PipEracillin/Tazobactam Versus mERoPENem for Treatment of AmpC Producing Blood Stream Infections (SPICE-M)

PipEracillin/Tazobactam vs mERoPENem for Treatment of AmpC-producing Bloodstream Infections: an Extension of the Original PETERPEN Trial

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.

Study Overview

• Status: Withdrawn
• Conditions: Bacteremia; Enterobacteriaceae Infections; Beta Lactam Resistant Bacterial Infection
• Intervention / Treatment: Drug: Meropenem; Drug: Piperacillin / Tazobactam Injection

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.

• Study Type: Interventional
• Phase: Phase 4

Contacts and Locations

Study Locations

• Israel
  • Haifa, Israel
    • Rambam Health Care Campus
  • Jerusalem, Israel
    • Hadassah Medical Center
  • Petah tikva, Israel
    • Rabin Medical Center, Beilinson Hospital
  • Ramat Gan, Israel
    • Sheba Tel HaShomer Medical Campus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adults (age ≥ 18 years)
2. 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.
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 study pathogens 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) or patient in palliative care

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: piperacillin tazobactam	Drug: Piperacillin / Tazobactam Injection; 4.5 grams QID
Active Comparator: meropenem	Drug: Meropenem; 1 gram TID

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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]

Secondary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Rambam Health Care Campus
• Collaborators: Hadassah Medical Organization; Rabin Medical Center; The Chaim Sheba Medical Center
• Investigators: Principal Investigator: 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; Study Director: Roni Bitterman, MD, Rambam Health Care Campus; Study Director: Noa Eliakim-Raz, MD, Rabin Medical Center, Beilinson campus

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2022
• Primary Completion (Actual): July 21, 2025
• Study Completion (Actual): July 21, 2025

Study Registration Dates

• First Submitted: April 4, 2022
• First Submitted That Met QC Criteria: April 29, 2022
• First Posted (Actual): May 2, 2022

Study Record Updates

• Last Update Posted (Actual): July 24, 2025
• Last Update Submitted That Met QC Criteria: July 21, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: meropenem; bacteremia; enterobacteriaceae; extended spectrum beta-lactamase; piperacillin tazobactam
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Bacterial Infections and Mycoses; Gram-Negative Bacterial Infections; Bacteremia; Infections; Communicable Diseases; Bacterial Infections; Enterobacteriaceae Infections; Anti-Bacterial Agents; Anti-Infective Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; beta-Lactamase Inhibitors; Meropenem; Tazobactam; Piperacillin, Tazobactam Drug Combination; Piperacillin
• Other Study ID Numbers: 0295-18-RMB

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No