scholarly journals Pragmatic options for dose optimization of ceftazidime/avibactam with aztreonam in complex patients

2020 ◽  
Author(s):  
Marco Falcone ◽  
Francesco Menichetti ◽  
Dario Cattaneo ◽  
Giusy Tiseo ◽  
Sara Baldelli ◽  
...  
Keyword(s):  
Critically Ill ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Optimal Dosing ◽  
Complex Patients ◽  
Daily Dose ◽  
Fourth Dose ◽  
High Doses ◽  
Dosing Strategy ◽  
Dosing Nomogram

Abstract Background Avibactam is a β-lactamase inhibitor that is combined with aztreonam against Enterobacterales co-expressing serine- and metallo-β-lactamases (MBL). Optimal dosing of aztreonam with avibactam is not well-defined in critically ill patients and contingent on ceftazidime/avibactam product labelling. Objectives To identify a pragmatic dosing strategy for aztreonam with avibactam to maximize the probability of target attainment (PTA). Methods We conducted a prospective observational pharmacokinetic study. Five blood samples were collected around the fourth dose of aztreonam or ceftazidime/avibactam and assayed for all three drugs. Population pharmacokinetic (PK) analysis coupled with Monte Carlo simulations were used to create a dosing nomogram for aztreonam and ceftazidime/avibactam based on drug-specific pharmacodynamic (PD) targets. Results A total of 41 participants (59% male) median age of 75 years (IQR 63–79 years) were enrolled. They were critically ill (46%) with multiple comorbidities and complications including burns (20%). Population PK analysis identified higher volume of distribution and lower clearance (CL) compared with typical value expectations for aztreonam and ceftazidime/avibactam. Estimated glomerular filtration (eGFR) rate using the CKD-EPI equation predicted CL for all three drugs. The need for high doses of aztreonam and ceftazidime/avibactam above those in the existing product labels are not predicted by this analysis with the exception of ceftazidime/avibactam for patients with eGFR of 6–15 mL/min, in whom suboptimal PTA of ≤71% is predicted. Conclusions Pragmatic and lower daily-dose options are predicted for aztreonam and ceftazidime/avibactam when the eGFR is <90 mL/min. These options should be tested prospectively.

scholarly journals Influence of Mechanical Ventilation on the Pharmacokinetics of Vancomycin Administered by Continuous Infusion in Critically Ill Patients

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Susanna Edith Medellín-Garibay ◽  
Silvia Romano-Moreno ◽  
Pilar Tejedor-Prado ◽  
Noelia Rubio-Álvaro ◽  
Aida Rueda-Naharro ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Creatinine Clearance ◽  
Continuous Infusion ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Volume Of Distribution ◽  
Stochastic Simulations ◽  
Population Pharmacokinetic

ABSTRACT Pathophysiological changes involved in drug disposition in critically ill patients should be considered in order to optimize the dosing of vancomycin administered by continuous infusion, and certain strategies must be applied to reach therapeutic targets on the first day of treatment. The aim of this study was to develop a population pharmacokinetic model of vancomycin to determine clinical covariates, including mechanical ventilation, that influence the wide variability of this antimicrobial. Plasma vancomycin concentrations from 54 critically ill patients were analyzed simultaneously by a population pharmacokinetic approach. A nomogram for dosing recommendations was developed and was internally evaluated through stochastic simulations. The plasma vancomycin concentration-versus-time data were best described by a one-compartment open model with exponential interindividual variability associated with vancomycin clearance and the volume of distribution. Residual error followed a homoscedastic trend. Creatinine clearance and body weight significantly dropped the objective function value, showing their influence on vancomycin clearance and the volume of distribution, respectively. Characterization based on the presence of mechanical ventilation demonstrated a 20% decrease in vancomycin clearance. External validation (n = 18) was performed to evaluate the predictive ability of the model; median bias and precision values were 0.7 mg/liter (95% confidence interval [CI], −0.4, 1.7) and 5.9 mg/liter (95% CI, 5.4, 6.4), respectively. A population pharmacokinetic model was developed for the administration of vancomycin by continuous infusion to critically ill patients, demonstrating the influence of creatinine clearance and mechanical ventilation on vancomycin clearance, as well as the implications for targeting dosing rates to reach the therapeutic range (20 to 30 mg/liter).

scholarly journals Population Pharmacokinetics of Piperacillin following Continuous Infusion in Critically Ill Patients and Impact of Renal Function on Target Attainment

2020 ◽  
Vol 64 (7) ◽  
Author(s):  
Vibeke Klastrup ◽  
Anders Thorsted ◽  
Merete Storgaard ◽  
Steffen Christensen ◽  
Lena E. Friberg ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Bacterial Infections ◽  
Population Pharmacokinetic ◽  
Target Attainment ◽  
Content Type ◽  
Daily Dose ◽  
Linear Elimination ◽  
Severe Infections

ABSTRACT Pharmacokinetic changes are often seen in patients with severe infections. Administration by continuous infusion has been suggested to optimize antibiotic exposure and pharmacokinetic/pharmacodynamic (PK/PD) target attainment for β-lactams. In an observational study, unbound piperacillin concentrations (n = 196) were assessed in 78 critically ill patients following continuous infusion of piperacillin-tazobactam (ratio 8:1). The initial dose of 8, 12, or 16 g (piperacillin component) was determined by individual creatinine clearance (CRCL). Piperacillin concentrations were compared to the EUCAST clinical breakpoint MIC for Pseudomonas aeruginosa (16 mg/liter), and the following PK/PD targets were evaluated: 100% free time (fT) > 1× MIC and 100% fT > 4× MIC. A population pharmacokinetic model was developed using NONMEM 7.4.3 consisting of a one-compartment disposition model with linear elimination separated into nonrenal and renal (linearly increasing with patient CRCL) clearances. Target attainment was predicted and visualized for all individuals based on the utilized CRCL dosing algorithm. The target of 100% fT > 1× MIC was achieved for all patients based on the administered dose, but few patients achieved the target of 100% fT > 4× MIC. Probability of target attainment for a simulated cohort of patients showed that increasing the daily dose by 4-g increments (piperacillin component) did not result in substantially improved target attainment for the 100% fT > 4× MIC target. To conclude, in patients with high CRCL combined with high-MIC bacterial infections, even a continuous infusion (CI) regimen with a daily dose of 24 g may be insufficient to achieve therapeutic concentrations.

ORGAN FAILURE AND C-REACTIVE PROTEIN BOTH AFFECT MIDAZOLAM CLEARANCE IN CRITICALLY ILL CHILDREN: A POPULATION PK MODEL

2015 ◽  
Vol 101 (1) ◽  
pp. e1.8-e1
Author(s):  
Nienke J Vet ◽  
Janneke M Brussee ◽  
Matthijs de Hoog ◽  
Miriam G Mooij ◽  
Carin WM Verlaat ◽  
...  
Keyword(s):  
Body Weight ◽  
Organ Failure ◽  
Critically Ill ◽  
Volume Of Distribution ◽  
Critically Ill Children ◽  
Population Pharmacokinetic ◽  
C Reactive Protein ◽  
Population Pharmacokinetic Modeling ◽  
Reactive Protein ◽  
Organ Failures

ObjectivesTo study the effect of organ failure and inflammation on midazolam clearance in critically ill children, using population pharmacokinetic modeling.MethodsA total of 83 critically ill children (median age 5 months (range 1 day-17 years), n=523 samples) receiving intravenous midazolam for continuous sedation during mechanical ventilation were included. Disease severity was described using the validated and clinically used scores PELOD, PIM2 and PRISM II. Cytokines (IL-1, IL-2, IL-6, TNF-a) and C-reactive protein (CRP) were used as markers for inflammation. A population pharmacokinetic model for midazolam was developed using NONMEM 7.3. Body weight, age, severity of organ failure and inflammatory markers were considered as potential covariates.ResultsIn a two-compartmental PK model, body weight was found as most significant covariate for clearance and volume of distribution. Moreover, both severity of organ failure (PELOD) and inflammation (IL6 and CRP) were significant determinants of clearance (p<0.01), and either of these factors improved the model significantly. With increasing number of organ failures, midazolam clearance significantly reduced. CRP was linearly correlated with clearance (slope −0.095), with higher CRP levels resulting in lower clearances. Either one of the covariates could explain part of the variability in clearance.ConclusionFor midazolam clearance, apart from body weight, we found organ failure reflected by the PELOD score, and inflammation reflected by IL6 and CRP, as significant covariates. Most likely this effect is due to reduced activity of CYP3A in critically ill mechanically ventilated children. Both CRP concentration and organ failure should be considered when dosing midazolam and potentially other CYP3A substrates in critically ill children.

Population pharmacokinetics of piperacillin and tazobactam in critically ill patients receiving extracorporeal membrane oxygenation (an ASAP ECMO study)

2021 ◽  
Author(s):  
Vesa Cheng ◽  
Mohd H. Abdul-Aziz ◽  
Fay Burrows ◽  
Hergen Buscher ◽  
Young-Jae Cho ◽  
...  
Keyword(s):  
Extracorporeal Membrane Oxygenation ◽  
Population Pharmacokinetics ◽  
Critically Ill ◽  
Plasma Concentrations ◽  
Membrane Oxygenation ◽  
Optimal Dosing ◽  
Patient Groups ◽  
Dosing Strategy ◽  
Toxic Concentrations ◽  
Staged Testing

Our study aimed to describe the population pharmacokinetics (PK) of piperacillin and tazobactam in patients on extracorporeal membrane oxygenation (ECMO), with and without renal replacement therapy (RRT). We also aimed to use dosing simulations to identify the optimal dosing strategy for these patient groups. Serial piperacillin and tazobactam plasma concentrations were measured with data analysed using a population PK approach that included staged testing of patient and treatment covariates. Dosing simulations were conducted to identify the optimal dosing strategy that achieved piperacillin target exposures of 50% and 100% fraction of time free drug concentration is above MIC (% f T >MIC ) and toxic exposures of greater than 360 mg/L. Tazobactam target of percentage time free concentrations >2 mg/L was also assessed. Twenty-seven patients were enrolled, of which 14 patients were receiving concurrent RRT. Piperacillin and tazobactam were both adequately described by two-compartment models with body mass index, creatinine clearance and RRT as significant predictors of PK. There were no substantial differences between observed PK parameters and published parameters from non-ECMO patients. Based on dosing simulations, a 4.5 g 6-hourly regimen administered over 4-hours achieves high probabilities of efficacy at a piperacillin MIC of 16 mg/L while exposing patients to a <3% probability of toxic concentrations. In patients receiving ECMO and RRT a frequency reduction to 12-hourly dosing reduces the probability of toxic concentrations, although this remains at 7 – 9%. In ECMO patients, piperacillin and tazobactam should be dosed in line with standard recommendations for the critically ill.

scholarly journals Population Pharmacokinetics of Doripenem in Critically Ill Patients with Sepsis in a Malaysian Intensive Care Unit

2015 ◽  
Vol 60 (1) ◽  
pp. 206-214 ◽  
Author(s):  
Mohd H. Abdul-Aziz ◽  
Azrin N. Abd Rahman ◽  
Mohd-Basri Mat-Nor ◽  
Helmi Sulaiman ◽  
Steven C. Wallis ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Monte Carlo ◽  
Intensive Care ◽  
Population Pharmacokinetics ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Population Pharmacokinetic Analysis ◽  
Volume Of Distribution ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic

ABSTRACTDoripenem has been recently introduced in Malaysia and is used for severe infections in the intensive care unit. However, limited data currently exist to guide optimal dosing in this scenario. We aimed to describe the population pharmacokinetics of doripenem in Malaysian critically ill patients with sepsis and use Monte Carlo dosing simulations to develop clinically relevant dosing guidelines for these patients. In this pharmacokinetic study, 12 critically ill adult patients with sepsis receiving 500 mg of doripenem every 8 h as a 1-hour infusion were enrolled. Serial blood samples were collected on 2 different days, and population pharmacokinetic analysis was performed using a nonlinear mixed-effects modeling approach. A two-compartment linear model with between-subject and between-occasion variability on clearance was adequate in describing the data. The typical volume of distribution and clearance of doripenem in this cohort were 0.47 liters/kg and 0.14 liters/kg/h, respectively. Doripenem clearance was significantly influenced by patients' creatinine clearance (CLCR), such that a 30-ml/min increase in the estimated CLCRwould increase doripenem CL by 52%. Monte Carlo dosing simulations suggested that, for pathogens with a MIC of 8 mg/liter, a dose of 1,000 mg every 8 h as a 4-h infusion is optimal for patients with a CLCRof 30 to 100 ml/min, while a dose of 2,000 mg every 8 h as a 4-h infusion is best for patients manifesting a CLCRof >100 ml/min. Findings from this study suggest that, for doripenem usage in Malaysian critically ill patients, an alternative dosing approach may be meritorious, particularly when multidrug resistance pathogens are involved.

scholarly journals Model-oriented Dose Optimization of Voriconazole in Critically Ill Children

2021 ◽  
Author(s):  
Jun Wang ◽  
Hua Xu ◽  
Ran Li ◽  
Sanlan Wu ◽  
Jili Zou ◽  
...  
Keyword(s):  
Body Weight ◽  
Critically Ill ◽  
Maintenance Dose ◽  
Maximum Velocity ◽  
Critically Ill Children ◽  
Population Pharmacokinetic ◽  
Dosing Regimen ◽  
Final Model ◽  
Optimal Dosing ◽  
Dosing Regimens

Objective: This study aimed to employ a population pharmacokinetic (PK) model to optimize the dosing regimen of voriconazole (VRC) in children with a critical illness. Methods: A total of 99 children aged from 0.44 to 13.58 years old were included in this study. The stability and predictive performance of the final model were evaluated by statistical and graphical methods. The optimal dosing regimen was proposed for children with different body weight, CYP2C19 phenotype, and co-administration with omeprazole. Results: The PK of VRC was described by a two-compartment model with nonlinear Michaelis-Menten elimination. Body weight, CYP2C19 phenotype, and omeprazole were significant covariates on maximum velocity of elimination (V max ), which had an estimated typical value of 18.13 mg·h −1 . Bayesian estimation suggested that dose-normalized concentration and total exposure (C max /D, C min /D, AUC 24 /D) were significantly different between extensive metabolizers (EM) patients and poor metabolizer (PM) patients. To achieve the target concentration early, two loading doses of 9 mg·kg −1 q12h were reliable for most children, whereas three loading doses of 6-7.5 mg·kg −1 q8h were warranted for young children weighted ≤18kg (except PM patients). The maintenance doses decreased about 30-40% in PM patients than that in EM patients. For children aged < 2 years in EM, the maintenance dose could be as high as 9 mg·kg −1 . The maintenance dose of VRC was supposed to decrease slightly when co-administration with omeprazole. Conclusion: A population PK model of intravenous VRC for critically ill children has been successful developed. It is necessary to adjust dosing regimens according to CYP2C19 genotype. The optimal dosing regimens have been recommended basing on the final model.

scholarly journals An international survey on aminoglycoside practices in critically ill patients: the AMINO III study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Claire Roger ◽  
◽  
Benjamin Louart ◽  
Loubna Elotmani ◽  
Greg Barton ◽  
...  
Keyword(s):  
Septic Shock ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Multivariable Analysis ◽  
Therapeutic Drug ◽  
Target Attainment ◽  
Icu Patients ◽  
Optimal Dosing ◽  
Wide Variability ◽  
Dosing Strategy

Abstract Background While aminoglycosides (AG) have been used for decades, debate remains on their optimal dosing strategy. We investigated the international practices of AG usage specifically regarding dosing and therapeutic drug monitoring (TDM) in critically ill patients. We conducted a prospective, multicentre, observational, cohort study in 59 intensive-care units (ICUs) in 5 countries enrolling all ICU patients receiving AG therapy for septic shock. Results We enrolled 931 septic ICU patients [mean ± standard deviation, age 63 ± 15 years, female 364 (39%), median (IQR) SAPS II 51 (38–65)] receiving AG as part of empirical (761, 84%) or directed (147, 16%) therapy. The AG used was amikacin in 614 (66%), gentamicin in 303 (33%), and tobramycin in 14 (1%) patients. The median (IQR) duration of therapy was 2 (1–3) days, the number of doses was 2 (1–2), the median dose was 25 ± 6, 6 ± 2, and 6 ± 2 mg/kg for amikacin, gentamicin, and tobramycin respectively, and the median dosing interval was 26 (23.5–43.5) h. TDM of Cmax and Cmin was performed in 437 (47%) and 501 (57%) patients, respectively, after the first dose with 295 (68%) patients achieving a Cmax/MIC > 8 and 353 (71%) having concentrations above Cmin recommended thresholds. The ICU mortality rate was 27% with multivariable analysis showing no correlation between AG dosing or pharmacokinetic/pharmacodynamic target attainment and clinical outcomes. Conclusion Short courses of high AG doses are mainly used in ICU patients with septic shock, although wide variability in AG usage is reported. We could show no correlation between PK/PD target attainment and clinical outcome. Efforts to optimize the first AG dose remain necessary. Trial registration Clinical Trials, NCT02850029, registered on 29th July 2016, retrospectively registered, https://www.clinicaltrials.gov

scholarly journals Pharmacokinetics of piperacillin in critically ill Australian Indigenous patients with severe sepsis

2016 ◽  
pp. AAC.01657-16 ◽  
Author(s):  
Danny Tsai ◽  
Penelope Stewart ◽  
Rajendra Goud ◽  
Stephen Gourley ◽  
Saliya Hewagama ◽  
...  
Keyword(s):  
Severe Sepsis ◽  
Critically Ill ◽  
Total Body Weight ◽  
Compartment Model ◽  
Central Compartment ◽  
Volume Of Distribution ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Population Pharmacokinetic Study

Objectives: There are no available pharmacokinetic data to guide piperacillin dosing in critically ill Australian Indigenous patients despite numerous reported physiological differences. This study aimed to describe the population pharmacokinetics of piperacillin in critically ill Australian Indigenous patients with severe sepsis.Methods: A population pharmacokinetic study of Indigenous patients with severe sepsis was conducted in a remote hospital intensive care unit. Plasma samples were collected over two dosing intervals and assayed by validated chromatography. Population pharmacokinetic modelling was conducted using Pmetrics®.Results: Nine patients were recruited and a two compartment model adequately described the data. Piperacillin clearance (CL), volume of distribution of the central compartment (Vc), distribution rate constant from central to peripheral compartment and from peripheral to central compartment were 5.6 ± 3.2 L/h, 14.5 ± 6.6 L, 1.5 ± 0.4 h-1and 1.8 ± 0.9 h-1respectively, where CL and Vcwere found to be described by creatinine clearance (CrCL) and total body weight respectively.Conclusion: In this patient population, piperacillin demonstrated high interindividual pharmacokinetic variability. CrCL were found to be the most important determinant of piperacillin pharmacokinetics.

scholarly journals Optimal empiric treatment for KPC-2-producing Klebsiella pneumoniae infections in critically ill patients with normal or decreased renal function using Monte Carlo simulation

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Guoan Wang ◽  
Wei Yu ◽  
Yushan Cui ◽  
Qingyi Shi ◽  
Chen Huang ◽  
...  
Keyword(s):  
Monte Carlo Simulation ◽  
Monte Carlo ◽  
Renal Function ◽  
Klebsiella Pneumoniae ◽  
Critically Ill ◽  
Normal Renal Function ◽  
Critically Ill Patients ◽  
Population Pharmacokinetic ◽  
Loading Dose ◽  
Daily Dose

Abstract Background Limited clinical studies describe the pharmacodynamics of fosfomycin (FOS), tigecycline (TGC) and colistin methanesulfonate (CMS) in combination against KPC-producing Klebsiella pneumoniae (KPC-Kp). Population pharmacokinetic models were used in our study. Monte Carlo simulation was conducted to calculate probability of target attainment (PTA) and cumulative fraction of response (CFR) of each agent alone and in combination against KPC-Kp in patients with normal or decreased renal function. Results The simulated regimen of FOS 6 g q8h reached ≥90% PTA against a MIC of 64 mg/L in patients with normal renal function. For patients with renal impairment, FOS 4 g q8h could provide sufficient antimicrobial coverage against a MIC of 128 mg/L. And increasing the daily dose could result to the cut-off value to 256 mg/L in decreased renal function. For TGC, conventional dosing regimens failed to reach 90% PTA against a MIC of 2 mg/L. Higher loading and daily doses (TGC 200/400 mg loading doses followed by 100 mg q12h/200 mg q24h) were needed. For CMS, none achieved 90% PTA against a MIC of 2 mg/L in normal renal function. Against KPC-Kp, the regimens of 200/400 mg loading dose followed by 100 q12h /200 mg q24h achieved > 80% CFRs regardless of renal function, followed by CMS 9 million IU loading dose followed by 4.5/3 million IU q12h in combination with FOS 8 g q8h (CFR 75–91%). Conclusions The use of a loading dose and high daily dose of TGC and CMS in combination with FOS can provide sufficient antimicrobial coverage against critically ill patients infected with KPC-Kp.

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