None listed
Conditions
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.
Interventions
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 ex
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.
Sponsors
Queesland Children's Hospital
Eligibility
Sex/Gender
All
Age
No minimum to 18 Years
Healthy volunteers
No
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
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
Outcome results
None listed