Care Campus
Collaborators
The Chaim Sheba Medical Center, Rabin Medical Center, Hadassah Medical Organization
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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.
Detailed Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Beta Lactam Resistant Bacterial Infection, Enterobacteriaceae Infections, Bacteremia
Keywords
bacteremia, enterobacteriaceae, extended spectrum beta-lactamase, meropenem, piperacillin tazobactam
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
1000 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
piperacillin tazobactam
Arm Type
Experimental
Arm Title
meropenem
Arm Type
Active Comparator
Intervention Type
Drug
Intervention Name(s)
Piperacillin / Tazobactam Injection
Intervention Description
4.5 grams QID
Intervention Type
Drug
Intervention Name(s)
Meropenem
Intervention Description
1 gram TID
Primary Outcome Measure Information:
Title
All-cause mortality
Description
Primary Outcome Measure
Time Frame
30 days from randomization
Title
Treatment failure
Description
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]
Secondary Outcome Measure Information:
Title
All-cause mortality
Description
Number of deceased patients
Time Frame
14 and 90 days from randomization]
Title
Number of participants with treatment failure
Description
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
Title
Number of participants with microbiological failure
Description
Repeat positive blood cultures with index pathogen on day 4 or later from randomization
Time Frame
7 days and 14 days from randomization
Title
Number of participants with recurrent positive blood cultures (relapse)
Description
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
Title
Number of participants with Clostridium difficile associated diarrhea
Description
Diarrhea with positive Clostridium difficile toxin test
Time Frame
90 days from randomization
Title
Secondary bacterial infections
Description
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
Title
Number of participants with hospital re-admissions
Description
Hospital re-admission, excluding index hospitalization
Time Frame
90 days from randomization
Title
Number of participants with development of antimicrobial resistance
Description
clinical isolates resistant to piperacillin/tazobactam and meropenem and any carbapenem-resistant bacteria
Time Frame
90 days from randomization
Title
Carriage of carbapenemase-producing Enterobacteriaceae (CPE) and non-CPE carbapenem-resistant Enterobacteriaceae in-hospital detected by weekly rectal surveillance of carriage while in-hospital
Description
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
Title
Total in-hospital days
Description
Total of in-hospital days per participant, including all admissions
Time Frame
30 days and 90 days from randomization
Title
Total antibiotic days
Description
Total antibiotic days per participant within all admissions
Time Frame
30 days and 90 days from randomization
Title
Adverse events
Description
diarrhea, liver function test abnormalities, antibiotic rash or other immediate-type allergy, acute kidney injury defined according to RIFLE criteria
Time Frame
30 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
120 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Adults (age ≥ 18 years)
New onset BSI due to Serratia marcescens, Providencia spp., Morganella morganii, Citrobacter freundii, and Enterobacter 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 study pathogens 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) or patient in palliative care
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Mical Paul, MD
Phone
+972-4-7772991
Email
m_paul@rambam.health.gov.il
First Name & Middle Initial & Last Name or Official Title & Degree
Roni Bitterman, MD
Phone
+972-4-7772991
Email
ro_oren@rambam.health.gov.il
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mical Paul, MD
Organizational Affiliation
Rambam Health Care Campus
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Dafna Yahav, MD
Organizational Affiliation
Sheba Tel HaShomer Medical Campus
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Alaa Atamna, MD
Organizational Affiliation
Rabin Medical Center, Beilinson Campus
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Roni Bitterman, MD
Organizational Affiliation
Rambam Health Care Campus
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Noa Eliakim-Raz, MD
Organizational Affiliation
Rabin Medical Center, Beilinson Campus
Official's Role
Study Director
Facility Information:
Facility Name
Rambam Health Care Campus
City
Haifa
Country
Israel
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mical Paul, MD
Email
m_paul@rambam.health.gov.il
First Name & Middle Initial & Last Name & Degree
Mical Paul, MD
Facility Name
Hadassah Medical Center
City
Jerusalem
Country
Israel
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jacob Strahilevits
Email
jstrahilevitz@hadassah.org.il
First Name & Middle Initial & Last Name & Degree
Jacob Strahilevits, MD
Facility Name
Rabin Medical Center, Beilinson Hospital
City
Petah tikva
Country
Israel
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alaa Atamna, MD
Email
a.atamna86@gmail.com
First Name & Middle Initial & Last Name & Degree
Alaa Atamna, MD
First Name & Middle Initial & Last Name & Degree
Noa Eliakim-Raz, MD
Facility Name
Sheba Tel HaShomer Medical Campus
City
Ramat Gan
Country
Israel
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Dafna Dahav, MD
First Name & Middle Initial & Last Name & Degree
Dafna Yahav, MD
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
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.
IPD Sharing Time Frame
following publication and for unlimited time
IPD Sharing Access Criteria
proposals should be sent to the principal investigator at m_paul@rambam.health.gov.il
Learn more about this trial
PipEracillin/Tazobactam Versus mERoPENem for Treatment of AmpC Producing Blood Stream Infections
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