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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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Chicago
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.
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.
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.
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.
@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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