scholarly journals Pharmacokinetic Variability and Target Attainment of Fluconazole in Critically Ill Patients

2021 ◽  
Vol 9 (10) ◽  
pp. 2068
Author(s):  
Ruth Van Daele ◽  
Joost Wauters ◽  
Katrien Lagrou ◽  
Raphaël Denooz ◽  
Marie-Pierre Hayette ◽  
...  
Keyword(s):  
Critically Ill ◽  
Trough Concentration ◽  
Critically Ill Patients ◽  
Inhibitory Concentration ◽  
Antifungal Drugs ◽  
Target Attainment ◽  
Augmented Renal Clearance ◽  
Time Curve ◽  
Concentration Time ◽  
Trough Concentrations

Background: Fluconazole is one of the oldest antifungal drugs. Previous studies have raised concerns considering variability in exposure and inadequate target attainment in critically ill patients. The current study aims to define variability and target attainment for fluconazole exposure in a large group of critically ill patients. Methods: In this pharmacokinetic study, daily plasma trough samples and, if possible, 24 h urine samples were collected to determine fluconazole concentration. A minimum target trough concentration of 10–15 mg/L was selected, corresponding to a free area under the concentration–time curve above the minimum inhibitory concentration (fAUC/MIC) of at least 100 for an MIC of 4 mg/L. Covariates that significantly influenced fluconazole exposure were identified. Results: In total, 288 plasma samples from 43 patients, with a median age of 66 years, were included. The median fluconazole trough concentration was 22.9 mg/L. A notable component of the measured concentrations was below the target trough concentrations (13% <10 mg/L and 27% <15 mg/L). The intra- and intersubject variability were 28.3% and 50.5%, respectively. The main covariates determining fluconazole exposure were the administered dose (mg/kg), augmented renal clearance, and renal replacement therapy. Conclusions: Fluconazole trough concentrations are variable in critically ill patients and a considerable number of these concentrations was below the predefined target trough concentrations.

scholarly journals Evaluating the Relationship between Vancomycin Trough Concentration and 24-Hour Area under the Concentration-Time Curve in Neonates

2018 ◽  
Vol 62 (4) ◽  
pp. e01647-17 ◽  
Author(s):  
Sheng-Hsuan Tseng ◽  
Chuan Poh Lim ◽  
Qi Chen ◽  
Cheng Cai Tang ◽  
Sing Teang Kong ◽  
...  
Keyword(s):  
Steady State ◽  
Trough Concentration ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
Vancomycin Trough ◽  
Trough Concentrations ◽  
The Relationship

ABSTRACT Bacterial sepsis is a major cause of morbidity and mortality in neonates, especially those involving methicillin-resistant Staphylococcus aureus (MRSA). Guidelines by the Infectious Diseases Society of America recommend the vancomycin 24-h area under the concentration-time curve to MIC ratio (AUC24/MIC) of >400 as the best predictor of successful treatment against MRSA infections when the MIC is ≤1 mg/liter. The relationship between steady-state vancomycin trough concentrations and AUC24 values (mg·h/liter) has not been studied in an Asian neonatal population. We conducted a retrospective chart review in Singapore hospitals and collected patient characteristics and therapeutic drug monitoring data from neonates on vancomycin therapy over a 5-year period. A one-compartment population pharmacokinetic model was built from the collected data, internally validated, and then used to assess the relationship between steady-state trough concentrations and AUC24. A Monte Carlo simulation sensitivity analysis was also conducted. A total of 76 neonates with 429 vancomycin concentrations were included for analysis. Median (interquartile range) was 30 weeks (28 to 36 weeks) for postmenstrual age (PMA) and 1,043 g (811 to 1,919 g) for weight at the initiation of treatment. Vancomycin clearance was predicted by weight, PMA, and serum creatinine. For MRSA isolates with a vancomycin MIC of ≤1, our major finding was that the minimum steady-state trough concentration range predictive of achieving an AUC24/MIC of >400 was 8 to 8.9 mg/liter. Steady-state troughs within 15 to 20 mg/liter are unlikely to be necessary to achieve an AUC24/MIC of >400, whereas troughs within 10 to 14.9 mg/liter may be more appropriate.

scholarly journals Cerebrospinal Fluid Penetration of Ceftolozane-Tazobactam in Critically Ill Patients with an Indwelling External Ventricular Drain

2020 ◽  
Vol 65 (1) ◽  
pp. e01698-20 ◽  
Author(s):  
Fekade B. Sime ◽  
Melissa Lassig-Smith ◽  
Therese Starr ◽  
Janine Stuart ◽  
Saurabh Pandey ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
External Ventricular Drain ◽  
Compartment Model ◽  
Time Data ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
Unbound Concentration

ABSTRACTThe aim of this study was to describe the pharmacokinetics of ceftolozane-tazobactam in plasma and cerebrospinal fluid (CSF) of infected critically ill patients. In a prospective observational study, critically ill patients (≥18 years) with an indwelling external ventricular drain received a single intravenous dose of 3.0 g ceftolozane-tazobactam. Serial plasma and CSF samples were collected for measurement of unbound ceftolozane and tazobactam concentration by liquid chromatography. Unbound concentration-time data were modeled in R using Pmetrics. Dosing simulations were performed using the final model. A three-compartment model adequately described the data from 10 patients. For ceftolozane, the median (interquartile range [IQR]) area under the unbound concentration-time curve from time zero to infinity (fAUC0-inf) in the CSF and plasma were 30 (19 to 128) h·mg/liter and 323 (183 to 414) h·mg/liter, respectively. For tazobactam, these values were 5.6 (2 to 24) h·mg/liter and 52 (36 to 80) h·mg/liter, respectively. Mean ± standard deviation (SD) CSF penetration ratios were 0.2 ± 0.2 and 0.2 ± 0.26 for ceftolozane and tazobactam, respectively. With the regimen of 3.0 g every 8 h, a probability of target attainment (PTA) of ≥0.9 for 40% fT>MIC in the CSF was possible only when MICs were ≤0.25 mg/liter. The CSF cumulative fractional response for Pseudomonas aeruginosa-susceptible MIC distribution was 73%. The tazobactam PTA for the minimal suggested exposure of 20% fT>1 mg/liter was 12%. The current maximal dose of ceftolozane-tazobactam (3.0 g every 8 h) does not provide adequate CSF exposure for treatment of Gram-negative meningitis or ventriculitis unless the MIC for the causative pathogen is very low (≤0.25 mg/liter).

scholarly journals Predictors of Inadequate Linezolid Concentrations after Standard Dosing in Critically Ill Patients

2016 ◽  
Vol 60 (9) ◽  
pp. 5254-5261 ◽  
Author(s):  
Max Taubert ◽  
Michael Zoller ◽  
Barbara Maier ◽  
Sebastian Frechen ◽  
Christina Scharf ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Strong Predictor ◽  
Simulated Patients ◽  
Population Pharmacokinetic ◽  
Target Attainment ◽  
Serum Samples ◽  
Time Curve ◽  
Blood Concentrations ◽  
Registration Number

ABSTRACTAdequate linezolid blood concentrations have been shown to be associated with an improved clinical outcome. Our goal was to assess new predictors of inadequate linezolid concentrations often observed in critically ill patients. Fifty-two critically ill patients with severe infections receiving standard dosing of linezolid participated in this prospective observational study. Serum samples (median, 32 per patient) were taken on four consecutive days, and total linezolid concentrations were quantified. Covariates influencing linezolid pharmacokinetics were identified by multivariate analysis and a population pharmacokinetic model. Target attainment (area under the concentration-time curve over 12 h [AUC12]/MIC ratio of >50; MIC = 2 mg/liter) was calculated for both the study patients and a simulated independent patient group (n= 67,000). Target attainment was observed for only 36% of the population on both days 1 and 4. Independent covariates related to significant decreases of linezolid concentrations included higher weight, creatinine clearance rates, and fibrinogen and antithrombin concentrations, lower concentrations of lactate, and the presence of acute respiratory distress syndrome (ARDS). Linezolid clearance was increased in ARDS patients (by 82%) and in patients with elevated fibrinogen or decreased lactate concentrations. In simulated patients, most covariates, including fibrinogen and lactate concentrations and weight, showed quantitatively minor effects on target attainment (difference of ≤9% between the first and fourth quartiles of the respective parameters). In contrast, the presence of ARDS had the strongest influence, with only ≤6% of simulated patients reaching this target. In conclusion, the presence of ARDS was identified as a new and strong predictor of insufficient linezolid concentrations, which might cause treatment failure. Insufficient concentrations might also be a major problem in patients with combined alterations of other covariate parameters. (This study has been registered at ClinicalTrials.gov under registration number NCT01793012.)

scholarly journals Successful Treatment of Invasive MRSA Infections in Children Using Area Under the Vancomycin Concentration-Time Curve Divided by the Minimum Inhibitory Concentration (AUC/MIC) to Measure Vancomycin Exposure

2021 ◽  
Vol 1 (S1) ◽  
pp. s31-s31
Author(s):  
Leslie Chiang ◽  
Alice Pong ◽  
John Bradley ◽  
Paige Anderson ◽  
William Murray
Keyword(s):  
Minimum Inhibitory Concentration ◽  
Clinical Outcomes ◽  
Inhibitory Concentration ◽  
Renal Toxicity ◽  
Time Curve ◽  
Vancomycin Concentration ◽  
Concentration Time ◽  
Serum Trough ◽  
Trough Concentrations ◽  
Dosing Method

Background: Vancomycin is the treatment of choice for invasive methicillin-resistant Staphylococcus aureus (MRSA) infections. Previous guidelines issued by the Infectious Diseases Society of America (IDSA) recommended targeting vancomycin serum trough concentrations of 15–20 mg/L; however, troughs <15 mg/L are also associated with increased odds of renal toxicity. To minimize toxicity, recently updated ASHP/IDSA/PIDS vancomycin dosing guidelines recommend the use of an area under the vancomycin concentration-time curve divided by the minimum inhibitory concentration (AUC/MIC) pharmacodynamic index to measure vancomycin exposure, with an AUC/MIC ratio >400 correlating with clinical efficacy. However, data on vancomycin therapeutic drug monitoring (TDM) in children are limited. Our institutional practice since January 2009 has been to use AUC/MIC, rather than serum trough concentrations, to guide vancomycin dosing. In this study, we describe clinical outcomes in vancomycin-treated children with invasive MRSA infections using this dosing method. Methods: We performed a retrospective chart review of children hospitalized with invasive MRSA infections between 2006 and 2019 at Rady Children’s Hospital in San Diego, California. Clinical, microbiologic, and pharmacologic data including the site of MRSA infection, clinical failure or cure, occurrence of acute kidney injury (AKI), vancomycin MIC, vancomycin AUC, and serum trough concentrations were collected. Results: In total, 61 invasive MRSA cases were reviewed: 20 were admitted January 2016 through December 2008, and 41 were admitted January 2009 through June 2019 (Figure 1). Most patients did not have medical comorbidities. The most common types of infections were primary bacteremia (34%) and osteomyelitis (32%). Of 61 children, 50 (82%) had positive clinical outcomes regardless of vancomycin dosing method. Of 20 patients, 8 (40%) admitted prior to January 2009 developed AKI, compared with 5 (12%) of 41 patients admitted after January 2009. Conclusions: In our retrospective review, most patients had clinically successful outcomes regardless of which dosing strategy was used. We found higher rates of renal toxicity in patients who were admitted prior to 2009, with TDM based on measuring peak and trough concentrations, compared with those using AUC/MIC for TDM. Our findings suggest that AUC/MIC TDM for invasive MRSA infections may be associated with lower rates of renal toxicity.Funding: NoDisclosures: None

scholarly journals Low but Sufficient Anidulafungin Exposure in Critically Ill Patients

2013 ◽  
Vol 58 (1) ◽  
pp. 304-308 ◽  
Author(s):  
Marjolijn J. P. van Wanrooy ◽  
Michael G. G. Rodgers ◽  
Donald R. A. Uges ◽  
Jan P. Arends ◽  
Jan G. Zijlstra ◽  
...  
Keyword(s):  
Disease Severity ◽  
Critically Ill ◽  
Plasma Protein ◽  
Critically Ill Patients ◽  
Time Curve ◽  
Minimum Concentration ◽  
Content Type ◽  
Protein Levels ◽  
Concentration Time ◽  
Liquid Chromatography Tandem Mass

ABSTRACTThe efficacy of anidulafungin is driven by the area under the concentration-time curve (AUC)/MIC ratio. Patients in intensive care may be at risk for underexposure. In critically ill patients with an invasiveCandidainfection, the anidulafungin exposure and a possible correlation with disease severity or plasma protein levels were explored. Concentration-time curves were therefore obtained at steady state. Anidulafungin concentrations were measured with a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The MIC values of theCandidaspecies were determined with the Etest. The target AUC/MIC ratio was based on European Committee on Antimicrobial Susceptibility Testing (EUCAST) data. Twenty patients were included. The patients received a maintenance dose of 100 mg once daily after a loading dose of 200 mg on the first day. The mean (±standard deviation) AUC, maximum concentration of drug in plasma (Cmax), and minimum concentration of drug in plasma (Cmin) were 69.8 ± 24.1 mg · h/liter, 4.7 ± 1.4 mg/liter, and 2.2 ± 0.8 mg/liter, respectively. The MIC values of all culturedCandidaspecies were below the EUCAST MIC breakpoints. The exposure to anidulafungin in relation to the MIC that was determined appeared sufficient in all patients. The anidulafungin exposure was low in our critically ill patients. However, combined with the low MICs of the isolatedCandidastrains, the lower exposure observed in comparison to the exposure in the general patient population resulted in favorable AUC/MIC ratios, based on EUCAST data. No correlation was observed between anidulafungin exposure and disease severity or plasma protein concentrations. In patients with less-susceptibleCandida albicansorglabratastrains, we recommend considering determining the anidulafungin exposure to ensure adequate exposure. (This trial has been registered at ClinicalTrials.gov under registration no. NCT01047267.)

scholarly journals Simplified Equations Using Two Concentrations To Calculate Area under the Curve for Antimicrobials with Concentration-Dependent Pharmacodynamics: Daptomycin as a Motivating Example

2014 ◽  
Vol 58 (6) ◽  
pp. 3162-3167 ◽  
Author(s):  
Manjunath P. Pai ◽  
Alessandro Russo ◽  
Andrea Novelli ◽  
Mario Venditti ◽  
Marco Falcone
Keyword(s):  
Healthy Volunteers ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Antimicrobial Agents ◽  
Population Pharmacokinetic ◽  
Good Precision ◽  
Time Data ◽  
Time Curve ◽  
Dosing Interval ◽  
Concentration Time

ABSTRACTThe effects of several antimicrobial agents are predicted by the ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC). Peak (Cp) and trough (Ct) concentrations are often measured clinically as surrogates of AUC because actual computation of AUC from 1 or 2 samples requires sophisticated mathematical methods. Given that the effects of daptomycin are predicted by AUC/MIC, our objective was to compare simple equation calculated AUC based onCpandCtto model integrated AUC. A standard population pharmacokinetic model was used to simulate 5,000 daptomycin concentration-time profiles after 5 doses of 6 mg/kg of body weight/day (0.5-h infusions). The AUC for the 24-h period was computed by integration and by equations with 110Cp-Ctcombination pairs. TheCptime points were in 15-min increments between 0.5 h and 3 h andCtin 15-min increments within an hour of the end of the dosing interval for each dose. The precision and bias of the calculated AUC relative to the integrated AUC were determined to identifyCp-Ctpairs associated with the lowest bias and highest precision. The equations were further validated using two daptomycin concentration-time data sets from healthy volunteers and critically ill patients. The precision and bias of calculated AUC were based primarily onCp, and use of a daptomycinCp1.5 h to 3 h from the start of infusion was associated with a bias of <10% and anR2of >0.95. Data from the healthy volunteers and critically ill patients also demonstrated declining bias with use ofCp≥1.5 h from the start of infusion with relatively good precision. Simplified equations using a daptomycinCpapproximately 2 h from the start of infusion and aCtwithin an hour of the end of the dosing interval should yield precise and unbiased estimates of daptomycin AUC.

scholarly journals Pharmacodynamic Target Attainment for Meropenem and Piperacillin/Tazobactam Using a PK/PD-based Dosing Calculator in Critically Ill Patients

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S27-S27 ◽  
Author(s):  
Emily Heil ◽  
David P Nicolau ◽  
Gwen Robinson ◽  
Andras Farkas ◽  
Kerri Thom
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Plasma Concentrations ◽  
Future Research ◽  
Target Attainment ◽  
Research Support ◽  
Dosing Strategies ◽  
Trough Concentrations ◽  
Culture Positive ◽  
Antibiotic Dosing

Abstract Background Unbound plasma concentrations of β-lactam antibiotics vary widely and attainment of PK/PD targets is highly variable in critically ill patients, which may affect microbiologic cure or contribute to toxicity. PK/PD-based antibiotic dosing programs may provide more accurate doses that achieve predicted targets for a cultured organism. Methods This was a single center, prospective study of critically ill patients with culture positive gram-negative infections treated with meropenem (MEM) or piperacillin/tazobactam (TZP). A PK/PD-based antibiotic dosing app was used to select doses that had a probability of target attainment (PTA) of 90% or greater for time above MIC (fT&gt;MIC) of at least 40% for MEM and 50% for TZP. Total meropenem, piperacillin and tazobactam mid-point and trough concentrations were obtained at steady-state and adjusted for protein binding, to assess target attainment. Results Thirty-six patients were enrolled; 20 received MEM and 16 TZP. Antibiotic concentrations varied widely amongst patients, particularly with TZP. MEM and TZP concentrations are displayed in Table 1 and Figure 1. Doses evaluated for &gt;90% probability of target attainment in the dosing calculator differed from standard package labeled doses for 25% (5/20) of MEM and 18.8% (3/16) of TZP patients. All (20/20) MEM and 94% (15/16) TZP patients maintained fT&gt;MIC for the entire dosing interval. Conclusion A PK/PD based antibiotic dosing calculator that provides individualized β-lactam doses can lead to altered doses that may increase probability of target attainment in critically ill patients. Future research is needed to review the relevance of PK/PD-based dose adjustments on clinical outcomes. Disclosures D. P. Nicolau, Shionogi & Co.: Research Contractor, Research support; A. Farkas, Optimum Dosing Strategies: Employee, Salary.

scholarly journals A Quasi-Experiment To Study the Impact of Vancomycin Area under the Concentration-Time Curve-Guided Dosing on Vancomycin-Associated Nephrotoxicity

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Natalie A. Finch ◽  
Evan J. Zasowski ◽  
Kyle P. Murray ◽  
Ryan P. Mynatt ◽  
Jing J. Zhao ◽  
...  
Keyword(s):  
Trough Concentration ◽  
Proportional Hazards ◽  
Cox Proportional Hazards ◽  
Time Curve ◽  
Cox Proportional Hazards Regression ◽  
Proportional Hazards Regression ◽  
Concentration Time ◽  
Trough Concentrations ◽  
The Impact ◽  
Quasi Experiment

ABSTRACT Evidence suggests that maintenance of vancomycin trough concentrations at between 15 and 20 mg/liter, as currently recommended, is frequently unnecessary to achieve the daily area under the concentration-time curve (AUC24) target of ≥400 mg · h/liter. Many patients with trough concentrations in this range have AUC24 values in excess of the therapeutic threshold and within the exposure range associated with nephrotoxicity. On the basis of this, the Detroit Medical Center switched from trough concentration-guided dosing to AUC-guided dosing to minimize potentially unnecessary vancomycin exposure. The primary objective of this analysis was to assess the impact of this intervention on vancomycin-associated nephrotoxicity in a single-center, retrospective quasi-experiment of hospitalized adult patients receiving intravenous vancomycin from 2014 to 2015. The primary analysis compared the incidence of nephrotoxicity between patients monitored by assessment of the AUC24 and those monitored by assessment of the trough concentration. Multivariable logistic and Cox proportional hazards regression examined the independent association between the monitoring strategy and nephrotoxicity. Secondary analysis compared vancomycin exposures (total daily dose, AUC, and trough concentrations) between monitoring strategies. Overall, 1,280 patients were included in the analysis. After adjusting for severity of illness, comorbidity, duration of vancomycin therapy, and concomitant receipt of nephrotoxins, AUC-guided dosing was independently associated with lower nephrotoxicity by both logistic regression (odds ratio, 0.52; 95% confidence interval [CI], 0.34 to 0.80; P = 0.003) and Cox proportional hazards regression (hazard ratio, 0.53; 95% CI, 0.35 to 0.78; P = 0.002). AUC-guided dosing was associated with lower total daily vancomycin doses, AUC values, and trough concentrations. Vancomycin AUC-guided dosing was associated with reduced nephrotoxicity, which appeared to be a result of reduced vancomycin exposure.

scholarly journals Limited-Sampling Strategies for Anidulafungin in Critically Ill Patients

2014 ◽  
Vol 59 (2) ◽  
pp. 1177-1181 ◽  
Author(s):  
Marjolijn J. P. van Wanrooy ◽  
Johannes H. Proost ◽  
Michael G. G. Rodgers ◽  
Jan G. Zijlstra ◽  
Donald R. A. Uges ◽  
...  
Keyword(s):  
Linear Regression ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Sampling Strategies ◽  
Time Curve ◽  
Limited Sampling ◽  
Concentration Time

ABSTRACTEfficacy of anidulafungin is driven by the area under the concentration-time curve (AUC)/MIC ratio. Determination of the anidulafungin AUC along with MIC values can therefore be useful. Since obtaining a full concentration-time curve to determine an AUC is not always feasible or appropriate, limited-sampling strategies may be useful in adequately estimating exposure. The objective of this study was to develop a model to predict the individual anidulafungin exposure in critically ill patients using limited-sampling strategies. Pharmacokinetic data were derived from 20 critically ill patients with invasive candidiasis treated with anidulafungin. These data were used to develop a two-compartment model in MW\Pharm using an iterative 2-stage Bayesian procedure. Limited-sampling strategies were subsequently investigated using two methods, a Bayesian analysis and a linear regression analysis. The best possible strategies for these two methods were evaluated by a Bland-Altman analysis for correlation of the predicted and observed AUC from 0 to 24 h (AUC0–24) values. Anidulafungin exposure can be adequately estimated with the concentration from a single sample drawn 12 h after the start of the infusion either by linear regression (R2= 0.99; bias, 0.05%; root mean square error [RMSE], 3%) or using a population pharmacokinetic model (R2= 0.89; bias, −0.1%; RMSE, 9%) in critically ill patients and also in less severely ill patients, as reflected by healthy volunteers. Limited sampling can be advantageous for future studies evaluating the pharmacokinetics and pharmacodynamics of anidulafungin and for therapeutic drug monitoring in selected patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01047267.)

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