A study to minimise the risks of emergence of drug-resistant bacteria in patients with Intensive Care Unit pulmonary infection by determining the optimal approach to administer existing antimicrobial treatments

ISRCTN	ISRCTN47673027
DOI	https://doi.org/10.1186/ISRCTN47673027
ClinicalTrials.gov (NCT)	Nil known
Clinical Trials Information System (CTIS)	2019-003166-40
Integrated Research Application System (IRAS)	259350
Protocol serial number	CPMS 42609, IRAS 259350
Sponsor	North Bristol NHS Trust
Funder	NIHR Central Commissioning Facility (CCF); Grant Codes: PB-PG-1013-32031

Submission date: 17/08/2021
Registration date: 26/04/2022
Last edited: 27/09/2022

Recruitment status: Stopped
Overall study status: Stopped
Condition category: Infections and Infestations

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims
Resistance to antimicrobial drugs (antibiotics) has been identified in the UK, European Union and many other countries as an important problem which, if not addressed, will have a major effect on how patients will be looked after in the future. Combination antimicrobial therapy is used clinically to prevent emergence of resistance in mycobacterial or HIV disease and it has been suggested that combination antibacterial therapy may reduce the risks of emergence of resistance for infections in critically ill patients.

The study has been designed to establish the feasibility of conducting a larger scale randomised controlled trial to determine whether a combination of both antibiotic dose individualization and combination antimicrobial therapy are clinically effective in reducing the risks of bacterial resistance and improving clinical outcomes. This study will be using tazobactam-piperacillin (Tazocin) and cidomicin (Gentamicin) as the investigational medicinal products.

Who can participate?
The study will recruit patients who have been admitted to the ICU and have been on a ventilator for five or more days, with suspected pulmonary infection. The study excludes patients under the age of 18, patients with specific co-morbidities, pregnant women and prisoners.

What does the study involve?
This is a Phase II, four arm unblinded feasibility study. Patients in ICU with proven Gram-negative pulmonary infection as indicated by a bronchoalveolar lavage culture will be recruited to the study and randomised onto one of four arms. All patients will have additional tests (above standard of care) as part of the study. Patients on two of the study arms will have additional blood draws for analysis for personalised drug-dosing using a dose personalisation algorithm.

Antimicrobial resistance will be established using standard methodologies and strains will be typed and the mechanism of resistance established.

What are the possible benefits and risks of participating?
Benefits: This research will benefit patients by offering a route to potentially stop emergence of resistant bacteria in patients with ICU pulmonary infection by determining the optimal approach to administer existing antimicrobials to reduce the risk of resistance. The potential impact of these approaches are enormous. The findings from this study have implications for other clinical scenarios where the emergence of drug resistance is problematic – for example, treatment of neutropenic sepsis or the management of blood stream infection.

The work will likely have impact on local policy making – potentially increasing use of combination chemotherapy as well as the wider application of therapeutic drug monitoring – such changes, once shown to be effective, will lead to improvements in service delivery.

Risks: There are minimal additional risks associated with the study. Drug related reactions are a possible occurrence for patients. There are a number of known reactions to both penicillin-class antibiotics and for aminoglycoside-class antibiotics. As these drugs are being administered in a clinical setting there is a low risk to patients. Risk from drug interactions between piperacillin-tazobactam and gentamicin are minimal. Bronchoscopy is a safe procedure which is perform frequently in critically ill patients with a low incidence of complication.

Where is the study run from?
This is a multi-centre study which is being conducted by North Bristol NHS Trust and Manchester University NHS Foundation Trust (UK)

When is the study starting and how long is it expected to run for?
January 2019 to March 2024

Who is funding the study?
The study is funded by the National Institute of Health Research (NIHR) Research for Patient Benefit (RfPB) programme (UK)

Who is the main contact?
Professor Alasdair MacGowan, Alasdair.Macgowan@nbt.nhs.uk

Contact information

Prof Alasdair MacGowan
Principal investigator

Pathology Sciences Building
Southmead Hospital
Bristol
BS10 5NB
United Kingdom

ORCID ID	0000-0002-6720-5268
Phone	+44 117 323 5651
Email	alasdair.macgowan@nbt.nhs.uk

Mr Alan Noel
Scientific

Pathology Sciences Building
Southmead Hospital
Bristol
BS10 5NB
United Kingdom

Phone	+44 117 323 5651
Email	Alan.Noel@nbt.nhs.uk

Dr Timothy Felton
Scientific

Acute Intensive Care Unit
Manchester University NHS Foundation Trust
Southmoor Road
Manchester
M23 9LT
United Kingdom

ORCID ID	0000-0001-6868-6633
Phone	+44 161 275 1682
Email	Tim.Felton@manchester.ac.uk

Dr Tony Timlin
Public

Research & Innovation
North Bristol NHS Trust
Learning & Research (Level 3)
Southmead Hospital
Bristol
BS10 5NB
United Kingdom

ORCID ID	0000-0002-9780-5221
Phone	+44 117 414 9330
Email	Tony.Timlin@nbt.nhs.uk

Study information

Primary study design	Interventional
Study design	Randomized; Interventional; Design type: Treatment, Process of Care, Drug, Complex Intervention
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	Minimising the risks of emergence of antibiotic resistance during therapy by precise regimen individualisation and use of combination therapy
Study acronym	MINIRES
Study objectives	The overall aim of this study is to investigate the feasibility of conducting a randomised controlled trial to determine whether a combination of both antibiotic dose individualisation and combination antimicrobial therapy are clinically effective in reducing the risks of bacterial resistance and improving clinical outcomes. This hypothesis will be tested with intubated critically ill patients undergoing critical care who develop Gram-negative pulmonary infection requiring antibiotics.
Ethics approval(s)	Approved 07/01/2021, North West – Greater Manchester (GM) South Multi-centre Research Ethics Committee (MREC) (Barlow House, 3rd Floor, 4 Minshull Street, Manchester, M1 3DZ, UK; +44 161 625 7820; Elaine.hutchings@northwest.nhs.uk), ref: 20/NW/0041
Health condition(s) or problem(s) studied	Pulmonary infection
Intervention	80 patients over two sites will be recruited onto study. Patients shall be randomised on a 1:1:1:1 basis throughout the study and allocated using pre-generated lists produced by a statistician at the Liverpool Cancer Trials Unit (LCTU). Lists shall be produced using permuted blocks algorithm with random block sizes of 4 and 8. Stratification factors used in the study are randomising centre and age. The patients will be randomised onto one of four arms: Arm A: Standard care piperacillin-tazobactam Arm B: Standard care piperacillin-tazobactam & gentamicin Arm C: Drug personalised piperacillin-tazobactam Arm D: Drug personalised piperacillin-tazobactam & gentamicin All patients will receive a course of IV antibiotics over 5-7 days as per the randomisation. All patients will have blood draws through a central line conducted on a daily basis as part of standard of care in ICU. Patients on Arm C & Arm D will have additional blood draws on up to 3 day days of study treatment. These bloods will be analysed and a personalised dose calculated. Patient's will receive a bronchoscopy and bronchoalveolar lavage on days 1 and 7. If the patient has regained consciousness prior to day 7 a sample from the extubation procedure will be used instead. Patients will have a rectal swab on days 1 and 7. If the patient has regained consciousness prior to day 7 a stool sample will be taken instead. Adverse events will be monitored up to day 28 or discharge from the ICU, whichever is first.
Intervention type	Drug
Phase	Not Applicable
Drug / device / biological / vaccine name(s)	Piperacillin, tazobactam, gentamicin
Primary outcome measure(s)	1. Clinical cure measured using resolution of temperature, reduction of CRP, change of antibiotics from trial medications by 7 days 2. Emergence of resistance measured using culture of respiratory secretions and rectal swabs taken at day 0 and at 7 days 3. Ventilator free days measured using clinical recording of ventilation status at 28 days 4. Mortality measured using recorded death on relevant healthcare data bases at 28 days 5. Mortality measured using recorded death on NHS record at 3 months 6. Proportion of patients with gentamicin and/or piperacillin related toxicity measured monitoring of adverse reactions and events throughout the study with focus on adverse reactions listed on both drugs Summary of Product Characteristics(SmPC) at the end of the study 7. Duration of ICU stay measured using relevant hospital IT systems at ICU discharge 8. Duration of hospitalisation measured using ..relevant hospital IT systems. at hospital discharge 9. Proportion of patients achieving pre-determined pharmacodynamics targets for piperacillin-tazobactam and gentamicin measured using pathogen specific MIC values and drug determination on days 1 to 5. 10. Clinical efficacy, defined as the suppression of emergence of antimicrobial resistance after 7 days antimicrobial therapy, measured using pathogen isolation and susceptibility testing from respiratory secretions and rectal swabs taken on day 0 and at 7 days
Key secondary outcome measure(s)	There are no secondary outcome measures
Completion date	31/03/2024
Reason abandoned (if study stopped)	Lack of staff/facilities/resources

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	All
Target sample size at registration	80
Key inclusion criteria	1. Intubated patients with clinician suspected Gram-negative pulmonary infection requiring antibacterial therapy 2. Adults aged 18 years upwards 3. Patient admitted to ICU for at least 5 days 4. Patient ventilated for at least 48 hours Inclusion criteria for analysis: Infection with a piperacillin-tazobactam and gentamicin susceptible Gram-negative organism.
Key exclusion criteria	1. Patients for whom informed consent cannot be obtained 2. Allergies or intolerance to piperacillin-tazobactam or gentamicin 3. Neutropaenic sepsis 4. Past medical history of cystic fibrosis 5. Other underlying infections pulmonary process unlikely to respond to piperacillin/tazobactam with or without gentamicin (i.e. tuberculosis, fungal pneumonia) 6. Subject unlikely to survive longer than 24 hours 7. Prisoners 8. Pregnant women 9. Non-NHS patients
Date of first enrolment	01/09/2022
Date of final enrolment	31/12/2023

Locations

Countries of recruitment

United Kingdom

Study participating centres

North Bristol NHS Trust

Southmead Hospital
Southmead Road
Westbury-on-trym
Bristol
BS10 5NB
United Kingdom

Manchester University NHS Foundation Trust

Cobbett House
Oxford Road
Manchester
M13 9WL
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
IPD sharing plan	The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request to Alasdair.Macgowan@nbt.nhs.uk

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
HRA research summary			28/06/2023	No	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes

Editorial Notes

27/09/2022: The study has been stopped.
21/06/2022: The recruitment start date has been changed from 01/06/2022 to 01/09/2022.
17/08/2021: Trial's existence confirmed by the NIHR.