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Population pharmacokinetics and dosing simulations of cefuroxime in critically ill patients: non-standard dosing approaches are required to achieve therapeutic exposures

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Abstract
Objectives: To investigate the population pharmacokinetics of cefuroxime in critically ill patients. Methods: In this observational pharmacokinetic study, multiple blood samples were taken over one dosing interval of intravenous cefuroxime. Blood samples were analysed using a validated ultra HPLC tandem mass spectrometry technique. Population pharmacokinetic analysis and dosing simulations were performed using non-linear mixed-effects modelling. Results: One hundred and sixty blood samples were collected from 20 patients. CLCR ranged between 10 and 304 mL/min. A two-compartment model with between-subject variability on CL, V of the central compartment and V of the peripheral compartment described the data adequately. Twenty-four hour urinary CLCR was supported as a descriptor of drug CL. The population model for CLwas CL u1xCLCR/100, where u1 is the typical cefuroxime CL in the population, which is 9.0 L/h. The mean V was 22.5 L. Dosing simulations showed failure to achieve the pharmacokinetic/pharmacodynamic target of 65% fT. MIC for an MIC of 8 mg/L with standard dosing regimens for patients with CLCR = 50 mL/min. Conclusions: Administration of standard doses by intermittent bolus is likely to result in underdosing for many critically ill patients. Continuous infusion of higher than normal doses after a loading dose is more likely to achieve pharmacokinetic/pharmacodynamic targets. However, even continuous infusion of high doses (up to 9 g per day) does not guarantee adequate levels for all patients with a CLCR of = 300 mL/min if the MIC is 8 mg/L.
Keywords
cephalosporins, beta-lactams, antibiotics, PK/PD, critical care medicine, ICUs, AUGMENTED RENAL CLEARANCE, BETA-LACTAM ANTIBIOTICS, SEPTIC SHOCK, MEROPENEM, CEFEPIME, CEFTAZIDIME, INFECTIONS, PNEUMONIA, SEPSIS, MODEL

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MLA
Carlier, Mieke, MICHAEL NOE, Jason A Roberts, et al. “Population Pharmacokinetics and Dosing Simulations of Cefuroxime in Critically Ill Patients: Non-standard Dosing Approaches Are Required to Achieve Therapeutic Exposures.” JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY 69.10 (2014): 2797–2803. Print.
APA
Carlier, Mieke, NOE, M., Roberts, J. A., Stove, V., Verstraete, A., Lipman, J., & De Waele, J. (2014). Population pharmacokinetics and dosing simulations of cefuroxime in critically ill patients: non-standard dosing approaches are required to achieve therapeutic exposures. JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 69(10), 2797–2803.
Chicago author-date
Carlier, Mieke, MICHAEL NOE, Jason A Roberts, Veronique Stove, Alain Verstraete, Jeffrey Lipman, and Jan De Waele. 2014. “Population Pharmacokinetics and Dosing Simulations of Cefuroxime in Critically Ill Patients: Non-standard Dosing Approaches Are Required to Achieve Therapeutic Exposures.” Journal of Antimicrobial Chemotherapy 69 (10): 2797–2803.
Chicago author-date (all authors)
Carlier, Mieke, MICHAEL NOE, Jason A Roberts, Veronique Stove, Alain Verstraete, Jeffrey Lipman, and Jan De Waele. 2014. “Population Pharmacokinetics and Dosing Simulations of Cefuroxime in Critically Ill Patients: Non-standard Dosing Approaches Are Required to Achieve Therapeutic Exposures.” Journal of Antimicrobial Chemotherapy 69 (10): 2797–2803.
Vancouver
1.
Carlier M, NOE M, Roberts JA, Stove V, Verstraete A, Lipman J, et al. Population pharmacokinetics and dosing simulations of cefuroxime in critically ill patients: non-standard dosing approaches are required to achieve therapeutic exposures. JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY. 2014;69(10):2797–803.
IEEE
[1]
M. Carlier et al., “Population pharmacokinetics and dosing simulations of cefuroxime in critically ill patients: non-standard dosing approaches are required to achieve therapeutic exposures,” JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, vol. 69, no. 10, pp. 2797–2803, 2014.
@article{5742388,
  abstract     = {Objectives: To investigate the population pharmacokinetics of cefuroxime in critically ill patients. 
Methods: In this observational pharmacokinetic study, multiple blood samples were taken over one dosing interval of intravenous cefuroxime. Blood samples were analysed using a validated ultra HPLC tandem mass spectrometry technique. Population pharmacokinetic analysis and dosing simulations were performed using non-linear mixed-effects modelling. 
Results: One hundred and sixty blood samples were collected from 20 patients. CLCR ranged between 10 and 304 mL/min. A two-compartment model with between-subject variability on CL, V of the central compartment and V of the peripheral compartment described the data adequately. Twenty-four hour urinary CLCR was supported as a descriptor of drug CL. The population model for CLwas CL u1xCLCR/100, where u1 is the typical cefuroxime CL in the population, which is 9.0 L/h. The mean V was 22.5 L. Dosing simulations showed failure to achieve the pharmacokinetic/pharmacodynamic target of 65% fT. MIC for an MIC of 8 mg/L with standard dosing regimens for patients with CLCR = 50 mL/min. 
Conclusions: Administration of standard doses by intermittent bolus is likely to result in underdosing for many critically ill patients. Continuous infusion of higher than normal doses after a loading dose is more likely to achieve pharmacokinetic/pharmacodynamic targets. However, even continuous infusion of high doses (up to 9 g per day) does not guarantee adequate levels for all patients with a CLCR of = 300 mL/min if the MIC is 8 mg/L.},
  author       = {Carlier, Mieke and NOE, MICHAEL and Roberts, Jason A and Stove, Veronique and Verstraete, Alain and Lipman, Jeffrey and De Waele, Jan},
  issn         = {0305-7453},
  journal      = {JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY},
  keywords     = {cephalosporins,beta-lactams,antibiotics,PK/PD,critical care medicine,ICUs,AUGMENTED RENAL CLEARANCE,BETA-LACTAM ANTIBIOTICS,SEPTIC SHOCK,MEROPENEM,CEFEPIME,CEFTAZIDIME,INFECTIONS,PNEUMONIA,SEPSIS,MODEL},
  language     = {eng},
  number       = {10},
  pages        = {2797--2803},
  title        = {Population pharmacokinetics and dosing simulations of cefuroxime in critically ill patients: non-standard dosing approaches are required to achieve therapeutic exposures},
  url          = {http://dx.doi.org/10.1093/jac/dku195},
  volume       = {69},
  year         = {2014},
}

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