PipEracillin/Tazobactam Versus mERoPENem for Treatment of AmpC Producing Blood Stream Infections

Bacteremia Clinical Trial

— SPICE-M  

Official title:

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

Clinical Trial Details — Status: Suspended

Administrative data

• NCT number: NCT05355350
• Other study ID #: 0295-18-RMB
• Status: Suspended
• Phase: Phase 4
• Start date: July 1, 2022
• Est. completion date: April 15, 2028

Study information

• Verified date: April 2024
• Source: Rambam Health Care Campus
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Suspended
• Enrollment: 1000
• Est. completion date: April 15, 2028
• Est. primary completion date: April 15, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 120 Years

Eligibility

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

Related Conditions & MeSH terms

• Bacteremia
• Bacterial Infections
• Beta Lactam Resistant Bacterial Infection
• Communicable Diseases
• Enterobacteriaceae Infections
• Infections

Intervention

Drug:
• Piperacillin / Tazobactam Injection
4.5 grams QID
• Meropenem
1 gram TID

Locations

Country	Name	City	State
Israel	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

Sponsors (4)

Lead Sponsor	Collaborator
Rambam Health Care Campus	Hadassah Medical Organization, Rabin Medical Center, The Chaim Sheba Medical Center

Country where clinical trial is conducted

Israel, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	All-cause mortality	Primary Outcome Measure	30 days from randomization
Primary	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	All-cause mortality	Number of deceased patients	14 and 90 days from randomization]
Secondary	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
Secondary	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
Secondary	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
Secondary	Number of participants with Clostridium difficile associated diarrhea	Diarrhea with positive Clostridium difficile toxin test	90 days from randomization
Secondary	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
Secondary	Number of participants with hospital re-admissions	Hospital re-admission, excluding index hospitalization	90 days from randomization
Secondary	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
Secondary	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
Secondary	Total in-hospital days	Total of in-hospital days per participant, including all admissions	30 days and 90 days from randomization
Secondary	Total antibiotic days	Total antibiotic days per participant within all admissions	30 days and 90 days from randomization
Secondary	Adverse events	diarrhea, liver function test abnormalities, antibiotic rash or other immediate-type allergy, acute kidney injury defined according to RIFLE criteria	30 days