scholarly journals Optimization of flucloxacillin dosing regimens in critically ill patients using population pharmacokinetic modelling of total and unbound concentrations

2020 ◽  
Vol 75 (9) ◽  
pp. 2641-2649
Author(s):  
Nynke G L Jager ◽  
Reinier M van Hest ◽  
Jiao Xie ◽  
Gloria Wong ◽  
Marta Ulldemolins ◽  
...  
Keyword(s):  
Protein Binding ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Binding Capacity ◽  
Compartment Model ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Population Pk ◽  
Non Linear ◽  
Dosing Regimens

Abstract Background Initial appropriate anti-infective therapy is associated with improved outcomes in patients with severe infections. In critically ill patients, altered pharmacokinetic (PK) behaviour is common and known to influence the achievement of PK/pharmacodynamic targets. Objectives To describe population PK and optimized dosing regimens for flucloxacillin in critically ill patients. Methods First, we developed a population PK model, estimated between-patient variability (BPV) and identified covariates that could explain BPV through non-linear mixed-effects analysis, using total and unbound concentrations obtained from 35 adult critically ill patients treated with intermittent flucloxacillin. Second, we validated the model using external datasets from two different countries. Finally, frequently prescribed dosing regimens were evaluated using Monte Carlo simulations. Results A two-compartment model with non-linear protein binding was developed and validated. BPV of the maximum binding capacity decreased from 42.2% to 30.4% and BPV of unbound clearance decreased from 88.1% to 71.6% upon inclusion of serum albumin concentrations and estimated glomerular filtration rate (eGFR; by CKD-EPI equation), respectively. PTA (target of 100%fT>MIC) was 91% for patients with eGFR of 33 mL/min and 1 g q6h, 87% for patients with eGFR of 96 mL/min and 2 g q4h and 71% for patients with eGFR of 153 mL/min and 2 g q4h. Conclusions For patients with high creatinine clearance who are infected with moderately susceptible pathogens, therapeutic drug monitoring is advised since there is a risk of underexposure to flucloxacillin. Due to the non-linear protein binding of flucloxacillin and the high prevalence of hypoalbuminaemia in critically ill patients, dose adjustments should be based on unbound concentrations.

scholarly journals Are Standard Dosing Regimens of Ceftriaxone Adapted for Critically Ill Patients with Augmented Creatinine Clearance?

2019 ◽  
Vol 63 (3) ◽  
Author(s):  
Julien Ollivier ◽  
Cédric Carrié ◽  
Nicolas d’Houdain ◽  
Sarah Djabarouti ◽  
Laurent Petit ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Creatinine Clearance ◽  
Critically Ill ◽  
Drug Monitoring ◽  
Critically Ill Patients ◽  
Free Fraction ◽  
Compartment Model ◽  
Therapeutic Drug ◽  
Target Attainment ◽  
Dosing Regimens

ABSTRACT The objective of the present study was to determine whether augmented renal clearance (ARC) impacts negatively on ceftriaxone pharmacokinetic (PK)/pharmacodynamic (PD) target attainment in critically ill patients. Over a 9-month period, all critically ill patients treated with ceftriaxone were eligible. During the first 3 days of antimicrobial therapy, every patient underwent 24-h creatinine clearance (CLCR) measurements and therapeutic drug monitoring of unbound ceftriaxone. ARC was defined by a CLCR of ≥150 ml/min. Empirical underdosing was defined by a trough unbound ceftriaxone concentration under 2 mg/liter (percentage of the time that the concentration of the free fraction of drug remained greater than the MIC [fT>MIC], 100%). Monte Carlo simulation (MCS) was performed to determine the probability of target attainment (PTA) of different dosing regimens for various MICs and three groups of CLCR (<150, 150 to 200, and >200 ml/min). Twenty-one patients were included. The rate of empirical ceftriaxone underdosing was 62% (39/63). A CLCR of ≥150 ml/min was associated with empirical target underdosing with an odds ratio (OR) of 8.8 (95% confidence interval [CI] = 2.5 to 30.7; P < 0.01). Ceftriaxone PK concentrations were best described by a two-compartment model. CLCR was associated with unbound ceftriaxone clearance (P = 0.02). In the MCS, the proportion of patients who would have failed to achieve a 100% fT>MIC was significantly higher in ARC patients for each dosage regimen (OR = 2.96; 95% CI = 2.74 to 3.19; P < 0.01). A dose of 2 g twice a day was best suited to achieve a 100% fT>MIC. When targeting a 100% fT>MIC for the less susceptible pathogens, patients with a CLCR of ≥150 ml/min remained at risk of empirical ceftriaxone underdosing. These data emphasize the need for therapeutic drug monitoring in ARC patients.

scholarly journals Novel Population Pharmacokinetic Model for Linezolid in Critically Ill Patients and Evaluation of the Adequacy of the Current Dosing Recommendation

Pharmaceutics ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 54 ◽  
Author(s):  
Amaia Soraluce ◽  
Helena Barrasa ◽  
Eduardo Asín-Prieto ◽  
Jose Ángel Sánchez-Izquierdo ◽  
Javier Maynar ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Standard Dose ◽  
Compartment Model ◽  
Antimicrobial Treatment ◽  
Population Pharmacokinetic ◽  
Renal Replacement Therapies ◽  
Continuous Renal Replacement Therapies

Antimicrobial treatment in critically ill patients remains challenging. The aim of this study was to develop a population pharmacokinetic model for linezolid in critically ill patients and to evaluate the adequacy of current dosing recommendation (600 mg/12 h). Forty inpatients were included, 23 of whom were subjected to continuous renal replacement therapies (CRRT). Blood and effluent samples were drawn after linezolid administration at defined time points, and linezolid levels were measured. A population pharmacokinetic model was developed, using NONMEM 7.3. The percentage of patients that achieved the pharmacokinetic/pharmacodynamic (PK/PD) targets was calculated (AUC24/MIC > 80 and 100% T>MIC). A two-compartment model best described the pharmacokinetics of linezolid. Elimination was conditioned by the creatinine clearance and by the extra-corporeal clearance if the patient was subjected to CRRT. For most patients, the standard dose of linezolid did not cover infections caused by pathogens with MIC ≥ 2 mg/L. Continuous infusion may be an alternative, especially when renal function is preserved.

scholarly journals Population Pharmacokinetics and Probability of Target Attainment of Different Dosing Regimens of Ceftazidime in Critically Ill Patients with a Proven or Suspected Pseudomonas aeruginosa Infection

Antibiotics ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 612
Author(s):  
Annabel Werumeus Buning ◽  
Caspar J. Hodiamont ◽  
Natalia M. Lechner ◽  
Margriet Schokkin ◽  
Paul W. G. Elbers ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Hematologic Malignancy ◽  
Compartment Model ◽  
Target Attainment ◽  
Worst Case ◽  
Optimal Dosing ◽  
Population Pk ◽  
Pseudomonas Aeruginosa Infection

Altered pharmacokinetics (PK) of hydrophilic antibiotics in critically ill patients is common, with possible consequences for efficacy and resistance. We aimed to describe ceftazidime population PK in critically ill patients with a proven or suspected Pseudomonas aeruginosa infection and to establish optimal dosing. Blood samples were collected for ceftazidime concentration measurement. A population PK model was constructed, and probability of target attainment (PTA) was assessed for targets 100% T > MIC and 100% T > 4 × MIC in the first 24 h. Ninety-six patients yielded 368 ceftazidime concentrations. In a one-compartment model, variability in ceftazidime clearance (CL) showed association with CVVH. For patients not receiving CVVH, variability in ceftazidime CL was 103.4% and showed positive associations with creatinine clearance and with the comorbidities hematologic malignancy, trauma or head injury, explaining 65.2% of variability. For patients treated for at least 24 h and assuming a worst-case MIC of 8 mg/L, PTA was 77% for 100% T > MIC and 14% for 100% T > 4 × MIC. Patients receiving loading doses before continuous infusion demonstrated higher PTA than patients who did not (100% T > MIC: 95% (n = 65) vs. 13% (n = 15); p < 0.001 and 100% T > 4 × MIC: 20% vs. 0%; p = 0.058). The considerable IIV in ceftazidime PK in ICU patients could largely be explained by renal function, CVVH use and several comorbidities. Critically ill patients are at risk for underexposure to ceftazidime when empirically aiming for the breakpoint MIC for P. aeruginosa. A loading dose is recommended.

scholarly journals Population Pharmacokinetic Analysis of Colistin Methanesulfonate and Colistin after Intravenous Administration in Critically Ill Patients with Infections Caused by Gram-Negative Bacteria

2009 ◽  
Vol 53 (8) ◽  
pp. 3430-3436 ◽  
Author(s):  
D. Plachouras ◽  
M. Karvanen ◽  
L. E. Friberg ◽  
E. Papadomichelakis ◽  
A. Antoniadou ◽  
...  
Keyword(s):  
Steady State ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Colistin Methanesulfonate

ABSTRACT Colistin is used to treat infections caused by multidrug-resistant gram-negative bacteria (MDR-GNB). It is administered intravenously in the form of colistin methanesulfonate (CMS), which is hydrolyzed in vivo to the active drug. However, pharmacokinetic data are limited. The aim of the present study was to characterize the pharmacokinetics of CMS and colistin in a population of critically ill patients. Patients receiving colistin for the treatment of infections caused by MDR-GNB were enrolled in the study; however, patients receiving a renal replacement therapy were excluded. CMS was administered at a dose of 3 million units (240 mg) every 8 h. Venous blood was collected immediately before and at multiple occasions after the first and the fourth infusions. Plasma CMS and colistin concentrations were determined by a novel liquid chromatography-tandem mass spectrometry method after a rapid precipitation step that avoids the significant degradation of CMS and colistin. Population pharmacokinetic analysis was performed with the NONMEM program. Eighteen patients (6 females; mean age, 63.6 years; mean creatinine clearance, 82.3 ml/min) were included in the study. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.046 h and 2.3 h, respectively. The clearance of CMS was 13.7 liters/h. For colistin, a one-compartment model was sufficient to describe the data, and the estimated half-life was 14.4 h. The predicted maximum concentrations of drug in plasma were 0.60 mg/liter and 2.3 mg/liter for the first dose and at steady state, respectively. Colistin displayed a half-life that was significantly long in relation to the dosing interval. The implications of these findings are that the plasma colistin concentrations are insufficient before steady state and raise the question of whether the administration of a loading dose would benefit critically ill patients.

scholarly journals Population Pharmacokinetic Study of the Suitability of Standard Dosing Regimens of Amikacin in Critically Ill Patients with Open-Abdomen and Negative-Pressure Wound Therapy

2020 ◽  
Vol 64 (4) ◽  
Author(s):  
Cédric Carrié ◽  
Faustine Delzor ◽  
Stéphanie Roure ◽  
Vincent Dubuisson ◽  
Laurent Petit ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Body Weight ◽  
Monte Carlo Simulations ◽  
Critically Ill ◽  
Negative Pressure ◽  
Critically Ill Patients ◽  
Open Abdomen ◽  
Population Pharmacokinetic ◽  
Pressure Therapy ◽  
Dosing Regimens

ABSTRACT The aim was to assess the appropriateness of recommended regimens for empirical MIC coverage in critically ill patients with open-abdomen and negative-pressure therapy (OA/NPT). Over a 5-year period, every critically ill patient who received amikacin and who underwent therapeutic drug monitoring (TDM) while being treated by OA/NPT was retrospectively included. A population pharmacokinetic (PK) modeling was performed considering the effect of 10 covariates (age, sex, total body weight [TBW], adapted body weight [ABW], body surface area [BSA], modified sepsis-related organ failure assessment [SOFA] score, vasopressor use, creatinine clearance [CLCR], fluid balance, and amount of fluids collected by the NPT over the sampling day) in patients who underwent continuous renal replacement therapy (CRRT) or did not receive CRRT. Monte Carlo simulations were employed to determine the fractional target attainment (FTA) for the PK/pharmacodynamic [PD] targets (maximum concentration of drug [Cmax]/MIC ratio of ≥8 and a ratio of the area under the concentration-time curve from 0 to 24 h [AUC0–24]/MIC of ≥75). Seventy critically ill patients treated by OA/NPT (contributing 179 concentration values) were included. Amikacin PK concentrations were best described by a two-compartment model with linear elimination and proportional residual error, with CLCR and ABW as significant covariates for volume of distribution (V) and CLCR for CL. The reported V) in non-CRRT and CRRT patients was 35.8 and 40.2 liters, respectively. In Monte Carlo simulations, ABW-adjusted doses between 25 and 35 mg/kg were needed to reach an FTA of >85% for various renal functions. Despite an increased V and a wide interindividual variability, desirable PK/PD targets may be achieved using an ABW-based loading dose of 25 to 30 mg/kg. When less susceptible pathogens are targeted, higher dosing regimens are probably needed in patients with augmented renal clearance (ARC). Further studies are needed to assess the effect of OA/NPT on the PK parameters of antimicrobial agents.

scholarly journals Application of Pharmacometrics in Pharmacotherapy: Open-Source Software for Vancomycin Therapeutic Drug Management

Pharmaceutics ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 224 ◽  
Author(s):  
Soo Hyeon Bae ◽  
Dong-Seok Yim ◽  
Hyemi Lee ◽  
Ae-Ryoung Park ◽  
Ji-Eun Kwon ◽  
...  
Keyword(s):  
Open Source ◽  
Open Source Software ◽  
Compartment Model ◽  
Therapeutic Drug ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Drug Management ◽  
Korean Patients ◽  
Population Pk ◽  
R Shiny

The population pharmacokinetic (PK) parameters that are implemented in therapeutic drug management (TDM) software were generally obtained from a Western population and might not be adequate for PK prediction with a Korean population. This study aimed to develop a population PK model for vancomycin using Korean data to improve the quality of TDM for Korean patients. A total of 220 patients (1020 observations) who received vancomycin TDM services were included in the dataset. A population PK analysis was performed using non-linear mixed effects modeling, and a covariate evaluation was conducted. A two-compartment model with first-order elimination best explained the vancomycin PK, with estimates of 2.82 L/h, 31.8 L, 11.7 L/h, and 75.4 L for CL, V1, Q, and V2, respectively. In the covariate analysis, weight correlated with the volume of the peripheral compartment, and creatinine clearance, hemodialysis, and continuous renal replacement therapy treatments contributed to the clearance of vancomycin. The results show the clear need to optimize the PK parameters used for TDM in Korean patients. Specifically, V1 should be smaller for Korean patients, and renal replacement therapies should be considered in TDM practice. This final model was successfully applied in R shiny as open-source software for Koreans.

scholarly journals Amikacin Initial Dose in Critically Ill Patients: a Nonparametric Approach To Optimize A Priori Pharmacokinetic/Pharmacodynamic Target Attainments in Individual Patients

2019 ◽  
Vol 63 (11) ◽  
Author(s):  
Clément Boidin ◽  
Laurent Bourguignon ◽  
Sabine Cohen ◽  
Claire Roger ◽  
Jean-Yves Lefrant ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
A Priori ◽  
Predictive Performance ◽  
Compartment Model ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Data Set ◽  
Nonparametric Approach ◽  
The Right

ABSTRACT Amikacin is commonly used for probabilistic antimicrobial therapy in critically ill patients with sepsis. Its narrow therapeutic margin makes it challenging to determine the right individual dose that ensures the highest efficacy target attainment rate (TAR) in this setting. This study aims to develop a new initial dosing approach for amikacin by optimizing the a priori TAR in this population. A population pharmacokinetic model was built with a learning data set from critically ill patients who received amikacin. It was then used to design an initial dosing approach maximizing a priori TAR for a target ratio of ≥8 for the peak concentration to the MIC (Cmax/MIC) or of ≥75 for the ratio of the area under the concentration-time curve from 0 to 24 h to the MIC (AUC0–24/MIC). In the 166 patients included, 53% had amikacin Cmax of ≥64 mg/liter with a median dose of 23.4 mg/kg. A two-compartment model with creatinine clearance and body surface area as covariates best described the data and showed good predictive performance. Our dosing approach was successful in optimizing TAR for Cmax/MIC, with a rate of 92.9% versus 67.9% using a 30-mg/kg regimen, based on an external subset of data and assuming a MIC of 8 mg/liter. Mean optimal doses were higher (3.5 ± 0.5 g) than with the 30-mg/kg regimen (2.1 ± 0.3 g). Suggested doses varied with the MIC, the target index, and desired TAR threshold. A dosing algorithm based on the method is proposed for a large range of patient covariates. Clinical studies are necessary to confirm efficacy and safety of this optimized dosing approach.

scholarly journals Using Population Pharmacokinetics To Determine Gentamicin Dosing during Extended Daily Diafiltration in Critically Ill Patients with Acute Kidney Injury

2010 ◽  
Vol 54 (9) ◽  
pp. 3635-3640 ◽  
Author(s):  
Jason A. Roberts ◽  
Jonathan Field ◽  
Adam Visser ◽  
Rosemary Whitbread ◽  
Mandy Tallot ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Monte Carlo ◽  
Monte Carlo Simulations ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Kidney Injury ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic

ABSTRACT The objective of the present prospective pharmacokinetic study was to describe the variability of plasma gentamicin concentrations in critically ill patients with acute kidney injury (AKI) necessitating extended daily diafiltration (EDD-f) using a population pharmacokinetic model and to subsequently perform Monte Carlo dosing simulations to determine which dose regimen achieves the pharmacodynamic targets the most consistently. We collected data from 28 gentamicin doses in 14 critically ill adult patients with AKI requiring EDD-f and therapeutic gentamicin. Serial plasma samples were collected. A population pharmacokinetic model was used to describe the pharmacokinetics of gentamicin and perform Monte Carlo simulations with doses of between 3 mg/kg of body weight and 7 mg/kg and at various time points before commencement of EDD-f to evaluate the optimal dosing regimen for achieving pharmacodynamic targets. A two-compartment pharmacokinetic model adequately described the gentamicin clearance while patients were on and off EDD-f. The plasma half-life of gentamicin during EDD-f was 13.8 h, whereas it was 153.4 h without EDD-f. Monte Carlo simulations suggest that dosing with 6 mg/kg every 48 h either 30 min or 1 h before the commencement of EDD-f results in 100% attainment of the target maximum concentration drug in plasma (<10 mg/liter) and sufficient attainment of the target area under the concentration-time curve from 0 to 24 h (AUC0-24; 70 to 120 mg·h/liter). None of the simulated dosing regimens satisfactorily achieved the targets of the minimum concentrations of drug in plasma (<1.0 mg/liter) at 24 h. In conclusion, dosing of gentamicin 30 min to 1 h before the commencement of an EDD-f treatment enables attainment of target peak concentrations for maximal therapeutic effect while enhancing drug clearance to minimize toxicity. Redosing in many patients should occur after 48 h, and we recommend the use of therapeutic drug monitoring to guide dosing to optimize achievement of the AUC0-24 targets.

scholarly journals Exploring population pharmacokinetic models in patients treated with vancomycin during continuous venovenous haemodiafiltration (CVVHDF)

Critical Care ◽  
2021 ◽  
Vol 25 (1) ◽  
Author(s):  
Marcus Kirwan ◽  
Reema Munshi ◽  
Hannah O’Keeffe ◽  
Conor Judge ◽  
Mary Coyle ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Maintenance Dose ◽  
Structural Model ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Loading Dose ◽  
Dose Monitoring ◽  
Population Pk ◽  
Vasopressor Use

Abstract Background Therapeutic antibiotic dose monitoring can be particularly challenging in septic patients requiring renal replacement therapy. Our aim was to conduct an exploratory population pharmacokinetic (PK) analysis on PK of vancomycin following intermittent infusion in critically ill patients receiving continuous venovenous haemodiafiltration (CVVHDF); focussing on the influence of dialysis-related covariates. Methods This was a retrospective single-centre tertiary level intensive care unit (ICU) study, which included patients treated concurrently with vancomycin and CVVHDF between January 2015 and July 2016. We extracted clinical, laboratory and dialysis data from the electronic healthcare record (EHR), using strict inclusion criteria. A population PK analysis was conducted with a one-compartment model using the PMetrics population PK modelling package. A base structural model was developed, with further analyses including clinical and dialysis-related data to improve model prediction through covariate inclusion. The final selected model simulated patient concentrations using probability of target attainment (PTA) plots to investigate the probability of different dosing regimens achieving target therapeutic concentrations. Results A total of 106 vancomycin dosing intervals (155 levels) in 24 patients were examined. An acceptable 1-compartment base model was produced (Plots of observed vs. population predicted concentrations (Obs–Pred) R2 = 0.78). No continuous covariates explored resulted in a clear improvement over the base model. Inclusion of anticoagulation modality and vasopressor use as categorical covariates resulted in similar PK parameter estimates, with a trend towards lower parameter estimate variability when using regional citrate anti-coagulation or without vasopressor use. Simulations using PTA plots suggested that a 2 g loading dose followed by 750 mg 12 hourly as maintenance dose, commencing 12 h after loading, is required to achieve adequate early target trough concentrations of at least 15 mg/L. Conclusions PTA simulations suggest that acceptable trough vancomycin concentrations can be achieved early in treatment with a 2 g loading dose and maintenance dose of 750 mg 12 hourly for critically ill patients on CVVHDF.

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