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Trial registered on ANZCTR


Registration number
ACTRN12621000606886
Ethics application status
Approved
Date submitted
18/01/2021
Date registered
20/05/2021
Date last updated
28/04/2024
Date data sharing statement initially provided
20/05/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
PharmacoKinetic modelling for Antibiotics and Antifungals in Paediatric Patients on Life-saving therapies (Extracorporeal Therapies) - Phase 1 and 2
Scientific title
PharmacoKinetic modelling for Antimicrobials in Paediatric Patients on Extracorporeal Therapies (APET)
Secondary ID [1] 302554 0
nil known
Universal Trial Number (UTN)
U1111-1259-8035
Trial acronym
APET
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Critical illness in children and infants 319431 0
Sepsis in children and infants 320730 0
Condition category
Condition code
Infection 317399 317399 0 0
Studies of infection and infectious agents
Public Health 317400 317400 0 0
Health service research
Infection 318582 318582 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 setting will be critically ill children in the Paediatric Intensive Care at Queensland Children's Hospital and the University Children's Hospital in Zurich. These children will be on one or more of the study intravenous antimicrobials: piperacillin/tazobactam, vancomycin, cefotaxime, gentamicin ampicillin, meropenem, flucloxacillin, fluconazole, voriconazole, micafungin, teicoplanin, ceftazidime or anidulafungin and on extracorporeal therapies of extracorporeal membrane oxygenation and/or extracorporeal continuous renal replacement therapy. Timely and effective antimicrobial treatments improves outcomes and ensures pharmacodynamic attainment.

PHASE ONE will be a prospective observational study of critically ill infants and children that will use current dose regimens at Queensland Children's Hospital PICU for the above antimicrobials, and assess the antimicrobial concentrations at various time points to determine the pharmacokinetic parameters for the antimicrobials on extracorporeal membrane oxygenation and/or extracorporeal continuous renal replacement therapy. The antimicrobial concentrations will be taken ideally after the first dose, or within the first 24 hours of commencement.
SAMPLING Each child will have no more than 5 samples in 6 hours, or 8 samples in 12 hours. The sample amount required is 0.6 mL of whole blood and a total whole blood volume maximum of 4.8 mL for 8 samples, or 3 mL for 5 samples, allowing assessment for multiple antimicrobial concentrations, this is below the recommended blood samples recommendations for the World Health Organisation. However, to minimise sampling discarded clinical care samples will be utilised to minimise blood volume per child for the antimicrobial concentrations. The time points for sampling will be based on the current antimicrobial dosing frequency. An example of the time and frequency of samples for piperacillin/tazobactam prescribed 6 h, is displayed below: Sample time point 1: at time zero prior to commencement of antimicrobial, time point 2: 30 minutes after infusion time point 3:120 minutes after infusion time point 4: 240 minutes after infusion and time point 5: 300 minutes after infusion. The sampling can commence at time zero before commencement of the antimicrobial or at after any antimicrobial dose, and will only be for the one time frequency period. The observation period for the patient will be until cessation of the antimicrobial in the Paediatric Intensive Care Unit.
ANALYSIS: Antimicrobial concentrations from the plasma samples will be analysed at The University of Queensland Centre for Clinical Research, (UQCCR). All samples will be assayed using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) methodology already available for the antimicrobials at UQCCR.

PHASE 2 Pharmacokinetics analysis of the study antimicrobials in extracorporeal therapies will be undertaken using a population pharmacokinetic modelling approach with P-Metrics 3.5.1, utilising the concentrations from the patient's plasma samples. Antimicrobial concentrations will be used to develop robust population pharmacokinetic models. These models will be used in simulations to develop novel dosing regimens to achieve therapeutic concentrations based on the relevant pharmacokinetic/pharmacodynamic targets for each antimicrobial. The inclusion of clinical covariates (e.g. markers for renal function or albumin levels) in the model will characterise developmental and /or acute pathophysiological alterations of critically ill children or infants on extracorporeal therapies.These pharmacokinetic models developed will take into account individual clinical variables for example but not limited to albumin, urea, creatinine, urine output and liver function tests and vasoactive medication support. Pharmacokinetic models will be developed for each antimicrobial, taking into account the clinical breakpoints for antimicrobial using the mean inhibitory concentration (MIC) for the antimicrobial using either patient’s blood culture results or the European Committee on Antimicrobial Susceptibility Testing (EUCAST) to ensure pharmacodynamic attainment.

TIMEFRAME: Phase 1: is anticipated 12-18 months, Phase 2 will be conducted in parallel with Phase 1 as samples become available for pharmacokinetic modelling and is anticipated to be undertaken in 12-24 months.

SURVEY: The families will be given a survey to complete if their child is recruited in the study. The aim is to understand families recognition and escalation of sepsis, and the impact of sepsis on the family unit when their child is admitted to the paediatric intensive care unit (PICU). The survey will assist further development and education for future families in PICU.
Intervention code [1] 318844 0
Not applicable
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 325454 0
To evaluate the current dose regimen for pharmacokinetic parameters for ampicillin on extracorporeal membrane oxygenation and/or continuous renal replacement therapy for critically ill paediatric patients. The pharmacokinetic parameters will include but not limited to concentration maximum, volume of distribution, clearance, half-life and area under the curve.
Timepoint [1] 325454 0
Whole blood samples will be collected at the various time points depending on frequency of ampicillin.
Time Point 1: pre infusion of the initial antimicrobial dose, and or start of extracorporeal therapy. This sampling would be standard blood sampling for clinical patient care for extracorporeal therapies.
Time Point 2: 30 minutes post antimicrobial dose (all intervals)
Time Point 3: 120 minutes post antimicrobial dose (all intervals)
Time Point 4: 240 minutes if 6,8- or 12-hour antimicrobial interval dose, and standard blood sampling for clinical patient care for extracorporeal therapies
Time Point 5: 300 minutes if 6 and 12 hourly antimicrobial interval
Time Point 6: 360 minutes post antimicrobial dose (all intervals)
Time Point 7: 480 minutes if 8, 12 hourly and 24-hour antimicrobial interval, and standard blood sampling for clinical patient care for extracorporeal therapies
Time Point 8: 720 minutes 12- and 24-hourly interval and standard blood sampling for clinical patient care for extracorporeal therapies
The bedside nursing guide will assist with time points for the samples. The samples will be taken from indwelling catheter, that the child already has for clinical care sampling.
Primary outcome [2] 325455 0
To evaluate the current dose regimen for pharmacokinetic parameters for cefotaxime on extracorporeal membrane oxygenation and/or continuous renal replacement therapy for critically ill paediatric patients. The pharmacokinetic parameters will include but not limited to concentration maximum, volume of distribution, clearance, half-life and area under the curve
Timepoint [2] 325455 0
Whole blood samples will be collected at the various time points depending on frequency of the cefotaxime
Time Point 1: pre infusion of the initial antimicrobial dose, and or start of extracorporeal therapy. This sampling would be standard blood sampling for clinical patient care for extracorporeal therapies.
Time Point 2: 30 minutes post antimicrobial dose (all intervals)
Time Point 3: 120 minutes post antimicrobial dose (all intervals)
Time Point 4: 240 minutes if 6,8- or 12-hour antimicrobial interval dose, and standard blood sampling for clinical patient care for extracorporeal therapies
Time Point 5: 300 minutes if 6 and 12 hourly antimicrobial interval
Time Point 6: 360 minutes post antimicrobial dose (all intervals)
Time Point 7: 480 minutes if 8, 12 hourly and 24-hour antimicrobial interval, and standard blood sampling for clinical patient care for extracorporeal therapies
The bedside nursing guide will assist with time points for the samples. The samples will be taken from indwelling catheter, that the child already has for clinical care sampling.
Primary outcome [3] 326916 0
Primary Outcome: To evaluate the current dose regimen for pharmacokinetic parameters for flucloxacillin on extracorporeal membrane oxygenation and/or continuous renal replacement therapy for critically ill paediatric patients. The pharmacokinetic parameters will include but not limited to concentration maximum, volume of distribution, clearance, half-life and area under the curve.
Timepoint [3] 326916 0
Whole blood samples will be collected at the various time points depending on frequency of flucloxacillin.
Time Point 1: pre infusion of the initial antimicrobial dose, and or start of extracorporeal therapy. This sampling would be standard blood sampling for clinical patient care for extracorporeal therapies.
Time Point 2: 30 minutes post antimicrobial dose (all intervals)
Time Point 3: 120 minutes post antimicrobial dose (all intervals)
Time Point 4: 240 minutes if 6,8- or 12-hour antimicrobial interval dose, and standard blood sampling for clinical patient care for extracorporeal therapies
Time Point 5: 300 minutes if 6 and 12 hourly antimicrobial interval
Time Point 6: 360 minutes post antimicrobial dose (all intervals)
Time Point 7: 480 minutes if 8, 12 hourly and 24-hour antimicrobial interval, and standard blood sampling for clinical patient care for extracorporeal therapies
The bedside nursing guide will assist with time points for the samples. The samples will be taken from indwelling catheter, that the child already has for clinical care sampling.
Secondary outcome [1] 388012 0
Family survey was designed specifically for this study.
An outcome of the survey will be family's recognition of sepsis.

Timepoint [1] 388012 0
The survey will be administered to families at any time during their child's admission, up until their child's discharge from the Paediatric Intensive Care Unit
Secondary outcome [2] 393108 0
This family survey will provide information about on the escalation of care of child and the level of escalation of care provided to the child assessed by the study specific survey.

Timepoint [2] 393108 0
The survey will be administered to families at any time during their child's admission, up until their child's discharge from the Paediatric Intensive Care Unit
Secondary outcome [3] 393109 0
Understanding of the impacts on the family unit when their child is admitted to the PICU. This will be assessed by a survey designed specifically for this study.
Timepoint [3] 393109 0
The survey will be administered to families at any time during their child's admission, up until their child's discharge from the Paediatric Intensive Care Unit
Secondary outcome [4] 393119 0
Primary Outcome To evaluate the current dose regimen for pharmacokinetic parameters for gentamicin on extracorporeal membrane oxygenation and/or continuous renal replacement therapy for critically ill paediatric patients. The pharmacokinetic parameters will include but not limited to concentration maximum, volume of distribution, clearance, half-life and area under the curve.
Timepoint [4] 393119 0
Whole blood samples will be collected at the various time points depending on frequency of gentamicin.
Time Point 1: pre infusion of the initial antimicrobial dose, and or start of extracorporeal therapy. This sampling would be standard blood sampling for clinical patient care for extracorporeal therapies.
Time Point 2: 30 minutes post antimicrobial dose (all intervals)
Time Point 3: 120 minutes post antimicrobial dose (all intervals)
Time Point 4: 360 minutes post antimicrobial dose (all intervals)
Time Point 5: 420 minutes if 24 hourly antimicrobial interval
Time Point 6: 480 minutes if 8, 12 hourly and 24-hour antimicrobial interval, and standard blood sampling for clinical patient care for extracorporeal therapies
Time Point 7: 720 minutes 12- and 24-hourly interval and standard blood sampling for clinical patient care for extracorporeal therapies
Time Point 8: 1320 minutes if 24 hourly interval and standard blood sampling for clinical patient care for extracorporeal therapies
The bedside nursing guide will assist with time points for the samples. The samples will be taken from indwelling catheter, that the child already has for clinical care sampling.
Secondary outcome [5] 393120 0
Primary Outcome To evaluate the current dose regimen for pharmacokinetic parameters for meropenem on extracorporeal membrane oxygenation and/or continuous renal replacement therapy for critically ill paediatric patients. The pharmacokinetic parameters will include but not limited to concentration maximum, volume of distribution, clearance, half-life and area under the curve.
Timepoint [5] 393120 0
Whole blood samples will be collected at the various time points depending on frequency of meropenem.
Time Point 1: pre infusion of the initial antimicrobial dose, and or start of extracorporeal therapy. This sampling would be standard blood sampling for clinical patient care for extracorporeal therapies.
Time Point 2: 30 minutes post antimicrobial dose (all intervals)
Time Point 3: 120 minutes post antimicrobial dose (all intervals)
Time Point 4: 240 minutes if 6,8- or 12-hour antimicrobial interval dose, and standard blood sampling for clinical patient care for extracorporeal therapies
Time Point 5: 360 minutes post antimicrobial dose (all intervals)
Time Point 6: 480 minutes if 8, 12 hourly and 24-hour antimicrobial interval, and standard blood sampling for clinical patient care for extracorporeal therapies
The bedside nursing guide will assist with time points for the samples. The samples will be taken from indwelling catheter, that the child already has for clinical care sampling.
Secondary outcome [6] 393126 0
Primary Outcome To evaluate the current dose regimen for pharmacokinetic parameters for piperacillin/tazobactam on extracorporeal membrane oxygenation and/or continuous renal replacement therapy for critically ill paediatric patients. The pharmacokinetic parameters will include but not limited to concentration maximum, volume of distribution, clearance, half-life and area under the curve.
Timepoint [6] 393126 0
Whole blood samples will be collected at the various time points depending on frequency of piperacillin/tazobactam
Time Point 1: pre infusion of the initial antimicrobial dose, and or start of extracorporeal therapy. This sampling would be standard blood sampling for clinical patient care for extracorporeal therapies.
Time Point 2: 30 minutes post antimicrobial dose (all intervals)
Time Point 3: 120 minutes post antimicrobial dose (all intervals)
Time Point 4: 240 minutes if 6,8- or 12-hour antimicrobial interval dose, and standard blood sampling for clinical patient care for extracorporeal therapies
Time Point 5: 300 minutes if 6 and 12 hourly antimicrobial interval
Time Point 6: 360 minutes post antimicrobial dose (all intervals)
Time Point 7: 480 minutes if 8, 12 hourly and 24-hour antimicrobial interval, and standard blood sampling for clinical patient care for extracorporeal therapies
The bedside nursing guide will assist with time points for the samples. The samples will be taken from indwelling catheter, that the child already has for clinical care sampling.
Secondary outcome [7] 393128 0
Primary Outcome To evaluate the current dose regimen for pharmacokinetic parameters for vancomycin on extracorporeal membrane oxygenation and/or continuous renal replacement therapy for critically ill paediatric patients. The pharmacokinetic parameters will include but not limited to concentration maximum, volume of distribution, clearance, half-life and area under the curve.
Timepoint [7] 393128 0
Whole blood samples will be collected at the various time points depending on frequency of vancomycin
Time Point 1: pre infusion of the initial antimicrobial dose, and or start of extracorporeal therapy. This sampling would be standard blood sampling for clinical patient care for extracorporeal therapies.
Time Point 2: 30 minutes post antimicrobial dose (all intervals)
Time Point 3: 120 minutes post antimicrobial dose (all intervals)
Time Point 4: 240 minutes if 6,8- or 12-hour antimicrobial interval dose, and standard blood sampling for clinical patient care for extracorporeal therapies
Time Point 5: 300 minutes if 6 and 12 hourly antimicrobial interval
Time Point 6: 360 minutes post antimicrobial dose (all intervals)
Time Point 7: 480 minutes if 8, 12 hourly and 24-hour antimicrobial interval, and standard blood sampling for clinical patient care for extracorporeal therapies
The bedside nursing guide will assist with time points for the samples. The samples will be taken from indwelling catheter, that the child already has for clinical care sampling.
Secondary outcome [8] 393130 0
Primary Outcome To evaluate the current dose regimen for pharmacokinetic parameters for fluconazole on extracorporeal membrane oxygenation and/or continuous renal replacement therapy for critically ill paediatric patients. The pharmacokinetic parameters will include but not limited to concentration maximum, volume of distribution, clearance, half-life and area under the curve.
Timepoint [8] 393130 0
Whole blood samples will be collected at the various time points depending on frequency of fluconazole
Time Point 1: pre infusion of the initial antimicrobial dose, and or start of extracorporeal therapy. This sampling would be standard blood sampling for clinical patient care for extracorporeal therapies.
Time Point 2: 30 minutes post antimicrobial dose (all intervals)
Time Point 3: 120 minutes post antimicrobial dose (all intervals)
Time Point 4: 360 minutes post antimicrobial dose (all intervals)
Time Point 5: 420 minutes if 24 hourly antimicrobial interval
Time Point 6: 480 minutes if 8, 12 hourly and 24-hour antimicrobial interval, and standard blood sampling for clinical patient care for extracorporeal therapies
Time Point 7: 720 minutes 12- and 24-hourly interval and standard blood sampling for clinical patient care for extracorporeal therapies
Time Point 8: 1320 minutes if 24 hourly interval and standard blood sampling for clinical patient care for extracorporeal therapies
The bedside nursing guide will assist with time points for the samples. The samples will be taken from indwelling catheter, that the child already has for clinical care sampling.
Secondary outcome [9] 393132 0
Primary Outcome To evaluate the current dose regimen for pharmacokinetic parameters for voriconazole on extracorporeal membrane oxygenation and/or continuous renal replacement therapy for critically ill paediatric patients. The pharmacokinetic parameters will include but not limited to concentration maximum, volume of distribution, clearance, half-life and area under the curve.
Timepoint [9] 393132 0
Whole blood samples will be collected at the various time points depending on frequency of voriconazole
Time Point 1: pre infusion of the initial antimicrobial dose, and or start of extracorporeal therapy. This sampling would be standard blood sampling for clinical patient care for extracorporeal therapies.
Time Point 2: 30 minutes post antimicrobial dose (all intervals)
Time Point 3: 120 minutes post antimicrobial dose (all intervals)
Time Point 4: 240 minutes if 6,8- or 12-hour antimicrobial interval dose, and standard blood sampling for clinical patient care for extracorporeal therapies
Time Point 5: 300 minutes if 6 and 12 hourly antimicrobial interval
Time Point 6: 360 minutes post antimicrobial dose (all intervals)
Time Point 7: 480 minutes if 8, 12 hourly and 24-hour antimicrobial interval, and standard blood sampling for clinical patient care for extracorporeal therapies
Time Point 8: 720 minutes 12- and 24-hourly interval and standard blood sampling for clinical patient care for extracorporeal therapies
The bedside nursing guide will assist with time points for the samples. The samples will be taken from indwelling catheter, that the child already has for clinical care sampling.
Secondary outcome [10] 393134 0
Primary Outcome To evaluate the current dose regimen for pharmacokinetic parameters for micafungin on extracorporeal membrane oxygenation and/or continuous renal replacement therapy for critically ill paediatric patients. The pharmacokinetic parameters will include but not limited to concentration maximum, volume of distribution, clearance, half-life and area under the curve.
Timepoint [10] 393134 0
Whole blood samples will be collected at the various time points depending on frequency of micafungin
Time Point 1: pre infusion of the initial antimicrobial dose, and or start of extracorporeal therapy. This sampling would be standard blood sampling for clinical patient care for extracorporeal therapies.
Time Point 2: 30 minutes post antimicrobial dose (all intervals)
Time Point 3: 120 minutes post antimicrobial dose (all intervals)
Time Point 4: 360 minutes post antimicrobial dose (all intervals)
Time Point 5: 420 minutes if 24 hourly antimicrobial interval
Time Point 6: 480 minutes if 8, 12 hourly and 24-hour antimicrobial interval, and standard blood sampling for clinical patient care for extracorporeal therapies
Time Point 7: 720 minutes 12- and 24-hourly interval and standard blood sampling for clinical patient care for extracorporeal therapies
Time Point 8: 1320 minutes if 24 hourly interval and standard blood sampling for clinical patient care for extracorporeal therapies
The bedside nursing guide will assist with time points for the samples. The samples will be taken from indwelling catheter, that the child already has for clinical care sampling.
Secondary outcome [11] 410373 0
To evaluate the current dose regimen for pharmacokinetic parameters for ceftazidime on extracorporeal membrane oxygenation and/or continuous renal replacement therapy for critically ill paediatric patients. The pharmacokinetic parameters will include but not limited to concentration maximum, volume of distribution, clearance, half-life and area under the curve
Timepoint [11] 410373 0
Whole blood samples will be collected at the various time points depending on frequency of ceftazidime Time Point 1: pre infusion of the initial antimicrobial dose, and or start of extracorporeal therapy. This sampling would be standard blood sampling for clinical patient care for extracorporeal therapies. Time Point 2: 30 minutes post antimicrobial dose (all intervals) Time Point 3: 120 minutes post antimicrobial dose (all intervals) Time Point 4: 240 minutes if 6,8- or 12-hour antimicrobial interval dose, and standard blood sampling for clinical patient care for extracorporeal therapies Time Point 5: 300 minutes if 6 and 12 hourly antimicrobial interval Time Point 6: 360 minutes post antimicrobial dose (all intervals) Time Point 7: 480 minutes if 8, 12 hourly and 24-hour antimicrobial interval, and standard blood sampling for clinical patient care for extracorporeal therapies The bedside nursing guide will assist with time points for the samples. The samples will be taken from indwelling catheter, that the child already has for clinical care sampling.
Secondary outcome [12] 410374 0
Primary Outcome To evaluate the current dose regimen for pharmacokinetic parameters for anidulafungin on extracorporeal membrane oxygenation and/or continuous renal replacement therapy for critically ill paediatric patients. The pharmacokinetic parameters will include but not limited to concentration maximum, volume of distribution, clearance, half-life and area under the curve.
Timepoint [12] 410374 0
Whole blood samples will be collected at the various time points depending on frequency of anidulafungin Time Point 1: pre infusion of the initial antimicrobial dose, and or start of extracorporeal therapy. This sampling would be standard blood sampling for clinical patient care for extracorporeal therapies. Time Point 2: 30 minutes post antimicrobial dose (all intervals) Time Point 3: 120 minutes post antimicrobial dose (all intervals) Time Point 4: 360 minutes post antimicrobial dose (all intervals) Time Point 5: 420 minutes if 24 hourly antimicrobial interval Time Point 6: 480 minutes if 8, 12 hourly and 24-hour antimicrobial interval, and standard blood sampling for clinical patient care for extracorporeal therapies Time Point 7: 720 minutes 12- and 24-hourly interval and standard blood sampling for clinical patient care for extracorporeal therapies Time Point 8: 1320 minutes if 24 hourly interval and standard blood sampling for clinical patient care for extracorporeal therapies The bedside nursing guide will assist with time points for the samples. The samples will be taken from indwelling catheter, that the child already has for clinical care sampling.
Secondary outcome [13] 410375 0
Primary Outcome To evaluate the current dose regimen for pharmacokinetic parameters for teicoplanin on extracorporeal membrane oxygenation and/or continuous renal replacement therapy for critically ill paediatric patients. The pharmacokinetic parameters will include but not limited to concentration maximum, volume of distribution, clearance, half-life and area under the curve.
Timepoint [13] 410375 0
Whole blood samples will be collected at the various time points depending on frequency of teicoplanin Time Point 1: pre infusion of the initial antimicrobial dose, and or start of extracorporeal therapy. This sampling would be standard blood sampling for clinical patient care for extracorporeal therapies. Time Point 2: 30 minutes post antimicrobial dose (all intervals) Time Point 3: 120 minutes post antimicrobial dose (all intervals) Time Point 4: 360 minutes post antimicrobial dose (all intervals) Time Point 5: 420 minutes if 24 hourly antimicrobial interval Time Point 6: 480 minutes if 8, 12 hourly and 24-hour antimicrobial interval, and standard blood sampling for clinical patient care for extracorporeal therapies Time Point 7: 720 minutes 12- and 24-hourly interval and standard blood sampling for clinical patient care for extracorporeal therapies Time Point 8: 1320 minutes if 24 hourly interval and standard blood sampling for clinical patient care for extracorporeal therapies The bedside nursing guide will assist with time points for the samples. The samples will be taken from indwelling catheter, that the child already has for clinical care sampling.

Eligibility
Key inclusion criteria
Patient will be recruited if they meet the inclusion criteria.
INCLUSION CRITERIA
Paediatrics from birth up to 18 years of age admitted to Paediatric Intensive Care Unit at the Queensland Children’s Hospital and the University Children's Hospital Zurich are eligible if ALL of the following criteria are met.
1. Consent to continue approach (consent will be sought with a followup of written or phone consent to be obtained from the parent or carer, within 24 hours of inclusion in the study.
2. Paediatric patients requiring extracorporeal therapies either extracorporeal membrane oxygenation and/or continuous renal replacement therapy.
3. Patients are prescribed one or more of the following antimicrobials: cefotaxime, meropenem, ampicillin, piperacillin/tazobactam, vancomycin, gentamicin, flucloxacillin, fluconazole, voriconazole, fluconazole, micafungin, anidulafungin, ceftazidime and teicoplanin.
4. Patients may receive multiple antimicrobials concurrently.
5. indwelling catheter
Minimum age
No limit
Maximum age
18 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patient will not be included if they meet the exclusion criteria
EXCLUSION CRITERIA
Patients are excluded from the study if ONE OR MORE of the following criteria are met:
1. No consent to continue
2. Known allergy to study antimicrobial
3. Pregnancy
4. Ongoing massive blood transfusion requirements (>50% blood volume transfused in the previous 8 hours) 5. Haemoglobin is less than 70 g/L
6. Therapeutic plasma exchange in the preceding 24 hours
7. No arterial or venous access for sampling

Study design
Purpose
Screening
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
PHARMACOKINETIC MODEL Pharmacokinetics analysis of the study antimicrobials in extracorporeal membrane oxygenation and/or continuous renal replacement therapies will be undertaken using a population pharmacokinetic modelling approach with P-Metrics 3.5.1, utilising the concentrations from the patient's plasma samples. Antimicrobial concentrations will be used to develop robust population pharmacokinetic models. The inclusion of clinical covariates (e.g. markers for renal function or albumin levels) in the model will characterise development, the pharmacokinetic model will require selection and inclusion of clinical covariates based on the likelihood ratio test. Covariate inclusion will be based on biological plausibility and performed in a stepwise manner. Additionally, model diagnostics including an assessment of the ‘goodness-of-fit’ plots, precision of the parameter estimates, and a visual predictive check will be used for model evaluation.
ANALYSIS: Probability of achieving effective antimicrobial concentrations will assessed in Monte Carlo dosing simulations performed on the final model to determine the probability of achieving effective antimicrobial concentrations taking into account appropriate pharmacokinetic/pharmacodynamic targets for clinically relevant mean inhibitory concentrations (MIC)s for a variety of dose regimens and infusion durations (intermittent and extended). If the MIC is not available then the European Committee on Antimicrobial Susceptibility Testing (EUCAST) database to guide the MIC for all relevant pathogens for the antimicrobials. Building of the pharmacokinetic model will require selection and inclusion of clinical covariates based on the likelihood ratio test. Covariate inclusion will be based on biological plausibility and performed in a stepwise manner.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
31/05/2021
Actual
26/07/2021
Date of last participant enrolment
Anticipated
28/12/2024
Actual
Date of last data collection
Anticipated
28/05/2025
Actual
Sample size
Target
140
Accrual to date
85
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 17849 0
Queensland Children's Hospital - South Brisbane
Recruitment postcode(s) [1] 31706 0
4101 - South Brisbane

Funding & Sponsors
Funding source category [1] 306988 0
Hospital
Name [1] 306988 0
Children's Health Foundation
Country [1] 306988 0
Australia
Primary sponsor type
Hospital
Name
Queesland Children's Hospital
Address
Children Hospital Research and Grants Team
Queensland Children's Hospital Precinct
Graham Street
South Brisbane
Queensland 4101
Country
Australia
Secondary sponsor category [1] 307954 0
University
Name [1] 307954 0
The University Of Queensland
Address [1] 307954 0
The University of Queensland Centre for Clinical Research
RBWH Precinct
Herston Road
Brisbane
Queensland 4029
Country [1] 307954 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307121 0
Children's Health Queensland Hospital and Health Service Human Research Ethics Committee
Ethics committee address [1] 307121 0
Level 7, Centre for Children's Health Research
Queensland Children's Hospital Precinct
62 Graham Street, South Brisbane QLD 4101
Ethics committee country [1] 307121 0
Australia
Date submitted for ethics approval [1] 307121 0
29/08/2020
Approval date [1] 307121 0
30/09/2020
Ethics approval number [1] 307121 0
HREC/20/QCHQ/62592
Ethics committee name [2] 307223 0
The University of Queensland Human Ethics Research Board
Ethics committee address [2] 307223 0
Cumbrae-Stewart Building 72
The University of Queensland St Lucia, QLD 4072
Ethics committee country [2] 307223 0
Australia
Date submitted for ethics approval [2] 307223 0
30/09/2020
Approval date [2] 307223 0
19/10/2020
Ethics approval number [2] 307223 0
2020002359

Summary
Brief summary
The aims are to characterise key antimicrobials (cefotaxime, vancomycin, meropenem, ampicillin, gentamicin, piperacillin-tazobactam, flucloxacillin voriconazole, fluconazole, micafungin, ceftazidime, anidulafungin & teicoplanin) pharmacokinetics (PK) in critically ill children on extracorporeal membrane oxygenation (heart and/or lung support) & continuous renal replacement therapy (kidney support). We aim to design dosing regimens that will be optimised, to achieve maximal effective antimicrobial exposure. Participants will be critically ill children in the Paeditric Intensive Care Unit at Queensland Children's Hospital & University Children's Hospital, Zurich. Method: A prospective observational antimicrobial PK study of critically ill children on extracorporeal therapies. The PK analysis will be performed using a population PK modelling approach P-Metrics 3.5.1 using the concentrations from the patient plasma samples. Building PK models will include an assessment and correlations between the extracorporeal therapy settings, developmental factors and/or clinical factors for each child. Expected outcomes: Improved, optimised antimicrobial dosing treatment regimens for children on extracorporeal therapies.
Trial website
.
Trial related presentations / publications
Public notes
.1 ePoster presented presentation accepted World Federation Pediatric Critical Care conference Dec 2020 Cree M, Parker S, Schlapbach LJ, Roberts J.
"Pharmacokinetics of Antimicrobials in Children Treated with Extracorporeal Therapies- A Systematic Review"
2. ePoster presented presentation accepted World Federation Pediatric Critical Care conference Dec 2020. Cree M, Walsh E, Mattke A, Haisz E Vancomycin -Old Drug do we know how to dose in pediatric extracorporeal membrane oxygenation (ECMO)?
3. Cree M: ECMO and medications Paediatric ECMO course Brisbane QCH September 2020
4. Cree M, Schlapbach L. Meropenem are we adequately treating the paediatric critically ill patient. Abstracts World Congress of Intensive Care 2019 Australian Critical Care 2020:33: S24

Contacts
Principal investigator
Name 106102 0
Mrs Michele Cree
Address 106102 0
Pharmacy Department
Queensland Children's Hospital
501 Stanley Street
Queensland Children's Hospital
South Brisbane 4101 Queensland
Country 106102 0
Australia
Phone 106102 0
+61 422084627
Fax 106102 0
Email 106102 0
[email protected]
Contact person for public queries
Name 106103 0
Suzanne Parker
Address 106103 0
Level 7
The University of Queensland Centre for Clinical Research
Herston Road
Brisbane
Queensland 4029
Country 106103 0
Australia
Phone 106103 0
+61 403227297
Fax 106103 0
Email 106103 0
[email protected]
Contact person for scientific queries
Name 106104 0
Michele Cree
Address 106104 0
Pharmacy Department
Queensland Children's Hospital
501 Stanley Street
Queensland Children's Hospital
South Brisbane 4101 Queensland
Country 106104 0
Australia
Phone 106104 0
+61 422084627
Fax 106104 0
Email 106104 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
The individual participant data collected during the trial, after de-identification; individual participant pharmacokinetic parameters with be calculated (volume of distribution, clearance area under the curve and half life etc) and results published.
When will data be available (start and end dates)?
The pharmacokinetic parameter data is expected to be available immediately following the antimicrobial pharmacokinetic model publication, no end date has been determined, however it is anticipated completion by 2026.
Available to whom?
To researchers who provide a methodologically sound proposal.
Available for what types of analyses?
Analysis only to achieve the aims in the approved proposal.
How or where can data be obtained?
Access is subject to approvals by the Principal Investigator
(Michele Cree)
[email protected] or +61 436808426


What supporting documents are/will be available?




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.