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Augmented renal clearance implies a need for increased amoxicillin-clavulanic acid dosing in critically ill children

Pieter De Cocker UGent, Joseph F Standing, Charlotte IS Barker, Annik de Jaeger, EVELYN DHONT, Mieke Carlier, Alain Verstraete UGent, Joris Delanghe UGent, Hugo Robays UGent and Peter De Paepe UGent (2015) ANTIMICROBIAL AGENTS AND CHEMOTHERAPY. 59(11). p.7027-7035
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
SERUM CYSTATIN-C, SEVERE SEPSIS, BETA-LACTAM ANTIBIOTICS, IMPACT, QUANTIFICATION, MARKER, PHARMACOKINETICS, GLOMERULAR-FILTRATION, INTENSIVE-CARE-UNIT, CREATININE MEASUREMENTS
journal title
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Antimicrob. Agents Chemother.
volume
59
issue
11
pages
7027 - 7035
Web of Science type
Article
Web of Science id
000368238100043
JCR category
PHARMACOLOGY & PHARMACY
JCR impact factor
4.415 (2015)
JCR rank
34/253 (2015)
JCR quartile
1 (2015)
ISSN
0066-4804
DOI
10.1128/AAC.01368-15
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
7105645
handle
http://hdl.handle.net/1854/LU-7105645
date created
2016-02-29 11:33:55
date last changed
2017-02-17 15:16:58
@article{7105645,
  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.},
  author       = {De Cocker, Pieter and Standing, Joseph F and Barker, Charlotte IS and de Jaeger, Annik and DHONT, EVELYN and Carlier, Mieke and Verstraete, Alain and Delanghe, Joris and Robays, Hugo and De Paepe, Peter},
  issn         = {0066-4804},
  journal      = {ANTIMICROBIAL AGENTS AND CHEMOTHERAPY},
  keyword      = {SERUM CYSTATIN-C,SEVERE SEPSIS,BETA-LACTAM ANTIBIOTICS,IMPACT,QUANTIFICATION,MARKER,PHARMACOKINETICS,GLOMERULAR-FILTRATION,INTENSIVE-CARE-UNIT,CREATININE MEASUREMENTS},
  language     = {eng},
  number       = {11},
  pages        = {7027--7035},
  title        = {Augmented renal clearance implies a need for increased amoxicillin-clavulanic acid dosing in critically ill children},
  url          = {http://dx.doi.org/10.1128/AAC.01368-15},
  volume       = {59},
  year         = {2015},
}

Chicago
De Cocker, Pieter, Joseph F Standing, Charlotte IS Barker, ANNIK DE JAEGER, EVELYN DHONT, MIEKE CARLIER, Alain Verstraete, Joris Delanghe, Hugo Robays, and Peter De Paepe. 2015. “Augmented Renal Clearance Implies a Need for Increased Amoxicillin-clavulanic Acid Dosing in Critically Ill Children.” Antimicrobial Agents and Chemotherapy 59 (11): 7027–7035.
APA
De Cocker, P., Standing, J. F., Barker, C. I., DE JAEGER, A., DHONT, E., CARLIER, M., Verstraete, A., et al. (2015). Augmented renal clearance implies a need for increased amoxicillin-clavulanic acid dosing in critically ill children. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 59(11), 7027–7035.
Vancouver
1.
De Cocker P, Standing JF, Barker CI, DE JAEGER A, DHONT E, CARLIER M, et al. Augmented renal clearance implies a need for increased amoxicillin-clavulanic acid dosing in critically ill children. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY. 2015;59(11):7027–35.
MLA
De Cocker, Pieter, Joseph F Standing, Charlotte IS Barker, et al. “Augmented Renal Clearance Implies a Need for Increased Amoxicillin-clavulanic Acid Dosing in Critically Ill Children.” ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 59.11 (2015): 7027–7035. Print.