Augmented renal clearance implies a need for increased amoxicillin-clavulanic acid dosing in critically ill children.
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].).
Department 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.
Pieter A J G
PA
De Cock
Infection, Inflammation and Rheumatology Section, University College London, Institute of Child Health, University College London, London, United Kingdom CoMPLEX, University College London, London, United Kingdom Department of Pharmacy, Great Ormond Street Hospital, London, United Kingdom.
Joseph F
JF
Standing
Infection, Inflammation and Rheumatology Section, University College London, Institute of Child Health, University College London, London, United Kingdom Paediatric Infectious Diseases Research Group, Institute for Infection and Immunity, St. George's, University of London, London, United Kingdom.
Charlotte I S
CI
Barker
Department of Pediatric Intensive Care, Ghent University Hospital, Ghent, Belgium.
Annick
A
de Jaeger
Department of Pediatric Intensive Care, Ghent University Hospital, Ghent, Belgium.
Evelyn
E
Dhont
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium.
Mieke
M
Carlier
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium Department of Laboratory Medicine, Ghent University Hospital, Ghent, Belgium.
Alain G
AG
Verstraete
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium Department of Laboratory Medicine, Ghent University Hospital, Ghent, Belgium.
Joris R
JR
Delanghe
Department of Pharmacy, Ghent University Hospital, Ghent, Belgium.
Hugo
H
Robays
Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium.
Peter
P
De Paepe
D000293:Adolescent; D019980:Amoxicillin-Potassium Clavulanate Combination / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D016638:Critical Illness; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009010:Monte Carlo Method; D011446:Prospective Studies; D018805:Sepsis / Q000517:prevention & control
D000900:Anti-Bacterial Agents; D019980:Amoxicillin-Potassium Clavulanate Combination