Beta-Lactam InfusioN Group Study (BLING III)

A Phase III Randomised Controlled Trial of Continuous Beta-lactam Infusion Compared With Intermittent Beta-lactam Dosing in Critically Ill Patients

The purpose of this study is to find out whether continuous infusion of beta-lactam antibiotics or intermittent infusion or beta-lactam antibiotics, offers more health advantages to patients or if there is no difference.

The investigators will be looking to see whether patients receiving beta-lactams via one administration method or the other have a better chance of recovering from their illness. They will also be looking at long term outcomes such as quality-of-life and healthcare resource use.

Sepsis is caused by toxic substances (toxins) from bacteria and other organism entering the bloodstream from a site of infection. In some people, the infection can progress to sepsis and septic shock where the functions of organs in the body are affected. Patients suffering from sepsis and septic shock are commonly managed in the intensive care unit (ICU) where they are prescribed antibiotics as standard therapy, as well as other therapies to support the functions of the body.

Beta-lactam antibiotics are a group of antibiotics commonly used to treat infection in patients with sepsis and septic shock.

Currently, beta-lactam antibiotics are most commonly given to patients be intermittent infusions, that is, given at regular intervals throughout 24 hours. New research suggests that giving beta-lactam antibiotics as a continuous infusion may mean that antibiotic concentrations in the blood remain more consistent and may be more effective at killing bacteria.

However, the benefit to the patient by giving beta-lactams via continuous infusion has not been tested in a high-quality, large clinical trial.

Study Overview

• Status: Completed
• Conditions: Sepsis
• Intervention / Treatment: Other: Continuous infusion; Other: Intermittent infusion

Detailed Description

Aim To conduct a multicentre randomised, controlled trial (RCT) to determine whether continuous infusion of a beta-lactam antibiotic (piperacillin-tazobactam or meropenem) results in decreased all cause Day 90 mortality compared with intermittent beta-lactam antibiotic infusion in critically ill patients with sepsis.

Hypothesis The BLING III Study will test the hypothesis that patients managed in the ICU with sepsis, the administration of beta-lactam antibiotics via continuous infusion decreases Day 90 mortality compared with intermittent infusion Design This BLING III study is a prospective, multicentre, open, phase III, RCT. Participants commenced on one of two beta-lactam antibiotics (piperacillin-tazobactam or meropenem) will be randomised to receive the beta-lactam antibiotic via either continuous infusion or intermittent infusion over 30 minutes for the treatment course while in the ICU for up to 90 days after randomisation. For participants where the beta-lactam antibiotic is subsequently changed from piperacillin-tazobactam to meropenem or vice versa for ongoing treatment of the infectious episode, the new prescription will continue to be administered in the allocated method (continuous infusion or intermittent infusion over 30 minutes).

Permuted block randomisation with variable block sizes and stratified by site will be conducted via a password-protected, secure web-based interface.

The primary endpoint for this trial will be death from all causes at 90 days.

7,000 patients will be enrolled into this study from approximately 70 ICUs worldwide, with approximately 35 ICUs in Australian and New Zealand hospitals.

For eligible patients, the administration method of beta-lactam antibiotic, either piperacillin-tazobactam or meropenem, will be randomised to either continuous infusion or intermittent infusion over 30 minutes. The choice of beta-lactam antibiotic and the dose and dosing interval (i.e. the dose the patient will receive in 24 hours) will be determined by the treating physician prior to randomisation.

For all patients, data will be collected at baseline and daily whilst in the ICU. Patients will be followed up to day 14, regardless of location in the hospital, to determine test of cure and to identify new acquisition, colonisation or infection with an multi-resistant organism. Additional follow up will occur at 90 days post randomisation.

• Study Type: Interventional
• Enrollment (Actual): 7203
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Bankstown, New South Wales, Australia, 2200
      • Bankstown Hospital
    • Blacktown, New South Wales, Australia, 2148
      • Blacktown Hospital
    • Camperdown, New South Wales, Australia, 2050
      • Royal Prince Alfred Hospital
    • Darlinghurst, New South Wales, Australia, 2010
      • St Vincents Hosptial
    • Gosford, New South Wales, Australia, 2250
      • Gosford Hospital
    • New Lambton Heights, New South Wales, Australia, 2305
      • John Hunter Hospital
    • Saint Leonards, New South Wales, Australia, 2065
      • Royal North Shore Hospital
    • Sydney, New South Wales, Australia
      • St George Hospital
    • Westmead, New South Wales, Australia, 2145
      • Westmead Hospital
  • Northern Territory
    • Casuarina, Northern Territory, Australia, 0811
      • Royal Darwin Hospital
  • Queensland
    • Auchenflower, Queensland, Australia, 4066
      • The Wesley Hospital
    • Brisbane, Queensland, Australia
      • Royal Brisbane and Women's Hospital
    • Caboolture, Queensland, Australia, 4510
      • Caboolture Hospital
    • Meadowbrook, Queensland, Australia, 4131
      • Logan Hospital
    • Redcliffe, Queensland, Australia, 4020
      • Redcliffe Hospital
    • Southport, Queensland, Australia, 4215
      • Gold Coast University Hospital
    • Woolloongabba, Queensland, Australia, 4102
      • Princess Alexandra Hospital
  • South Australia
    • Adelaide, South Australia, Australia
      • The Queen Elizabeth Hospital
    • Elizabeth Vale, South Australia, Australia, 5112
      • Lyell McEwin Hospital
  • Tasmania
    • Hobart, Tasmania, Australia, 7001
      • Royal Hobart Hospital
  • Victoria
    • Bendigo, Victoria, Australia, 3550
      • Bendigo Hospital
    • Box Hill, Victoria, Australia, 3128
      • Box Hill Hospital - Eastern Health
    • Geelong, Victoria, Australia, 3220
      • Geelong University Hospital
    • Heidelberg, Victoria, Australia, 3084
      • Austin Hospital
    • Melbourne, Victoria, Australia, 3050
      • Royal Melbourne Hospital
• Belgium
  • Antwerp, Belgium, 2610
    • Universitair Ziekenhuis Antwerpen
  • Antwerpen, Belgium, 2060
    • ZNA Stuivenberg
  • Brussels, Belgium, 1090
    • Universitair Ziekenhuis Brussel
  • Charleroi, Belgium
    • Civil Hospital Marie Curie
  • Gent, Belgium, 9000
    • Universitair Ziekenhuis Gent
  • Gent, Belgium, 9000
    • Maria Middelares
  • Ottignies, Belgium, 1340
    • Clinique Saint Pierre
  • Anderlecht
    • Brussels, Anderlecht, Belgium, , 1070
      • Hôpital Erasme
• France
  • Nancy, France
    • BRABOIS
  • Poitiers, France
    • Poitiers University Hospital
  • Bouche Du Rhone
    • Salon-de-Provence, Bouche Du Rhone, France, 13300
      • Ch Salon de Provence
  • Nimes
    • Nîmes, Nimes, France, 30900
      • Nimes University hospital
  • Vaucluse
    • Avignon, Vaucluse, France, 84902
      • Centre Hospitalier Henri Duffaut
• Malaysia
  • Kelantan
    • Kota Bharu, Kelantan, Malaysia, 16150
      • Hospital Universiti Sains Malaysia
  • Selangor
    • Kuala Lumpur, Selangor, Malaysia, 59100
      • University Malaya Medical Centre
• New Zealand
  • Auckland, New Zealand, 1142
    • Auckland City Hospital - CVICU
  • Auckland, New Zealand, 1142
    • Auckland City Hospital - DCCM
  • Auckland, New Zealand
    • Middlmore Hospital
  • Christchurch, New Zealand, 8011
    • Christchurch Hospital
  • Hamilton, New Zealand, 3240
    • Waikato Hospital
  • Wellington, New Zealand, 6021
    • Wellington Hospital
• Sweden
  • Helsingborg, Sweden, 25223
    • Helsingborg Hospital
  • Lund, Sweden, 22242
    • Skane Lund University Hospital
  • Malmo, Sweden, 21421
    • Skane University Malmo Hospital
• United Kingdom
  • Bristol, United Kingdom, BS1 3NU
    • Bristol Royal Infirmary
  • Cramlington, United Kingdom
    • Northumbria Specialist Emergency Hospital
  • Dundee, United Kingdom
    • Ninewells Hospital
  • Glasgow, United Kingdom
    • Glasgow Royal Infirmary
  • Hull, United Kingdom, HU3 2JZ
    • Hull Royal Infirmary
  • London, United Kingdom, N19 5NF
    • Whittington Health
  • Romford, United Kingdom
    • Queen's Hospital
  • Salford, United Kingdom, M6 8HD
    • Salford Royal Hospital
  • Berkshire
    • Reading, Berkshire, United Kingdom, RG1 5AN
      • Royal Berkshire Hospital
  • Brixton
    • London, Brixton, United Kingdom, SE5 9RS
      • Kings College Hospital
  • Bromley
    • Orpington, Bromley, United Kingdom, BR6 8ND
      • Princess Royal University Hospital
  • Buckinghamshire
    • Aylesbury, Buckinghamshire, United Kingdom, HP21 8AL
      • Stoke Mandeville Hospital
    • Milton Keynes, Buckinghamshire, United Kingdom, MK6 5LD
      • Milton Keynes University Hospital
  • Cheshire
    • Chester, Cheshire, United Kingdom, CH21UL
      • Countess of Chester Hospital
  • Dorset
    • Dorchester, Dorset, United Kingdom, DT1 2JY
      • Dorset County Hospital
    • Poole, Dorset, United Kingdom, BH15 2JB
      • Poole Hospital
  • Durham
    • Stockton-on-Tees, Durham, United Kingdom, TS19 8PE
      • University Hospital of North Tees
  • East Suffolk
    • Ipswich, East Suffolk, United Kingdom, IP4 5PD
      • Ipswich Hospital
  • England
    • Dartford, England, United Kingdom, DA28DA
      • Darent Valley Hospital
    • Maidstone, England, United Kingdom, ME169QQ
      • Maidstone Hospital
    • Plymouth, England, United Kingdom, PL68DH
      • Derriford Hospital
  • Essex
    • Chelmsford, Essex, United Kingdom, CM1 7ET
      • Broomfield Hospital
  • Glasgow
    • Clydebank, Glasgow, United Kingdom, G81 4HX
      • Golden Jubilee National Hospital
  • Greater Manchester
    • Bolton, Greater Manchester, United Kingdom, BL4 0JR
      • Royal Bolton Hospital
  • Hammersmith
    • London, Hammersmith, United Kingdom, SW6 8RF
      • Charing Cross Hospital
  • Hampshire
    • Basingstoke, Hampshire, United Kingdom, RG24 9NA
      • Basingstoke and North Hampshire Hospital
    • Portsmouth, Hampshire, United Kingdom, PO6 3LY
      • Queen Alexandra Hospital
    • Southampton, Hampshire, United Kingdom, SO16 6YD
      • Southampton General Hospital
    • Winchester, Hampshire, United Kingdom, SO22 5DG
      • Royal Hampshire County Hospital
  • Herefordshire
    • Hereford, Herefordshire, United Kingdom, HR1 2ER
      • Hereford County Hospital
  • Hertfordshire
    • Watford, Hertfordshire, United Kingdom, WD18 0HB
      • Watford General Hospital
  • Kent
    • Gillingham, Kent, United Kingdom, ME7 5NY
      • Medway Maritime Hospital
    • Kingston Upon Thames, Kent, United Kingdom, KT2 7QB
      • Kingston Hospital
    • Tunbridge Wells, Kent, United Kingdom, TN2 4QJ
      • Tunbridge Wells Hospital
  • Lancashire
    • Blackpool, Lancashire, United Kingdom, FY3 8NR
      • Blackpool Victoria Hospital
  • London
    • Chelsea, London, United Kingdom, SW3 6JJ
      • The Royal Marsden
    • Lambeth, London, United Kingdom, SE1 7EH
      • Guy's & St Thomas' Hospital London
    • Tooting, London, United Kingdom, SW17 0QT
      • St Georges Hospital
    • Whitechapel, London, United Kingdom, E1 1BB
      • The Royal London Hospital
  • Northhumberland
    • Newcastle, Northhumberland, United Kingdom, NE1 4LP
      • Royal Victoria Infirmary
  • Northumberland
    • Newcastle, Northumberland, United Kingdom, NE7 7DN
      • Newcastle Freeman Hospital
  • Nottinghamshire
    • Nottingham, Nottinghamshire, United Kingdom, NG7 2UH
      • The Queens Medical Centre
    • Sutton In Ashfield, Nottinghamshire, United Kingdom, NG17 4JL
      • Kingsmill Hospital
  • Paddington
    • London, Paddington, United Kingdom, W2 1NY
      • St Marys Hospital
  • Prescot
    • Rainhill, Prescot, United Kingdom, L35 5DR
      • Whiston Hospital
  • Shepherds Bush
    • London, Shepherds Bush, United Kingdom, W12 0HS,
      • Hammersmith Hospital
  • South Tees
    • Middlesbrough, South Tees, United Kingdom, TS4 3BW
      • James Cook University Hospital South Tees
  • Surrey
    • Frimley, Surrey, United Kingdom, GU16 7UJ
      • Frimley Park Hospital
    • Guildford, Surrey, United Kingdom, GU2 7XX
      • Royal Surrey County Hospital
  • Tyne And Wear
    • Sunderland, Tyne And Wear, United Kingdom, SR4 7TP
      • Sunderland Royal Hospital
  • Wales
    • Cardiff, Wales, United Kingdom, CF14 4XW
      • University Hospital of Wales
  • Warwickshire
    • Coventry, Warwickshire, United Kingdom, CV2 2DX
      • University Hospital Coventry & Warwickshire
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B12 2TH
      • Queen Elizabeth Medical Centre
  • West Yorkshire
    • Wakefield, West Yorkshire, United Kingdom, WF1 4DG
      • Pinderfields General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Documented site of infection or strong suspicion of infection
2. At the time of the assessment of suitability for the study, the treating physician expects the patient will require treatment in the ICU that extends beyond the next calendar day
3. The treating physician has chosen piperacillin-tazobactam or meropenem to treat the episode of infection
4. The treating physician is uncertain if administration of the chosen antibiotic by intermittent or continuous infusion is superior

5. One or more organ dysfunction entry criteria in the previous 24 hours

   • i. Mean arterial pressure < 60 mmHg for at least 1 hour
   • ii. Vasopressors required for > 4 hours
   • iii. Respiratory support using supplemental high flow nasal prongs, continuous positive airway pressure, bilevel positive airway pressure or invasive mechanical ventilation for at least 1 hour
   • iv. Serum creatinine concentration > 220 µmol/L

Exclusion Criteria:

1. Age less than 18 years
2. Receipt of piperacillin-tazobactam or meropenem for more than 24 hours during current infectious episode
3. Patients who are known or suspected to be pregnant
4. Patient has a known allergy to piperacillin-tazobactam or meropenem or penicillin
5. Receiving renal replacement therapy at the time of assessment for eligibility
6. The treating physician is not committed to provision of advanced life-support, including mechanical ventilation, dialysis and vasopressor administration, for at least the next 48 hours
7. Death is deemed imminent and inevitable
8. The patient has previously been enrolled in BLING III

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Continuous Infusion; The prescribed Beta-lactam is administered by a continuous infusion.	Other: Continuous infusion; Clinician prescribed beta-lactam antibiotic will be administered via continuous infusion for as long as prescribed whilst in the ICU
Other: Intermittent infusion; the prescribed Beta-lactam is administered by intermittent infusion over 30 minutes	Other: Intermittent infusion; Clinician prescribed beta-lactam antibiotic will be administered via intermittent infusion for as long as prescribed whilst in the ICU

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality	Patient mortality status assessed at 90 days after randomisation	90 Days after randomisation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Cure	Clinical cure will be defined as the completion of the beta-lactam antibiotic treatment course (on or prior to Day 14) without recommencement of antibiotic therapy within 48 hours of cessation. Participants discharged from hospital within 14 days following randomisation will be considered to meet the definition of clinical cure. Participants who decease while receiving the antibiotic treatment course or where antibiotic therapy is ceased in the setting of death being deemed imminent and inevitable, will be assessed as not meeting the criteria for clinical cure.	Day 14 post randomisation
New acquisition, colonisation or infection	New acquisition, colonisation or infection with an Multi-resistant organism (MRO) or Clostridium difficile diarrhoea	up to 14 days post randomisation or hospital discharge, whichever is sooner
All cause ICU mortality	Patient mortality status assessed at ICU discharge	up to 90 days
All cause hospital mortality	Patient mortality status assessed at hospital discharge	up to 90 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
ICU length of stay	Patient assessment of time spent in the ICU	up to 90 days
Hospital length of stay	Patient assessment of time spent in hospital.	up to 90 days
Quality of life	Quality of life measured with the European Quality of Life 5 Dimensions 5 Level (EQ-5D-5L)	90 days after randomisation
Health services use	Additional follow up at Day 90 for the purpose of economic evaluation will be conducted for Australian, New Zealand and sites from participating regions only. Follow up at Day 90 will include recording readmission to hospital and ICU within 90 days and will assess quality of life and functional capacity using the European Quality of Life 5 Dimensions 5 Level (EQ-5D-5L) questionnaire (if not deceased).38 The consent document used at participating sites will detail the inclusion of a quality of life questionnaire at Day 90.	up to 90 days after randomisation
Cost effectiveness analysis	A cost-effectiveness analysis at 90 days following randomisation will be conducted as a nested cohort in Australian, New Zealand and other potential regional sites. Cost data will be derived from health care utilisation to Day 90, estimated through standard per diem ICU and hospital costs. The analysis will be conducted from a health care payer perspective, comparing health care utilisation costs and quality-adjusted life years gained (measured by the EQ-5D-5L) between treatment arms. Where feasible, the cost-effectiveness analysis will be conducted in other country-specific regions. Depending on the outcome from the primary trial, several further analyses are planned including a longer-term cohort study and a modelled economic evaluation. The BLING III cost-effectiveness analysis will be informed by a separate Statistical Analysis Plan.	up to 90 days

Collaborators and Investigators

• Sponsor: The George Institute
• Collaborators: National Health and Medical Research Council, Australia; Australian and New Zealand Intensive Care Society Clinical Trials Group
• Investigators: Study Chair: Jeffrey Lipman, The George Institute

Publications and helpful links

General Publications

• Lipman J, Brett SJ, De Waele JJ, Cotta MO, Davis JS, Finfer S, Glass P, Knowles S, McGuinness S, Myburgh J, Paterson DL, Peake S, Rajbhandari D, Rhodes A, Roberts JA, Shirwadkar C, Starr T, Taylor C, Billot L, Dulhunty JM. A protocol for a phase 3 multicentre randomised controlled trial of continuous versus intermittent beta-lactam antibiotic infusion in critically ill patients with sepsis: BLING III. Crit Care Resusc. 2019 Mar;21(1):63-68.

Study record dates

Study Major Dates

• Study Start (Actual): March 26, 2018
• Primary Completion (Actual): April 12, 2023
• Study Completion (Actual): June 29, 2023

Study Registration Dates

• First Submitted: June 5, 2017
• First Submitted That Met QC Criteria: July 10, 2017
• First Posted (Actual): July 11, 2017

Study Record Updates

• Last Update Posted (Estimated): December 12, 2023
• Last Update Submitted That Met QC Criteria: December 10, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Sepsis; Beta-lactam antibiotics
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis
• Other Study ID Numbers: TGI-CCT254643

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Yet to be decided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No