Precision Dosing of Beta-lactam Antibiotics in Critically Ill Children

Phase 4Not Yet RecruitingNCT06929702

University Hospital, Ghent58 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Amoxicillin-clavulanate Piperacillin-tazobactam Meropenem

Interventions

Beta-lactam antibioticDRUG

amoxicillin-clavulanic acid, piperacillin-tazobactam, meropenem treatment

Beta-lactam model-informed precision dosingDEVICE

A dosing calculator is used for the prediction of starting doses (a priori dose predictions) and follow-up doses (a posteriori calculations), using a target 100% fT\>MIC.

Eligibility

Sex: ALLMin age: 0 YearsMax age: 18 Years

Medical Language ↔ Plain English

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).

Locations (1)

Ghent University Hospital

Ghent, Belgium

Outcomes

Primary Outcomes

Proportion of subjects reaching the therapeutic target 100% fT>MIC

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%.

Time frame: At 48 hours after start of beta-lactam treatment

Secondary Outcomes

Proportion of subjects reaching the therapeutic target 100% fT>MIC

The therapeutic target range is 10-40 mg/L for amoxicillin, 18-72 mg/L for piperacillin and 2-8 mg/L for meropenem.

Time frame: At 120 hours after start of beta-lactam treatment

Proportion of subjects reaching the therapeutic target 100% fT>MIC

The therapeutic target range is 10-40 mg/L for amoxicillin, 18-72 mg/L for piperacillin and 2-8 mg/L for meropenem.

Time frame: Within the interval 48 to 72 hours after start of beta-treatment

Hospital length-of-stay

Number of days from randomization to hospital discharge. Patients who are not discharged from hospital within 28 days will be censored at 28 days, the maximum follow up time. Patients who die before hospital discharge will also be censored at 28 days.

Time frame: From date of randomization until date of hospital discharge, with a maximum of 28 days.

Central Contacts

Pieter De Cock, Prof.

CONTACT

+32 9 332 29 69 pieter.decock@uzgent.be

Data from ClinicalTrials.gov

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