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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT02437045
Registration number
NCT02437045
Ethics application status
Date submitted
20/04/2015
Date registered
7/05/2015
Date last updated
10/05/2023
Titles & IDs
Public title
Trial of Meropenem Versus Piperacillin-Tazobactam on Mortality and Clinial Response
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Scientific title
Pilot RCT of Meropenem Versus Piperacillin-Tazobactam for Definitive Treatment of Bloodstream Infections Caused by AmpC Beta-lactamase Producing Enterobacter Spp., Citrobacter Freundii, Morganella Morganii, Providencia Spp. or Serratia Marcescens. in Low-risk Patients
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Secondary ID [1]
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HREC/14/QRBW/350
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Universal Trial Number (UTN)
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Trial acronym
MERINO II
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Bloodstream Infections
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Condition category
Condition code
Infection
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Studies of infection and infectious agents
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Infection
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Other infectious diseases
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Inflammatory and Immune System
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Other inflammatory or immune system disorders
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Meropenem
Treatment: Drugs - Piperacillin-tazobactam combination product
Active Comparator: Meropenem - Meropenem 1g every 8 hrs IV to day 4
Experimental: Piperacillin-tazobactam combination product - Piperacillin tazobactam 4.5g every 6 hrs IV to day 4
Treatment: Drugs: Meropenem
Meropenem is a carbapenem anti-bacterial used for the treatment of serious infections in patients.
Treatment: Drugs: Piperacillin-tazobactam combination product
Piperacillin-tazobactam is used for the treatment of patients with systemic and/or local bacterial infections.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Clinical and microbiological outcomes post bloodstream infection of patients treated with piperacillin/tazobactam and meropenem.
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Assessment method [1]
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Composite end-point of:
Death: up to 30 days post randomisation. Clinical failure - defined as ongoing fever (Tmax >=38.0oC) OR leucocytosis (white blood cell count >12x109/L) - assessed on day 5 post randomisation.
Microbiological failure - defined as positive blood culture or any sterile site specimen with same species as initial (index) blood culture on day 3-5.
Microbiological relapse - defined as growth from any sterile site of the same organism as in the original blood culture after day 5 but before day 30; If any of the above criteria are fulfilled post randomisation, the composite end-point has occurred. A composite end-point has been used as overall mortality is expected to be low in this subset of patients screened for 'low-risk' infections, and so is unlikely to be a useful primary outcome measure in isolation.
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Timepoint [1]
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Composite end point; up to day 30.
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Secondary outcome [1]
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Time to clinical resolution of infection.
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Assessment method [1]
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Time to clinical resolution of infection - defined as number of days from randomisation to resolution of fever (temperature >= 38.0 C)
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Timepoint [1]
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Resolution of infection will be monitored from day of randomisation up to study day five or when the patient exhibits a temperature below 38 degrees celcius.
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Secondary outcome [2]
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Clinical and microbiological success day 5.
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Assessment method [2]
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Clinical and microbiological success day 5 - defined as composite result of survival PLUS resolution of fever and leucocytosis (white blood cell count >12x109/L) PLUS sterilisation of blood cultures by day 5 post randomisation .
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Timepoint [2]
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Day five.
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Secondary outcome [3]
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Length of hospital and/or ICU stay post randomisation.
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Assessment method [3]
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Length of hospital and/or ICU stay post randomisation.
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Timepoint [3]
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Participants will be followed for the duration of their hospitalisation and/or up to the thirty day study time period.
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Secondary outcome [4]
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Requirement for ICU admission: if not in ICU at the time of enrolment, during days 1 to 5 post-randomisation.
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Assessment method [4]
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Requirement for ICU admission: if not in ICU at the time of enrolment, during days 1 to 5 post-randomisation.
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Timepoint [4]
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Days 1-5.
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Secondary outcome [5]
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Infection with a piperacillin-tazobactam / carbapenem resistant organism or Clostridium difficile.
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Assessment method [5]
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Infection with a piperacillin-tazobactam / carbapenem resistant organism or Clostridium difficile - defined as composite result of growth of a meropenem or piperacillin-tazobactam resistant Gram-negative organism from any clinical (non-screening) specimen collected from day 5 post randomisation to day 30. A positive stool test for Clostridium difficile (by toxin EIA and/or PCR, depending on the laboratory protocol of the study site) will also be recorded. This endpoint is important since one of the purposes of establishing an alternative to carbapenem therapy is to reduce infections with multi-drug resistant organisms and assess the comparative risk of C. difficile.
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Timepoint [5]
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Days 5-30.
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Secondary outcome [6]
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Microbiological failure with AmpC-mediated resistance.
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Assessment method [6]
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Microbiological failure with AmpC-mediated resistance -- defined as growth of the same Enterobacter, Serratia, Providencia spp., Morganella morganii or Citrobacter freundii as in the original blood culture from any blood culture or other clinical sample taken after day 5 but before 30 days - with emergent resistance likely due to AmpC de-repression (i.e. resistance to third generation cephalosporins, and /or piperacillin-tazobactam), and re-infection by new strain excluded by molecular typing.
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Timepoint [6]
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After day 5 before day 30.
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Secondary outcome [7]
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Colonisation with any multi-drug resistant organism.
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Assessment method [7]
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Colonisation with any multi-drug resistant organism - defined as the isolation from any screening site (nose/groin/axilla/rectal swabs) of multi-drug resistant bacteria (i.e. MRSA, VRE, ESBL-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, Pseudomonas or Acinetobacter) at any time from study enrolment to 30 days post initial blood culture collection. This will include any swabs or other specimens collected as part of routine clinical care at all study sites; at the RBWH site this will also include screening swabs taken at specific time-points for enhanced surveillance.
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Timepoint [7]
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Days 1-30.
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Secondary outcome [8]
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Requirement for escalation of antibiotic therapy.
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Assessment method [8]
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Requirement for escalation of antibiotic therapy (i.e. piperacillin-tazobactam to meropenem) or addition of second Gram-negative agent days 1 to 5.
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Timepoint [8]
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Days 1-5.
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Eligibility
Key inclusion criteria
- Bloodstream infection with Enterobacter spp., Serratia marcescens, Providencia spp.,
Morganella morganii or Citrobacter freundii (i.e. likely AmpC-producer), and
susceptibility to 3rd generation cephalosporins (i.e. ceftriaxone, cefotaxime or
ceftazidime), meropenem and piperacillin-tazobactam from at least one blood culture
draw. This will be determined in accordance with laboratory methods and susceptibility
breakpoints defined by protocols used in the recruiting site laboratories..
- No more than 72 hours has elapsed since the first positive blood culture collection.
- Patient is aged 18 years and over (>=21y in Singapore).
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
1. Patient not expected to survive more than 4 days
2. Patient allergic to a penicillin or a carbapenem
3. Patient with significant polymicrobial bacteraemia (that is, a Gram positive skin
contaminant in one set of blood cultures is not regarded as significant polymicrobial
bacteraemia).
4. Treatment is not with the intent to cure the infection (that is, palliative care is an
exclusion).
5. Pregnancy or breast-feeding.
6. Use of concomitant antimicrobials in the first 4 days after enrolment with known
activity against Gram-negative bacilli (except trimethoprim/sulphamethoxazole may be
continued as Pneumocystis prophylaxis).
7. Severe acute illness as defined by Pitt bacteraemia score of >4
8. Likely source to be from (proven or suspected at the time of randomisation) the
central nervous system, e.g. brain abscess, post-surgical meningitis, shunt infection
(due to concerns over CNS penetration of piperacillin/tazobactam)
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 4
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
1/04/2015
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
31/12/2020
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Sample size
Target
100
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Accrual to date
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Final
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Recruitment in Australia
Recruitment state(s)
NSW,QLD
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Recruitment hospital [1]
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John Hunter Hospital - New Lambton
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Recruitment hospital [2]
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Wollongong Hospital - Wollongong
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Recruitment hospital [3]
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Princess Alexandra Hospital - Brisbane
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Recruitment hospital [4]
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Royal Brisbane Hospital - Brisbane
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Recruitment postcode(s) [1]
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2305 - New Lambton
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Recruitment postcode(s) [2]
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- Wollongong
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Recruitment postcode(s) [3]
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4101 - Brisbane
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Recruitment postcode(s) [4]
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4170 - Brisbane
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Recruitment outside Australia
Country [1]
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Singapore
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State/province [1]
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Singapore
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Funding & Sponsors
Primary sponsor type
Other
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Name
The University of Queensland
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Address
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Country
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Ethics approval
Ethics application status
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Summary
Brief summary
Infections of the blood are extremely serious and require intravenous antibiotic treatment.
When the infection results from antibiotic resistant bacteria, the choice of antibiotic is an
extremely important decision. Some types of bacteria produce enzymes that may inactivate
essential antibiotics, related to penicillin, called 'beta-lactams'. Furthermore high level
production of these enzymes can occur during therapy and lead to clinical failure, even when
an antibiotic appears effective by laboratory testing. However, this risk of this occurring
in clinical practice has only been well described in a limited range of antibiotic classes in
a type of bacteria called Enterobacter. There is currently uncertainty as to whether a
commonly used, and highly effective antibiotic, called piperacillin-tazobactam is subject to
the same risk of resistance developing while on treatment. Infections caused by Enterobacter
(and other bacteria with similar resistance mechanisms) are often treated with an alternative
drug called meropenem (a carbapenem antibiotic), which is effective but has an extremely
broad-spectrum of activity. Excessive use of carbapenems is driving further resistance to
this antibiotic class - which represent our 'lastline' of antibiotic defence. As such, we
need studies to help us see whether alternatives to meropenem are an effective and safe
choice. No study has ever directly tested whether these two antibiotics have the same
effectiveness for this type of infection. The purpose of this study is to randomly assign
patients with blood infection caused by Enterobacter or related bacteria to either meropenem
or piperacillin/tazobactam in order to test whether these antibiotics have similar
effectiveness.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT02437045
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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David Paterson, Professor
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Address
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The University of Queensland Centre for Clinical Research
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT02437045
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