Individualised amoxicillin-clavulanate dosing recommendations for critically ill children with augmented clearance
Evelyn Dhont1, Joseph F Standing2, Emma Beel3
1Department of Pediatric Intensive Care Medicine, Ghent University Hospital, Ghent, Belgium; Department of Basic and Applied Medical Sciences, Faculty of Medicine and Health Sciences, Ghent, University, Ghent, Belgium.
Insights
Current amoxicillin-clavulanate dosing for children after cardiac surgery may be too low. This study suggests more frequent dosing is needed to prevent infections and treatment failure in these vulnerable patients.
Area of Science:
- Pharmacology
- Pediatric Critical Care
- Infectious Diseases
Background:
- Children undergoing cardiac surgery are at high risk for postoperative infections.
- Amoxicillin-clavulanate is a critical antibiotic for these infections.
- Pharmacokinetic data for amoxicillin-clavulanate in pediatric cardiac surgery patients is lacking.
Purpose of the Study:
- To establish evidence-based amoxicillin-clavulanate dosing recommendations for children post-cardiac surgery.
- To analyze population pharmacokinetics and simulate target attainment.
- To optimize antibiotic therapy and prevent clinical failure.
Main Methods:
- Population pharmacokinetic analysis using NONMEM software.
- Inclusion of critically ill children (1 day to 15 years) post-cardiac surgery.
- Collection of amoxicillin and clavulanate blood samples for analysis.
Main Results:
- Augmented amoxicillin clearance was observed in pediatric cardiac surgery patients.
- Vasopressor use significantly decreased amoxicillin-clavulanate clearance.
- Four-hourly dosing is recommended for patients not on vasopressors to achieve therapeutic drug exposure.
Conclusions:
- Existing amoxicillin-clavulanate dosing regimens require updating in critically ill children post-cardiac surgery.
- Optimized dosing is essential to prevent subtherapeutic concentrations and treatment failure.
- Further research and updated guidelines are needed to ensure effective antibiotic use.
Objective:
Children who undergo cardiac surgery are prone to postoperative infections for which amoxicillin-clavulanate is a cornerstone antibiotic. Nevertheless, amoxicillin-clavulanate pharmacokinetics have not been studied in infants and children after cardiac surgery so far. Antibiotic exposure might be highly variable in this population due to the impact of growth, maturation, and specific pathophysiological and surgery-induced alterations. The objective of this study was to develop evidence-based amoxicillin-clavulanate dosing recommendations based on population pharmacokinetic analysis and probability of target attainment simulations in children after cardiac surgery.
Methods:
Critically ill children (aged 1 day to 15 y) who underwent cardiac surgery and who were treated postoperatively with amoxicillin-clavulanate (30-60 mg/kg/6 h based on the amoxicillin component, infused in 30 min) were included. Up to five amoxicillin and clavulanate blood samples were collected per dose at predefined sampling times. Population pharmacokinetics analysis was performed using nonlinear mixed effects modelling software NONMEM.
Results:
We collected 316 amoxicillin and 287 clavulanate blood samples from 37 patients. A three-compartment model for amoxicillin and a two-compartment model for clavulanate best described pharmacokinetics, with allometric weight scaling and maturation functions added a priori to scale for size and age. Clearance estimates were remarkably high, except in patients receiving vasopressors, which decreased clearance of amoxicillin-clavulanate by a third. Using a pharmacokinetic/pharmacodynamic target of 50%fT>MIC of 8 mg/L, patients not on vasopressors warranted 4-hourly dosing to achieve adequate drug exposure due to augmented amoxicillin clearance. Only in patients treated with vasopressors was the standard 6-hourly dosing regimen sufficient to attain amoxicillin concentrations above the MIC for half of the dosing interval.
Conclusions:
Current amoxicillin-clavulanate dosing regimens for critically ill children after cardiac surgery need to be updated to avoid subtherapeutic concentrations and clinical failure due to augmented clearance (ClinicalTrials.gov NCT02456974).
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