Clinical trial NCT05355350: PipEracillin/Tazobactam Versus mERoPENem for Treatment of AmpC Producing Blood Stream Infections
Official title: PipEracillin/Tazobactam vs mERoPENem for Treatment of AmpC-producing Bloodstream Infections: an Extension of the Original PETERPEN Trial
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE4
Conditions: Beta Lactam Resistant Bacterial Infection
Enterobacteriaceae Infections
Bacteremia
Keywords: bacteremia
enterobacteriaceae
extended spectrum beta-lactamase
meropenem
piperacillin tazobactam
Lead sponsor: Rambam Health Care Campus
Sponsor class: OTHER
Collaborators: name: The Chaim Sheba Medical Center
name: Rabin Medical Center
name: Hadassah Medical Organization
First posted: 2022-05-02
Enrollment: 1000
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: All-cause mortality
timeFrame: 30 days from randomization
measure: Treatment failure
timeFrame: 7 days from randomization]
Secondary outcomes:
measure: All-cause mortality
timeFrame: 14 and 90 days from randomization]
measure: Number of participants with treatment failure
timeFrame: 14 days and 30 days from randomization
measure: Number of participants with microbiological failure
timeFrame: 7 days and 14 days from randomization
measure: Number of participants with recurrent positive blood cultures (relapse)
timeFrame: 30 days and 90 days from randomization
measure: Number of participants with Clostridium difficile associated diarrhea
timeFrame: 90 days from randomization
measure: Secondary bacterial infections
timeFrame: 90 days from randomization
measure: Number of participants with hospital re-admissions
timeFrame: 90 days from randomization
measure: Number of participants with development of antimicrobial resistance
timeFrame: 90 days from randomization
measure: Carriage of carbapenemase-producing Enterobacteriaceae (CPE) and non-CPE carbapenem-resistant Enterobacteriaceae in-hospital detected by weekly rectal surveillance of carriage while in-hospital
timeFrame: 90 days from randomization
measure: Total in-hospital days
timeFrame: 30 days and 90 days from randomization
measure: Total antibiotic days
timeFrame: 30 days and 90 days from randomization
measure: Adverse events
timeFrame: 30 days
Other outcomes:
Locations:
city: Haifa
country: Israel
facility: Rambam Health Care Campus
city: Jerusalem
country: Israel
facility: Hadassah Medical Center
city: Petah tikva
country: Israel
facility: Rabin Medical Center, Beilinson Hospital
city: Ramat Gan
country: Israel
facility: Sheba Tel HaShomer Medical Campus
Study officials:
affiliation: Rambam Health Care Campus
name: Mical Paul, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Sheba Tel HaShomer Medical Campus
name: Dafna Yahav, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Rabin Medical Center, Beilinson Campus
name: Alaa Atamna, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Rambam Health Care Campus
name: Roni Bitterman, MD
role: STUDY_DIRECTOR
affiliation: Rabin Medical Center, Beilinson Campus
name: Noa Eliakim-Raz, MD
role: STUDY_DIRECTOR
References: