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, 59 (11), 7027-35

Augmented Renal Clearance Implies a Need for Increased Amoxicillin-Clavulanic Acid Dosing in Critically Ill Children

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Augmented Renal Clearance Implies a Need for Increased Amoxicillin-Clavulanic Acid Dosing in Critically Ill Children

Pieter A J G De Cock et al. Antimicrob Agents Chemother.

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].).

Figures

FIG 1
FIG 1
Goodness-of-fit diagnostic plots for amoxicillin and clavulanic acid. The plots show observations versus population predictions and individual predictions and conditional weighted residuals (CWRES) versus time after dose and population predictions. In the observation versus prediction plots, a line of identity (black solid line) and a Loess smooth line (red solid line) were included as a reference. In the CWRES plots, dashed lines at +2 and −2 standard deviations from the mean (solid line) were included to indicate the expected region of approximately 95% of the data.
FIG 2
FIG 2
Impact of covariates in the final model. The left-hand plot shows weight- and cystatin C-standardized amoxicillin clearance with age split by whether patients were on vasopressors. The right-hand plot shows weight- and age-standardized amoxicillin clearance plotted against measured cystatin C split by whether patients were on vasopressors. Note there is more than one clearance value per subject, since between-occasion variability was included. Open circles, patients not on vasopressors; open squares, patients on vasopressors. Solid line, population predicted values if the patients were not on vasopressors; broken line, population predicted values if the patients were on vasopressors.
FIG 3
FIG 3
Stratified visual predictive check for amoxicillin (CLAV = 0) and clavulanic acid (CLAV = 1). The gray shaded areas show the 95% confidence intervals of the simulated 5th, 50th, and 95th percentiles. The lines show the 5th, 50th and 95th percentiles of raw data.
FIG 4
FIG 4
Probability of target attainment (PTA) (n = 1,000 patients) for amoxicillin according to the dosing regimen, presence/absence of vasopressor therapy, and plasma cystatin C value. The three simulated dosing regimens were as follows: (i) 25 mg/kg every 12 h if under 3 months of age, otherwise every 8 h (British National Formulary for Children [BNF-C] [19]), (ii) 25 mg/kg every 6 h (Sanford Guide for Antimicrobial Therapy [9]), (iii) 25 mg/kg every 4 h (alternative dosing regimen) for bolus administration and 1-h infusion. Amoxicillin target was defined as 40% of time above a MIC of 8 mg/liter.

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