Trial of Meropenem Versus Piperacillin-Tazobactam on Mortality and Clinial Response

NCT02437045 | Completed Phase 4 DMC

• 1 other identifier: HREC/14/QRBW/350
• Study Type: interventional
• Target: 100
• Locations: 2 countries
• Sites: 6

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.

Conditions

Bloodstream Infections

Outcome Measures

Primary Outcomes (1)

• Clinical and microbiological outcomes post bloodstream infection of patients treated with piperacillin/tazobactam and meropenem.

  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.

  Composite end point; up to day 30.

Secondary Outcomes (8)

• Time to clinical resolution of infection.

  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.

• Clinical and microbiological success day 5.

  Day five.

• Length of hospital and/or ICU stay post randomisation.

  Participants will be followed for the duration of their hospitalisation and/or up to the thirty day study time period.

• Requirement for ICU admission: if not in ICU at the time of enrolment, during days 1 to 5 post-randomisation.

  Days 1-5.

• Infection with a piperacillin-tazobactam / carbapenem resistant organism or Clostridium difficile.

  Days 5-30.

Study Arms (2)

Meropenem

ACTIVE COMPARATOR

Meropenem 1g every 8 hrs IV to day 4

Drug: Meropenem

Piperacillin-tazobactam combination product

EXPERIMENTAL

Piperacillin tazobactam 4.5g every 6 hrs IV to day 4

Drug: Piperacillin-tazobactam combination product

Interventions

Meropenem DRUG

Meropenem is a carbapenem anti-bacterial used for the treatment of serious infections in patients.

Also known as: Merrem, Meronem

Meropenem

Piperacillin-tazobactam combination product DRUG

Piperacillin-tazobactam is used for the treatment of patients with systemic and/or local bacterial infections.

Also known as: Zosyn, Tazocin

Piperacillin-tazobactam combination product

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• Patient not expected to survive more than 4 days
• Patient allergic to a penicillin or a carbapenem
• 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).
• Pregnancy or breast-feeding.
• 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).
• Severe acute illness as defined by Pitt bacteraemia score of \>4
• 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)

Sponsors & Collaborators

• The University of Queensland: lead

Study Sites (6)

John Hunter Hospital

New Lambton, New South Wales, 2305, Australia

Location

Wollongong Hospital

Wollongong, New South Wales, Australia

Location

Princess Alexandra Hospital

Brisbane, Queensland, 4101, Australia

Location

Royal Brisbane Hospital

Brisbane, Queensland, 4170, Australia

Location

National University Hospital Singapore

Singapore, Singapore

Location

Tan Tock Seng Hospital

Singapore, Singapore

Location

Related Publications (1)

• Stewart AG, Paterson DL, Young B, Lye DC, Davis JS, Schneider K, Yilmaz M, Dinleyici R, Runnegar N, Henderson A, Archuleta S, Kalimuddin S, Forde BM, Chatfield MD, Bauer MJ, Lipman J, Harris-Brown T, Harris PNA; MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN). 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: A Pilot Multicenter Randomized Controlled Trial (MERINO-2). Open Forum Infect Dis. 2021 Aug 2;8(8):ofab387. doi: 10.1093/ofid/ofab387. eCollection 2021 Aug.

  PMID: 34395716 DERIVED

MeSH Terms

Conditions

Sepsis

Interventions

Meropenem; Piperacillin, Tazobactam Drug Combination

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Thienamycins; Carbapenems; beta-Lactams; Lactams; Amides; Organic Chemicals; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Tazobactam; Penicillanic Acid; Penicillins; Piperacillin; Ampicillin; Penicillin G; Sulfur Compounds; Sulfones; Drug Combinations; Pharmaceutical Preparations

Study Officials

• David Paterson, Professor

  The University of Queensland Centre for Clinical Research

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor David L. Paterson

Study Record Dates

• First Submitted: April 20, 2015
• First Posted: May 7, 2015
• Study Start: April 1, 2015
• Primary Completion: December 31, 2020
• Study Completion: December 31, 2020
• Last Updated: May 10, 2023

Record last verified: 2023-05

Locations

AU (4); SG (2)