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

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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.
Keywords
SERUM CYSTATIN-C, SEVERE SEPSIS, BETA-LACTAM ANTIBIOTICS, IMPACT, QUANTIFICATION, MARKER, PHARMACOKINETICS, GLOMERULAR-FILTRATION, INTENSIVE-CARE-UNIT, CREATININE MEASUREMENTS

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Citation

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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.
@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},
}

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