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Trial registered on ANZCTR


Registration number
ACTRN12619000693123
Ethics application status
Approved
Date submitted
16/04/2019
Date registered
8/05/2019
Date last updated
22/04/2020
Date data sharing statement initially provided
8/05/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Does guideline-based dosing of beta lactam antibiotics and vancomycin achieve the target drug concentrations more than therapeutic drug monitoring-based dosing in critically ill patients? (GUIDE TRIAL)
Scientific title
Does guideline-based dosing of beta lactam antibiotics and vancomycin achieve the target drug concentrations more than therapeutic drug monitoring-based dosing in critically ill patients? (GUIDE TRIAL)
Secondary ID [1] 296878 0
None
Universal Trial Number (UTN)
U1111-1229-0753
Trial acronym
GUIDE TRIAL
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Sepsis 312407 0
Serious infection 312408 0
Condition category
Condition code
Infection 310969 310969 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
The primary aim of the GUIDE TRIAL is to determine whether locally endorsed guideline based antibiotic dosing achieves pharmacodynamic target attainment of 100% fT>MIC for beta lactam antibiotics, or a steady state trough concentration of 15-20mg/L for vancomycin in critically ill patients. The GUIDE TRIAL is a single centred, prospective, observational study in critically ill patients admitted to the ICU with infections treated with the study antibiotics (piperacillin/tazobactam, flucloxacillin, meropenem, cefepime and vancomycin). All patients admitted over a 12 month period who meet the inclusion criteria are eligible for inclusion.

The local guideline titled ‘Antibiotic dosing, Critical Care’ is published as a guideline on the Hospital and Health Service intranet site. A manuscript describing the development of this guideline is currently under review in a peer-reviewed journal. The guideline was compiled from the primary literature and dosing regimens were selected by author consensus based on the available evidence. Briefly, the guideline sought to provide clinicians with a dosing nomogram based on renal function, continuous renal replacement therapy, and suspected augmented renal clearance. Information regarding pharmacokinetics, pharmacodynamics, drug penetration in site of action and minimum inhibitory concentration clinical breakpoints were aimed for inclusion. The local guideline is endorsed by the hospital and health service and used in practice currently in the ICU, therefore this study reflects current prescribing practices in the ICU and no interventions or exposures included in this study.

Patients prescribed beta lactams and vancomycin will require 4 blood samples to be taken (2 samples taken during day 1-3 of therapy, and 2 samples taken on day 4-6 of therapy). Samples are required to be taken at both 50% of the dosing interval and at 100% of the dosing interval. The duration of observations will be a maximum of six days.
Intervention code [1] 314212 0
Not applicable
Comparator / control treatment

A comparison between guideline-based versus TDM-based dosing in terms of PD target attainment will form part of secondary analysis. This comparison will be derived from previous PK/PD studies conducted in the Royal Brisbane and Women’s Hospital (RBWH) ICU. This comparative TDM data was collected between February and December 2009. In comparison to guideline-based dosing, TDM-based dosing is an individualised dosing approach where plasma samples are taken following 24- 48 hours of dosing and a drug assay is performed to quantify the drug concentration in plasma. A pre-defined drug concentration range is targeted and the daily dose or frequency of the drug administered is modified as required to maximise the likelihood of achieving the pre-defined concentration range.
Control group
Historical

Outcomes
Primary outcome [1] 319773 0
To determine whether locally endorsed guideline based antibiotic dosing achieves pharmacodynamic target attainment of 100% fT>MIC for beta lactam antibiotics, or a steady state trough concentration of 15-20mg/L for vancomycin in critically ill patients.

The concentration of the study antibiotics in the biological blood samples will be determined by chromatographic methods (HPLC and LC-MS/MS)
Timepoint [1] 319773 0
The drug concentrations will be measured at 4 time points.
2 samples taken during day 1-3 of therapy, and 2 samples taken on day 4-6 of therapy
Secondary outcome [1] 369491 0
To determine whether locally endorsed guideline-based antibiotic dosing achieves pharmacodynamic target attainment of 50% fT>MIC, 50% fT>4xMIC, or 100% fT>4xMIC for beta-lactam antibiotics in critically ill patients
The concentration of the study antibiotics in the biological blood samples will be determined by
chromatographic methods (HPLC and LC-MS/MS)
Timepoint [1] 369491 0
The drug concentrations will be measured at 4 time points.
2 samples taken during day 1-3 of therapy, and 2 samples taken on day 4-6 of therapy
Secondary outcome [2] 369492 0
Comparison of observed pharmacodynamic target attainment with clinical outcome of therapy.

The concentration of the study antibiotics in the biological blood samples will be determined by
chromatographic methods (HPLC and LC-MS/MS)

Clinical Outcomes is defined as either a positive or negative. A positive clinical outcome is defined as completion of treatment course without change or addition of antibiotic therapy, and with no additional antibiotics commenced with 48 h of cessation, or de-escalation to a narrower spectrum antibiotic. A negative clinical outcome is defined as any clinical outcome other than positive clinical outcome – death in ICU, escalation of therapy via either changing to an alternative class with a broader spectrum of activity, or commencement of combination antibiotic therapy.
Timepoint [2] 369492 0
Patient follow up will occur until 48 hours after completion of the course of antibiotics or until a negative clinical outcome has occurred. Mortality data will be collected on the day of ICU separation.
Patients prescribed beta lactams and vancomycin will require 4 blood samples to be taken (2 samples taken during day 1-3 of therapy, and 2 samples taken on day 4-6 of therapy). Samples are required to be taken at both 50% of the dosing interval and at 100% of the dosing interval.
Secondary outcome [3] 369496 0
Antimicrobial susceptibility results as determined by Etest and VITEK 2 MIC testing
Timepoint [3] 369496 0
Isolates will be collected as part of standard of care between Day 1 and Day 6 of antibiotic course.

Eligibility
Key inclusion criteria
• Written informed consent obtained from the patient or their legally authorised representative
• Aged 18 years or over
• Patient is an inpatient of the ICU
• Patient prescribed at least one of the study antibiotics to treat an infection
• Prescribed flucloxacillin, cefepime, piperacillin/tazobactam, meropenem or vancomycin
via a continuous or intermittent dosing regimen
• Suitable intravenous/intra-arterial access to facilitate sample collection
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Consent not obtained
• Aged less than 18 years
• Not being administered any of the study antibiotics
• Study antibiotics have been administered for greater than 72 hours prior to enrolment
• Limited or no intravenous/intra-arterial access.
• Known to be pregnant
• Prophylactic antibiotics

Study design
Purpose
Natural history
Duration
Cross-sectional
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Sample Size and Power
Based on findings from the DALI beta lactam study, it was determined that a sample size of 110 patients is required to achieve 80% power to detect 80% of the beta lactam cohort achieving 100%fT>MIC with an alpha of 0.05. Based on findings from the DALI vancomycin analysis paper and the 2012 Zelentisky et al. study, a sample size of 30 patients is required to achieve 80% power to detect 80% of the Vancomycin cohort achieving a trough concentration above 15mg/L with an alpha of 0.05. A 10% increase in the sample size was arbitrarily applied to account for missing data. Therefore, accounting for all study antibiotics, a total sample size of 150 patients is required. Each antibiotic requires 30 patients worth of data to allow multiple regression analysis to be performed, and to ensure an approximately even distribution of the study antibiotics is achieved for a sample size of 150.

Statistical Analysis
Baseline characteristics (median and IQR or number (%) where appropriate).
A rank-sum test will be performed to analyse the primary outcome.
Multiple regression analysis will be used to describe the impact of:
covariates on observed PD target attainment , and levels of target attainment on clinical outcomes.
Propensity score matching will be used to compare guideline-based versus TDM-based dosing in the matched cohort strategy and a rank -sum test will be used to describe the variation.




Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
13/05/2019
Actual
12/08/2019
Date of last participant enrolment
Anticipated
14/08/2020
Actual
Date of last data collection
Anticipated
21/08/2020
Actual
Sample size
Target
150
Accrual to date
73
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 13634 0
Sunshine Coast University Hospital - Birtinya
Recruitment postcode(s) [1] 26302 0
4575 - Birtinya

Funding & Sponsors
Funding source category [1] 301447 0
Hospital
Name [1] 301447 0
Sunshine Coast Hospital and Health Service: Study, Education and Research Trust Fund
Country [1] 301447 0
Australia
Primary sponsor type
Individual
Name
Paul Williams
Address
Pharmacy Department, Sunshine Coast University Hospital, 6 Doherty St, Birtinya, Queensland 4575, Australia
Country
Australia
Secondary sponsor category [1] 301139 0
None
Name [1] 301139 0
Address [1] 301139 0
Country [1] 301139 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302182 0
The Prince Charles Hospital Research and Ethics Committee
Ethics committee address [1] 302182 0
The Prince Charles Hospital
Building 14,
Rode Road,
Chermside, QLD, 4032
Ethics committee country [1] 302182 0
Australia
Date submitted for ethics approval [1] 302182 0
08/05/2018
Approval date [1] 302182 0
05/07/2018
Ethics approval number [1] 302182 0
HREC/18/QPCH/184

Summary
Brief summary
This study aims to investigate ‘guideline based antimicrobial dosing’ in terms of pharmacodynamic target attainment and clinical outcomes and compare these findings to a matched cohort of patients receiving Therapeutic Drug Monitoring (TDM) based dosing. A sample size of 150 ICU patients meeting the inclusion criteria is required. This study is a single centred, prospective, observational study in critically ill patients admitted to the ICU with infections treated with the study antibiotics. All patients admitted into the ICU over a 12 month period who meet the inclusion criteria are consider for inclusion. This research will fill a gap in contemporary studies in terms of describing the achievement of pharmacodynamic targets of guideline based antibiotic dosing compared to a matched cohort of TDM-based dosing.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 89398 0
Prof Jason Roberts
Address 89398 0
Burns, Trauma and Critical Care Research Centre, The University of Queensland,
Level 3, Ned Hanlon Building, Royal Brisbane & Women’s Hospital,
Butterfield St, Herston, Queensland, 4029 Australia
Country 89398 0
Australia
Phone 89398 0
+61736361847
Fax 89398 0
+61736463524
Email 89398 0
[email protected]
Contact person for public queries
Name 89399 0
Mr Paul Williams
Address 89399 0
Sunshine Coast University Hospital,
6 Doherty St,
Birtinya, Queensland 4575, Australia
Country 89399 0
Australia
Phone 89399 0
+61752022678
Fax 89399 0
+61752020844
Email 89399 0
[email protected]
Contact person for scientific queries
Name 89400 0
Mr Paul Williams
Address 89400 0
Sunshine Coast University Hospital,
6 Doherty St,
Birtinya, Queensland 4575, Australia
Country 89400 0
Australia
Phone 89400 0
+61752022678
Fax 89400 0
+61752020844
Email 89400 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
As per the study protocol, ethics approval, site specific approval and contractual agreements between the university and the hospital there are no provisions for individual participant data sharing publicly available for this trial.


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.