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Trial of Meropenem Versus Piperacillin-Tazobactam on Mortality and Clinial Response (MERINO II)

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ClinicalTrials.gov Identifier: NCT02437045
Recruitment Status : Recruiting
First Posted : May 7, 2015
Last Update Posted : May 2, 2018
Sponsor:
Information provided by (Responsible Party):
Professor David L. Paterson, The University of Queensland

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.

Condition or disease Intervention/treatment Phase
Bloodstream Infections Drug: Meropenem Drug: Piperacillin-tazobactam combination product Phase 4

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official 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
Study Start Date : April 2015
Estimated Primary Completion Date : September 2020
Estimated Study Completion Date : September 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Meropenem
Meropenem 1g every 8 hrs IV to day 4
Drug: Meropenem
Meropenem is a carbapenem anti-bacterial used for the treatment of serious infections in patients.
Other Names:
  • Merrem
  • Meronem

Experimental: Piperacillin-tazobactam combination product
Piperacillin tazobactam 4.5g every 6 hrs IV to day 4
Drug: Piperacillin-tazobactam combination product
Piperacillin-tazobactam is used for the treatment of patients with systemic and/or local bacterial infections.
Other Names:
  • Zosyn
  • Tazocin




Primary Outcome Measures :
  1. Clinical and microbiological outcomes post bloodstream infection of patients treated with piperacillin/tazobactam and meropenem. [ Time Frame: Composite end point; up to day 30. ]

    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.



Secondary Outcome Measures :
  1. Time to clinical resolution of infection. [ Time Frame: 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. ]
    Time to clinical resolution of infection - defined as number of days from randomisation to resolution of fever (temperature >= 38.0 C)

  2. Clinical and microbiological success day 5. [ Time Frame: Day five. ]
    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 .

  3. Length of hospital and/or ICU stay post randomisation. [ Time Frame: Participants will be followed for the duration of their hospitalisation and/or up to the thirty day study time period. ]
    Length of hospital and/or ICU stay post randomisation.

  4. Requirement for ICU admission: if not in ICU at the time of enrolment, during days 1 to 5 post-randomisation. [ Time Frame: Days 1-5. ]
    Requirement for ICU admission: if not in ICU at the time of enrolment, during days 1 to 5 post-randomisation.

  5. Infection with a piperacillin-tazobactam / carbapenem resistant organism or Clostridium difficile. [ Time Frame: Days 5-30. ]
    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.

  6. Microbiological failure with AmpC-mediated resistance. [ Time Frame: After day 5 before day 30. ]
    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.

  7. Colonisation with any multi-drug resistant organism. [ Time Frame: Days 1-30. ]
    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.

  8. Requirement for escalation of antibiotic therapy. [ Time Frame: Days 1-5. ]
    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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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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).

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02437045


Contacts
Contact: David Paterson, Professor david.antibiotics@gmail.com
Contact: Patrick Harris, Dr padstock@hotmail.com

Locations
Australia, New South Wales
John Hunter Hospital Recruiting
New Lambton, New South Wales, Australia, 2305
Contact: Joshua Davis, Doctor       Joshua.Davis@menzies.edu.au   
Wollongong Hospital Recruiting
Wollongong, New South Wales, Australia
Contact: Spiros Miyakis, Doctor       smiyakis@uow.edu.au   
Australia, Queensland
Princess Alexandra Hospital Recruiting
Brisbane, Queensland, Australia, 4101
Contact: Naomi Runnegar, Doctor       Naomi.Runnegar@health.qld.gov.au   
Royal Brisbane Hospital Recruiting
Brisbane, Queensland, Australia, 4170
Contact: David Paterson, Professor       david.antibiotics@gmail.com   
Singapore
National University Hospital Singapore Not yet recruiting
Singapore, Singapore
Contact: Sophia Archula, Doctor       sophia@nus.edu.sg   
Tan Tock Seng Hospital Not yet recruiting
Singapore, Singapore
Contact: Barnaby Young, Doctor       barnaby_young@ttsh.com.sg   
Sponsors and Collaborators
The University of Queensland
Investigators
Principal Investigator: David Paterson, Professor The University of Queensland Centre for Clinical Research

Responsible Party: Professor David L. Paterson, The University of Queensland
ClinicalTrials.gov Identifier: NCT02437045     History of Changes
Other Study ID Numbers: HREC/14/QRBW/350
First Posted: May 7, 2015    Key Record Dates
Last Update Posted: May 2, 2018
Last Verified: April 2018

Additional relevant MeSH terms:
Infection
Meropenem
Thienamycins
Tazobactam
Penicillanic Acid
Piperacillin
Piperacillin, tazobactam drug combination
Anti-Bacterial Agents
Anti-Infective Agents
beta-Lactamase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action