Augmented renal clearance implies a need for increased amoxicillin-clavulanic acid dosing in critically ill children
Pieter A J G De Cock1, Joseph F Standing2, Charlotte I S Barker3
1Department of Pharmacy, Ghent University Hospital, Ghent, Belgium Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium Department of Pediatric Intensive Care, Ghent University Hospital, Ghent, Belgium pieter.decock@uzgent.be.
Insights
Dosing of amoxicillin-clavulanic acid in critically ill children needs updates. Current regimens risk clinical failure due to subtherapeutic drug concentrations, necessitating more frequent administration for effective treatment.
Area of Science:
- Pharmacology
- Pediatric Intensive Care
- Infectious Diseases
Background:
- Limited data exists for amoxicillin-clavulanic acid dosing in critically ill children.
- Current dosing regimens may lead to subtherapeutic drug concentrations.
Purpose of the Study:
- To investigate the pharmacokinetics of amoxicillin and clavulanic acid in critically ill children.
- To determine optimal dosing strategies to improve clinical outcomes.
Main Methods:
- Population pharmacokinetic analysis of amoxicillin and clavulanic acid.
- Collected blood samples from 50 pediatric intensive care unit patients.
- Utilized Monte Carlo simulations to evaluate dosing regimens.
Main Results:
- A three-compartment model for amoxicillin and a two-compartment model for clavulanic acid were identified.
- Plasma cystatin C and vasopressor use influenced amoxicillin clearance.
- Four-hourly dosing of 25 mg/kg is required to achieve therapeutic targets.
Conclusions:
- Current amoxicillin-clavulanic acid dosing regimens are inadequate for critically ill children.
- More frequent dosing (every four hours) is recommended.
- Infusion over 1 hour is preferable for patients with augmented renal function.
Abstract:
There is little data available to guide amoxicillin-clavulanic acid dosing in critically ill children. The primary objective of this study was to investigate the pharmacokinetics of both compounds in this pediatric subpopulation. Patients admitted to the pediatric intensive care unit (ICU) in whom intravenous amoxicillin-clavulanic acid was indicated (25 to 35 mg/kg of body weight every 6 h) were enrolled. Population pharmacokinetic analysis was conducted, and the clinical outcome was documented. A total of 325 and 151 blood samples were collected from 50 patients (median age, 2.58 years; age range, 1 month to 15 years) treated with amoxicillin and clavulanic acid, respectively. A three-compartment model for amoxicillin and a two-compartment model for clavulanic acid best described the data, in which allometric weight scaling and maturation functions were added a priori to scale for size and age. In addition, plasma cystatin C and concomitant treatment with vasopressors were identified to have a significant influence on amoxicillin clearance. The typical population values of clearance for amoxicillin and clavulanic acid were 17.97 liters/h/70 kg and 12.20 liters/h/70 kg, respectively. In 32% of the treated patients, amoxicillin-clavulanic acid therapy was stopped prematurely due to clinical failure, and the patient was switched to broader-spectrum antibiotic treatment. Monte Carlo simulations demonstrated that four-hourly dosing of 25 mg/kg was required to achieve the therapeutic target for both amoxicillin and clavulanic acid. For patients with augmented renal function, a 1-h infusion was preferable to bolus dosing. Current published dosing regimens result in subtherapeutic concentrations in the early period of sepsis due to augmented renal clearance, which risks clinical failure in critically ill children, and therefore need to be updated. (This study has been registered at Clinicaltrials.gov as an observational study [NCT02456974].).
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