Population pharmacokinetics of ceftriaxone in critically ill septic patients: a reappraisal

Garot, Denis; Respaud, Renaud; Lanotte, Philippe; Simon, Nicolas; Mercier, Emmanuelle; Ehrmann, Stéphan; Perrotin, D.; Dequin, Pierre‐François; Guellec, Chantal Le

doi:10.1111/j.1365-2125.2011.04005.x

Cited by 73 publications

(73 citation statements)

References 24 publications

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“…The PK profile of ceftriaxone and sulbactam of FDC was compared with that of individual formulation of ceftriaxone and sulbactam, respectively. The PK of individual drugs is well characterized across populations (9,10). however, the Electronic supplementary material The online version of this article (doi:10.1208/s12249-015-0454-2) contains supplementary material, which is available to authorized users.…”

Section: Introductionmentioning

confidence: 99%

Population Pharmacokinetics of Fixed Dose Combination of Ceftriaxone and Sulbactam in Healthy and Infected Subjects

et al. 2015

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ABSTRACT. Increased antibacterial resistance (ABR) and limited drug discovery warrant optimized use of available antibiotics. One option is to rationally combine two antibiotics (fixed dose combination (FDC)) that may delay or prevent emergence of ABR in notorious pathogen. Major concern with FDC is the mutual interaction of its components that might influence their pharmacokinetic (PK) profile, requiring reassessing of whole formulation (adding cost and time). The interaction can be identified by comparing PK profile of a drug present in FDC with its independent entity. An open-label, crossover, single-dose comparative PK study of FDC (ceftriaxone and sulbactam) with their individual reference formulations was performed in 24 healthy adult subjects. No mutual PK interactions between ceftriaxone and sulbactam were observed. Pharmacokinetic data was used to develop a population-PK model to understand between-subject variability (BSV). Pharmacokinetics of ceftriaxone/sulbactam was explained by one and two compartment models, respectively. The subject's Bweight^was identified as a covariate explaining BSV. Both internal and external validations (healthy/infected subjects) were done. The modelderived population-PK parameters of FDC's active components in infected subjects were similar to literature reported values of individual components. Efficacies of various FDC dosage regimens over a range of minimum inhibitory concentrations (MICs) were assessed by Monte Carlo simulations using population-PK parameters of infected/healthy subjects. In infected subjects, 3 g FDC/24 h can treat bacteria with MIC ≤8 μg/mL, while for MIC 8-32 μg/mL, 3 g FDC/12 h is recommended. Lastly, the developed population-PK model was successfully used to predict drug exposure in pediatric population.

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Section: Introductionmentioning

confidence: 99%

Population Pharmacokinetics of Fixed Dose Combination of Ceftriaxone and Sulbactam in Healthy and Infected Subjects

et al. 2015

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“…The pharmacokinetics of -lactam antibiotics is difficult to predict in the critically ill patient population due to the unpredictable effects of pathophysiologic processes particularly during sever sepsis and malignancy [13,14]. The drug's apparent volume of distribution and clearance may be elevated leading to sub-therapeutic plasma concentrations [4,[15][16][17][18][19][20][21][22][23][24]. On the other hand clearance may be unchanged [17] or decreased [4,18] and in the presence of organ dysfunction such acute kidney injury, diminished clearance may lead to massive accumulation and toxicity [25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Simultaneous determination of seven β-lactam antibiotics in human plasma for therapeutic drug monitoring and pharmacokinetic studies

Sime

Roberts

et al. 2014

Journal of Chromatography B

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractThere is strong evidence in literature supporting the benefit of monitoring plasma concentrations of -lactam antibiotics in the critically ill to ensure appropriateness of dosing.The objective of this work was to develop a method for the simultaneous determination of total concentrations piperacillin, benzylpenicillin, flucloxacillin, meropenem, ertapenem, cephazolin and ceftazidime in human plasma. Sample preparation involved protein precipitation with acetonitrile containing 0.1% formic acid and subsequent dilution of supernatant with 0.1% formic acid in water. Chromatographic separation was achieved on a reversed phase column (C18, 2.6µm, 2.1* 50 mm) via gradient elution using water and acetonitrile, each containing 0.1% formic acid, as mobile phase. Tandem mass spectrometry (MSMS) analysis was performed, after electrospray ionization in the positive mode, with multiple reaction monitoring (MRM). The method is accurate with the inter-day and intra-day accuracies of quality control samples (QCs) ranging from 95%-107% and 95%-108%, respectively. It is also precise with intra-day and inter-day coefficient of variations ranging from 4 to 12 % and 5-14% respectively. The lower limit of quantification was 0.1g/mL for each antibiotic except flucloxacillin (0.25g/mL). Recovery was greater than 96% for all analytes except for ertapenem (78%). Coefficients of variation for the matrix effect were less than 10% over the six batches of plasma. Analytes were stable over three freeze-thaw cycles, and for reasonable hours on the bench top as well as post-preparation. This novel liquid chromatography tandem mass spectrometry method proved accurate, precise and applicable for therapeutic drug monitoring and pharmacokinetic studies of the selected -lactam antibiotics.Page 5 Highlights  We present a method for simultaneous determination of seven beta-lactams in plasma  The selected antibiotics are those commonly used in critically ill patients  The method is accurate, precise and meets validation requirements by guidelines  It proved applicable for therapeutic drug monitoring and pharmacokinetic studies

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“…1, 4, 8, 16, 3, 64 µg/mL. The population PK parameter utilized in simulations was clearance of 0.88 +/-0.431 L/h [30] and 4.8 +/-1.9 L/h [31] for ceftriaxone and vancomycin, respectively. The patient weight is an important covariate on drug's clearance, which was assumed to be 70 kg in the analysis.…”

Section: Monte Carlo Simulationsmentioning

confidence: 99%

“…In order to account for the randomness/variability in human PKs and MICs, Monte Carlo simulations of 1000 subjects were done to determine how likely the given exposure of FDC would achieve the target %T>MIC comb or AUC comb (reported as PTA). The PK parameters utilized were clearance of 0.88 +/-0.431 L/h and 4.8 +/-1.9 L/h and elimination rate constant of 0.113 and 0.11 h -1 for ceftriaxone and vancomycin respectively, on the basis of literature [30,31]. Monte Carlo simulations were done for both PK/PD indices i.e.…”

Section: Dosage Optimization Using Pk/pd Modeling: Pk/pd Model Develomentioning

confidence: 99%

Dose optimization of ceftriaxone-vancomycin combination using fractional inhibitory concentration kinetics in resistant bacteria

Sharma

Singla²,

Chaudhary³

et al. 2016

ADMET DMPK

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Population pharmacokinetics of ceftriaxone in critically ill septic patients: a reappraisal

Cited by 73 publications

References 24 publications

Population Pharmacokinetics of Fixed Dose Combination of Ceftriaxone and Sulbactam in Healthy and Infected Subjects

Population Pharmacokinetics of Fixed Dose Combination of Ceftriaxone and Sulbactam in Healthy and Infected Subjects

Simultaneous determination of seven β-lactam antibiotics in human plasma for therapeutic drug monitoring and pharmacokinetic studies

Dose optimization of ceftriaxone-vancomycin combination using fractional inhibitory concentration kinetics in resistant bacteria

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