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Trial registered on ANZCTR


Registration number
ACTRN12614001211651
Ethics application status
Approved
Date submitted
4/11/2014
Date registered
17/11/2014
Date last updated
18/11/2019
Date data sharing statement initially provided
19/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Pilot randomised controlled trial of meropenem versus piperacillin-tazobactam for definitive treatment of bloodstream infections.
Scientific title
Pilot Randomised Controlled Trial 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 spp.
Secondary ID [1] 285536 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
MERINO II
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Participants who have had a bloodstream infection with a specific gram negative bacteria, as defined by at least one positive blood culture, where the isolate is confirmed to be a likely AmpC-producer by resistance to Ampicillin, Amoxicillin/clavulanate and 1st generation cephalosporins (e.g. cephazolin). The isolate should also remain susceptible to piperacillin/tazobactam and meropenem. 293353 0
Condition category
Condition code
Infection 293627 293627 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The invervention treatment for this study is IV Piperacillin/tazobactam 4.5g every 6 hours. The study drug is to be administered for a minimum of 4 days and can be given for as long as 14 days. The duration of therapy will be determined by the treating clinician.
Intervention code [1] 290479 0
Treatment: Drugs
Comparator / control treatment
The comparator treatment for this study is IV Meropenem 1g every 8 hours. The study drug is to be administered for a minimum of 4 days and can be given for as long as 14 days. The duration of therapy will be determined by the treating clinician.
Control group
Active

Outcomes
Primary outcome [1] 293437 0
To compare the clinical and microbiological outcomes post bloodstream infection of patients treated with pipercillin-tazobactam and meropenem.
Composite end-point of:
* Death: up to 30 days post randomisation

* Clinical failure: defined as ongoing fever (Tmax >38 degrees) OR leucocytosis (white blood cell count >12x109/L) OR procalcitonin >80% of baseline value (at day 1) – assessed on day 5 post randomisation.

* Microbiological failure: defined as positive blood culture with same species as initial (index) blood culture on day 3-5.

* Microbiologic relapse: defined as growth 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.
Timepoint [1] 293437 0
Death: up to 30 days post randomisation.
Clinical failure – day 5 post randomisation.
Microbiological failure – day 3-5 post randomisation.
Microbiologic relapse – after day 5 but before day 30 post randomisation.
Secondary outcome [1] 311041 0
(1) Mortality.
Timepoint [1] 311041 0
(1) Mortality at 7 and 30 days post enrolment in each arm
Secondary outcome [2] 311043 0
(2) Time to clinical and microbiologic resolution of infection.
Timepoint [2] 311043 0
(2) Defined as number of days from randomisation to resolution of fever (temperature > 38 degrees) and leucocytosis (white blood cell count >12x109/L) PLUS sterilisation of blood cultures.
Secondary outcome [3] 311044 0
(3) Resolution of inflammatory response, assessed by daily records of participants vital signs and blood specimen results.
Timepoint [3] 311044 0
(3) To compare the decline in procalcitonin level by day 3 and 5 as a percentage of baseline value at day 1 (randomisation).
Secondary outcome [4] 311045 0
(4) Length of hospital or ICU stay post initial bacteraemia.
Timepoint [4] 311045 0
(4) Length of hospital and/or ICU stay post initial bacteraemia measured at the time of hospital discharge.
Secondary outcome [5] 311046 0
(5) AmpC-mediated relapse (bacteraemia) –– 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 taken after the end of the period of study drug administration but before 30 days – with emergent resistance likely due to AmpC de-repression (i.e. resistance to third generation cephalosporins or piperacillin-tazobactam or ticarcillin-clavulanate), and re-infection by new strain excluded by molecular typing
Timepoint [5] 311046 0
(5) After the end of the period of study drug administration but before 30 days.
Secondary outcome [6] 311047 0
(6) AmpC-mediated relapse (any site) – defined as the growth of same Enterobacter, Serratia, Providencia spp., Morganella morganii or Citrobacter freundii from any clinical site with an antibiogram suggestive of an AmpC de-repressed phenotype (i.e. resistance to third generation cephalosporins OR piperacillin-tazobactam or ticarcillin-clavulanate by EUCAST standards) and re-infection by new strain excluded by molecular typing.
Timepoint [6] 311047 0
By study day 30.
Secondary outcome [7] 311048 0
(7) Superinfection with a piperacillin-tazobactam / carbapenem resistant organism or Clostridium difficile – defined as growth of a meropenem or piperacillin-tazobactam resistant organism from any clinical specimen collected from day 4 of study drug administration to day 30 (including clinically significant resistant Gram positive bacteria or Candida from sterile sites) Likely skin contaminants (e.g. coagulase-negative staphylococci in a single blood culture) will not be regarded as secondary infection. 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.
Timepoint [7] 311048 0
(7) From day 4 of study drug administration to day 30.
Secondary outcome [8] 311049 0
(8) 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.
Timepoint [8] 311049 0
(8) At any time from study enrolment to 30 days post initial blood culture collection.
Secondary outcome [9] 311050 0
(9) Requirement for ICU admission: if not in ICU at the time of enrolment, during days 1 to 5 post-randomisation.
Timepoint [9] 311050 0
(9) During days 1 to 5 post-randomisation.

Eligibility
Key inclusion criteria
a. 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.
b. No more than 72 hours has elapsed since the first positive blood culture collection.
c. Patient is aged 18 years and over (>=21y in Singapore).
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
a. Patient not expected to survive more than 4 days
b. Patient allergic to a penicillin or a carbapenem
c. 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).
d. Treatment is not with the intent to cure the infection (that is, palliative care is an exclusion).
e. Pregnancy or breast-feeding.
f. 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).
g. 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)

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Eligible patients will have an initial screening visit which will include a clinical record review, discussion with the treating team and brief patient interview to determine suitability for inclusion. The patient will then have the study explained to them and be offered an opportunity to be recruited & consent. Patients will then be randomly assigned to either meropenem or piperacillin-tazobactam in a 1:1 ratio according to a randomisation list prepared in advance.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Random sequence will be generated using random permuted blocks of unequal length. The randomisation process will be overseen by the Queensland Clinical Trials & Biostatistics Centre (QCTBC) of The University of Queensland, and will be facilitated by an online module within the REDCap data management system.

Treatment blinding will not be performed given the different dosing regimens of the two agents. Although clinical and vital sign parameters will be recorded by the study team, assessment of the primary and secondary end-points will be performed by an independent assessor, blinded to the treatment allocations.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/01/2015
Actual
27/07/2015
Date of last participant enrolment
Anticipated
31/12/2019
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
100
Accrual to date
76
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 3079 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [2] 5040 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [3] 5041 0
John Hunter Hospital Royal Newcastle Centre - New Lambton
Recruitment hospital [4] 5042 0
Wollongong Hospital - Wollongong
Recruitment hospital [5] 5043 0
Shellharbour Hospital - Mount Warrigal
Recruitment postcode(s) [1] 12528 0
2305 - New Lambton Heights
Recruitment postcode(s) [2] 12529 0
2500 - Wollongong
Recruitment postcode(s) [3] 12530 0
2528 - Mount Warrigal
Recruitment postcode(s) [4] 12526 0
4029 - Royal Brisbane Hospital
Recruitment postcode(s) [5] 12527 0
4102 - Woolloongabba
Recruitment outside Australia
Country [1] 7524 0
Singapore
State/province [1] 7524 0

Funding & Sponsors
Funding source category [1] 290139 0
Government body
Name [1] 290139 0
Pathology Queensland
Country [1] 290139 0
Australia
Funding source category [2] 290141 0
Charities/Societies/Foundations
Name [2] 290141 0
The Royal Brisbane & Women's Hospital Foundation
Country [2] 290141 0
Australia
Primary sponsor type
University
Name
The University of Queensland Centre for Clinical Research
Address
Building 71/918 RBWH Herston, Brisbane QLD 4029
Country
Australia
Secondary sponsor category [1] 288849 0
Other Collaborative groups
Name [1] 288849 0
Australasian Society for Infectious Diseases Clinical Research Network
Address [1] 288849 0
Suite 405, Level 4
5 Hunter Street
Sydney NSW 2000
Country [1] 288849 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291848 0
Royal Brisbane & Women's Hospital Human Research Ethics Committee
Ethics committee address [1] 291848 0
Royal Brisbane & Women's Hospital
Level 7 Block 7
Butterfield Street, Herston QLD 4029
Ethics committee country [1] 291848 0
Australia
Date submitted for ethics approval [1] 291848 0
25/08/2014
Approval date [1] 291848 0
29/09/2014
Ethics approval number [1] 291848 0
HREC/14/QRBW/350

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 'last-line' 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.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 52258 0
Prof David L. Paterson
Address 52258 0
Level 5 UQCCR Building 71/918 RBWH Herston, Brisbane QLD 4029
Country 52258 0
Australia
Phone 52258 0
+61 7 3346 6074
Fax 52258 0
+61 7 3346 5598
Email 52258 0
david.antibiotics@gmail.com
Contact person for public queries
Name 52259 0
Dr Patrick Harris
Address 52259 0
Level 5 UQCCR Building 71/918 RBWH Herston, Brisbane QLD 4029
Country 52259 0
Australia
Phone 52259 0
+61 7 3346 6081
Fax 52259 0
+61 7 3346 5598
Email 52259 0
p.harris@uq.edu.au
Contact person for scientific queries
Name 52260 0
Dr Patrick Harris
Address 52260 0
Level 5 UQCCR Building 71/918 RBWH Herston, Brisbane QLD 4029
Country 52260 0
Australia
Phone 52260 0
+ 61 7 3346 6081
Fax 52260 0
+61 7 3346 5598
Email 52260 0
p.harris@uq.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
This element is still yet to be determined by the study management committee.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.