Early Model-Informed Precision Dosing of Beta-lactam Antibiotics in Critically Ill Children: Big Solution for Small People?
Trial Snapshot
- Phase
- Phase 4
- Status
- Recruiting
- Sponsor
- University Hospital, Ghent
- Enrollment
- 58
- Locations
- 2
- Primary Endpoint
- Proportion of subjects reaching the therapeutic target 100% fT>MIC
Study Overview
Brief Summary
The overall objective of this study is to investigate the impact of early model-informed precision dosing (MIPD) on target attainment of three beta-lactam antibiotics (amoxicillin-clavulanic acid, piperacillin-tazobactam and meropenem) in critically ill children. This evaluation includes a comparison with the more standard approach on clinical and patient-oriented measures.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Double (Participant, Outcomes Assessor)
Masking Description
Participants and legal representatives are blinded for the allocation to the intervention or standard-of-care arm until the end of study. The statistician is kept blinded until after data analysis.
Eligibility Criteria
- Ages
- 0 Years to 18 Years (Child, Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Subject aged between 0 - 17 years 10 months.
- •Subject admitted to a participating ward unit (Neonatal Intensive Care Unit, Pediatric Intensive Care Unit, Pediatric Hematology-Oncology unit).
- •Strongly suspected or confirmed systemic infection.
- •Subject planned to start on intravenous amoxicillin-clavulanic acid, piperacillin-tazobactam or meropenem treatment at least aimed for a minimum duration of two days at time of inclusion. If the subject was previously treated with the same beta-lactam, the minimum interval to the previous beta-lactam treatment episode is
- •40 hours for amoxicillin-clavulanic acid (based on elimination half-life)
- •8 hours for piperacillin-tazobactam and meropenem (based on elimination half-life) Subject planned to start on intravenous amoxicillin (without clavulanic acid) will not be included.
- •Informed consent/assent signed by parents or legal representatives of the subject.
- •Not previously enrolled in this trial.
Exclusion Criteria
- •Subject with serum creatinine level ≥ 2 mg/L at inclusion.
- •Subject receiving (or planned to receive) haemofiltration, extracorporeal membrane oxygenation, hemodialysis or peritoneal dialysis, molecular adsorbent recirculating system or any other exchange technique.
- •Subject receiving (or planned to receive) body cooling.
- •Subject death is deemed imminent and inevitable.
- •Reporting of first dosing advice (based on blood sampling) is not possible within 28 hours (*) after start treatment.
- •The subject is known or suspected to be pregnant.
- •The subject has a known allergy to the specific beta-lactam antibiotic.
- •(*) The first (a posteriori) dose calculation and dose adjustment if necessary, is performed within a maximum timeframe of 28 hours after start of treatment (i.e. maximum timeframe to first dose adjustment).
Arms & Interventions
Standard of Care beta-lactam treatment
Beta-lactam standard-of-care dosing regimen, as currently used at participating wards, during 28 day study period
Intervention: Beta-lactam antibiotic (Drug)
Beta-lactam model-informed precision dosing
fT>MIC-based model-informed precision dosing of beta-lactam antibiotics using a dosing calculator during 28 day study period.
Intervention: Beta-lactam antibiotic (Drug)
Beta-lactam model-informed precision dosing
fT>MIC-based model-informed precision dosing of beta-lactam antibiotics using a dosing calculator during 28 day study period.
Intervention: Beta-lactam model-informed precision dosing (Device)
Outcomes
Primary Outcomes
Proportion of subjects reaching the therapeutic target 100% fT>MIC
Time Frame: At 48 hours after start of beta-lactam treatment
fT\>MIC refers to the percentage of the dosing interval during which the beta-lactam concentration remains above the Minimum Inhibitory Concentration (MIC). A target lower boundary for trough concentrations is set to achieve 100% fT\>MIC. A conservative upper threshold for trough concentrations of 100% fT\>4xMIC is used. Therefore, the therapeutic target range is 10-40 mg/L for amoxicillin (\*), 18-72 mg/L for piperacillin (\*\*) and 2-8 mg/L for meropenem (\*\*\*). (\*) 10 mg/L for amoxicillin: taking into account a EUCAST breakpoint (for Escherichia coli infections) of 8 mg/L and a plasma protein binding of 18%. (\*\*) 18 mg/L for piperacillin: taking into account a EUCAST breakpoint (for wild-type Pseudomonas spp. infections) of 16 mg/L and a plasma protein binding of 9%. (\*\*\*) 2 mg/L for meropenem: taking into account a EUCAST breakpoint of 2 mg/L (for wild-type Enterobacterales species) and a plasma protein binding of 2%.
Secondary Outcomes
- Proportion of subjects reaching the therapeutic target 100% fT>MIC(Within the interval 48 to 72 hours after start of beta-treatment)
- Hospital length-of-stay(From date of randomization until date of hospital discharge, with a maximum of 28 days.)
- Proportion of subjects reaching the therapeutic target 100% fT>MIC(At 120 hours after start of beta-lactam treatment)