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

Phase 4

Suspended

• Conditions: Beta Lactam Resistant Bacterial Infection; Enterobacteriaceae Infections; Bacteremia
• Interventions: Drug: Piperacillin / Tazobactam Injection; Drug: Meropenem

• Registration Number: NCT05355350
• Lead Sponsor: Rambam Health Care Campus

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.

Study Timeline

• Study First Submitted: 2022-04-04
• Study First Submitted QC: 2022-04-29
• Study First Posted: 2022-05-02
• Study Start: 2022-07-01
• Status Verified: 2024-04
• Last Update Submitted: 2024-04-15
• Last Update Posted: 2024-04-17
• Primary Completion: 2028-04-15
• Study Completion: 2028-04-15

Recruitment & Eligibility

• Status: SUSPENDED
• Sex: All
• Target Recruitment: 1000

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.

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
piperacillin tazobactam	Piperacillin / Tazobactam Injection	-
meropenem	Meropenem	-

Primary Outcome Measures

Name	Time	Method
Treatment failure	7 days from randomization]	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
All-cause mortality	30 days from randomization	Primary Outcome Measure

Secondary Outcome Measures

Name	Time	Method
Number of participants with treatment failure	14 days and 30 days from randomization	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 bacterial infections	90 days from randomization	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	90 days from randomization	Hospital re-admission, excluding index hospitalization
Number of participants with development of antimicrobial resistance	90 days from randomization	clinical isolates resistant to piperacillin/tazobactam and meropenem and any carbapenem-resistant bacteria
All-cause mortality	14 and 90 days from randomization]	Number of deceased patients
Number of participants with recurrent positive blood cultures (relapse)	30 days and 90 days from randomization	recurrent positive blood cultures with the index pathogen after prior sterilization of blood cultures or after end of treatment
Number of participants with microbiological failure	7 days and 14 days from randomization	Repeat positive blood cultures with index pathogen on day 4 or later from randomization
Number of participants with Clostridium difficile associated diarrhea	90 days from randomization	Diarrhea with positive Clostridium difficile toxin test
Carriage of carbapenemase-producing Enterobacteriaceae (CPE) and non-CPE carbapenem-resistant Enterobacteriaceae in-hospital detected by weekly rectal surveillance of carriage while in-hospital	90 days from randomization	New acquisition of carbapenemase-producing Enterobacteriaceae (CPE) and non-CPE carbapenem-resistant Enterobacteriaceae, detected through rectal surveillance or clinical cultures
Total in-hospital days	30 days and 90 days from randomization	Total of in-hospital days per participant, including all admissions
Total antibiotic days	30 days and 90 days from randomization	Total antibiotic days per participant within all admissions
Adverse events	30 days	diarrhea, liver function test abnormalities, antibiotic rash or other immediate-type allergy, acute kidney injury defined according to RIFLE criteria

Trial Locations

Locations (4)

Hadassah Medical Center; 🇮🇱 Jerusalem, Israel

Rabin Medical Center, Beilinson Hospital; 🇮🇱 Petah tikva, Israel

Sheba Tel HaShomer Medical Campus; 🇮🇱 Ramat Gan, Israel

Rambam Health Care Campus; 🇮🇱 Haifa, Israel