Scaling beta-lactam antimicrobial pharmacokinetics from early life to old age

Lonsdale, Dagan O, Baker, Emma H, Kipper, Karin, Barker, Charlotte, Philips, Barbara, Rhodes, Andrew, Sharland, Mike and Standing, Joseph F (2019) Scaling beta-lactam antimicrobial pharmacokinetics from early life to old age. British Journal of Clinical Pharmacology, 85 (2). pp. 316-346. ISSN 0306-5251

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Beta-lactam dose optimization in critical care is a current priority. We aimed to review the pharmacokinetics (PK) of three commonly used beta-lactams (amoxicillin ± clavulanate, piperacillin-tazobactam and meropenem) to compare PK parameters reported in critically and noncritically ill neonates, children and adults, and to investigate whether allometric and maturation scaling principles could be applied to describe changes in PK parameters through life.


A systematic review of PK studies of the three drugs was undertaken using MEDLINE and EMBASE. PK parameters and summary statistics were extracted and scaled using allometric principles to 70 kg individual for comparison. Pooled data were used to model clearance maturation and decline using a sigmoidal (Hill) function.


A total of 130 papers were identified. Age ranged from 29 weeks to 82 years and weight from 0.9-200 kg. PK parameters from critically ill populations were reported with wider confidence intervals than those in healthy volunteers, indicating greater PK variability in critical illness. The standard allometric size and sigmoidal maturation model adequately described increasing clearance in neonates, and a sigmoidal model was also used to describe decline in older age. Adult weight-adjusted clearance was achieved at approximately 2 years postmenstrual age. Changes in volume of distribution were well described by the standard allometric model, although amoxicillin data suggested a relatively higher volume of distribution in neonates.


Critical illness is associated with greater PK variability than in healthy volunteers. The maturation models presented will be useful for optimizing beta-lactam dosing, although a prospective, age-inclusive study is warranted for external validation.

Item Type: Article
Schools and Departments: Brighton and Sussex Medical School > Brighton and Sussex Medical School
Brighton and Sussex Medical School > Clinical and Experimental Medicine
Subjects: R Medicine > RC Internal medicine > RC0086 Medical emergencies. Critical care. Intensive care. First aid
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Depositing User: Ellen Thomas
Date Deposited: 15 May 2019 11:13
Last Modified: 03 Sep 2019 01:00

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