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

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).

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Low but Sufficient Anidulafungin Exposure in Critically Ill Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01607-13 ◽

2013 ◽

Vol 58 (1) ◽

pp. 304-308 ◽

Cited By ~ 18

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.)

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02355-14 ◽

2014 ◽

Vol 58 (6) ◽

pp. 3162-3167 ◽

Cited By ~ 20

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.

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Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Support Dose Selection for ME1100, an Arbekacin Inhalation Solution

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02367-19 ◽

2020 ◽

Vol 64 (10) ◽

Author(s):

Sujata M. Bhavnani ◽

Jeffrey P. Hammel ◽

Elizabeth A. Lakota ◽

M. Courtney Safir ◽

Brian D. VanScoy ◽

...

Keyword(s):

Compartment Model ◽

Simulated Patients ◽

Population Pharmacokinetic ◽

Total Drug ◽

Target Attainment ◽

Time Curve ◽

Content Type ◽

Concentration Time

ABSTRACT ME1100 (arbekacin inhalation solution) is an inhaled aminoglycoside that is being developed to treat patients with hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively). Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were undertaken to evaluate ME1100 regimens for the treatment of patients with HABP/VABP. The data used included a population pharmacokinetic (PPK) 4-compartment model with 1st-order elimination, nonclinical PK-PD targets from one-compartment in vitro and/or in vivo infection models, and in vitro surveillance data. Using the PPK model, total-drug epithelial lining fluid (ELF) concentration-time profiles were generated for simulated patients with varying creatinine clearance (CLcr) (ml/min/1.73 m2) values. Percent probabilities of PK-PD target attainment by MIC were determined based on the ratio of total-drug ELF area under the concentration-time curve (AUC) to MIC (AUC/MIC ratio) targets associated with 1- and 2-log10 CFU reductions from baseline for Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus. Percent probabilities of PKPD target attainment based on PK-PD targets for a 1-log10 CFU reduction from baseline at MIC values above the MIC90 value for K. pneumoniae (8 μg/ml), P. aeruginosa (4 μg/ml), and S. aureus (0.5 μg/ml) were ≥99.8% for ME1100 600 mg twice daily (BID) in simulated patients with CLcr values >80 to ≤120 ml/min/1.73 m2. ME1100 600 mg BID, 450 mg BID, and 600 mg once daily in simulated patients with CLcr values >50 to ≤80, >30 to ≤50, and 0 to ≤30 ml/min/1.73 m2, respectively, provided arbekacin exposures that best matched those for 600 mg BID in simulated patients with normal renal function. These data provide support for ME1100 as a treatment for patients with HABP/VABP.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00993-19 ◽

2019 ◽

Vol 63 (11) ◽

Cited By ~ 3

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.

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Optimization of fluconazole dosing for the prevention and treatment of invasive candidiasis based on the pharmacokinetics of fluconazole in critically-ill patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01554-20 ◽

2020 ◽

Author(s):

J. M. Boonstra ◽

A. G. Märtson ◽

I Sandaradura ◽

J. G. Kosterink ◽

T. S. van der Werf ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Plasma Concentrations ◽

Organ Transplant ◽

Compartment Model ◽

Pharmacokinetic Analysis ◽

Solid Organ ◽

Time Curve ◽

Final Population ◽

The Mean

Background: The efficacy of fluconazole is related to the area under the plasma concentration-time curve over the minimum inhibitory concentration of the microorganism. Physiological changes in critically ill patients may affect the exposure of fluconazole and therefore dosing adjustments might be needed. Objective: The aim of this study was to evaluate variability in fluconazole drug concentration in ICU patients and to develop a pharmacokinetic model to support personalized fluconazole dosing. Methods: A prospective observational pharmacokinetic study was performed in critically ill patients receiving fluconazole either as prophylaxis or as treatment. The association between fluconazole exposure and patient variables was studied. Pharmacokinetic modeling was performed with nonparametric adaptive grid (NPAG) algorithm using R package Pmetrics. Results: Data from 33 patients were available for pharmacokinetic analysis. Patients on dialysis and solid organ transplant patients had a significantly lower exposure to fluconazole. The population was best described with a one-compartment model, where the mean volume of distribution was 51.52 L (SD 19.81) and the mean clearance was 0.767 L/h (SD 0.46). Creatinine clearance was tested as a potential covariate in the model, but was not included in the final population model. A significant positive correlation was found between the fluconazole exposure (AUC) and the Cmin. Conclusion: Substantial variability in fluconazole plasma concentrations in critically-ill adults was observed, where the majority of patients were underexposed. Fluconazole Cmin TDM guided dosing can be used to optimize therapy in critically ill patients.

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Pharmacokinetic Variability and Target Attainment of Fluconazole in Critically Ill Patients

Microorganisms ◽

10.3390/microorganisms9102068 ◽

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.

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Penetration of Meropenem into Epithelial Lining Fluid of Patients with Ventilator-Associated Pneumonia

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01330-10 ◽

2011 ◽

Vol 55 (4) ◽

pp. 1606-1610 ◽

Cited By ~ 67

Author(s):

T. P. Lodise ◽

F. Sorgel ◽

D. Melnick ◽

B. Mason ◽

M. Kinzig ◽

...

Keyword(s):

Monte Carlo Simulation ◽

Monte Carlo ◽

Compartment Model ◽

Ventilator Associated Pneumonia ◽

Epithelial Lining ◽

Time Data ◽

Time Curve ◽

Epithelial Lining Fluid ◽

Time Profiles ◽

Concentration Time

ABSTRACTAntibiotic penetration to the infection site is critical for obtaining a good clinical outcome in patients with ventilator-associated pneumonia (VAP). Surprisingly few studies have quantified the penetration of β-lactam agents into the lung, as measured by the ratio of area under the concentration-time curve (AUC) in epithelial lining fluid (ELF) to AUC in plasma (AUCELF/AUCplasmaratio). These have typically involved noninfected patients. This study examines the penetration and pharmacodynamics of meropenem in the ELF among patients with VAP. Meropenem plasma and ELF concentration-time data were obtained from patients in a multicenter clinical trial. Concentration-time profiles in plasma and ELF were simultaneously modeled using a three-compartment model with zero-order infusion and first-order elimination and transfer (big nonparametric adaptive grid [BigNPAG]). A Monte Carlo simulation was performed to estimate the range of ELF/plasma penetration ratios one would expect to observe in patients with VAP, as measured by the AUCELF/AUCplasmaratio. The range of AUCELF/AUCplasmapenetration ratios predicted by the Monte Carlo simulation was large. The 10th percentile of lung penetration was 3.7%, while the 90th percentile of penetration was 178%. The variability of ELF penetration is such that if relatively high ELF exposure targets are required to attain multilog kill or resistance suppression for bacteria likePseudomonas aeruginosa, then even receiving the largest licensed dose of meropenem with an optimal prolonged infusion may not result in target attainment for a substantial fraction of the population.

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Influence of Hypovolemia on the Pharmacokinetics and Electroencephalographic Effect of γ-Hydroxybutyrate in the Rat

Anesthesiology ◽

10.1097/00000542-200211000-00027 ◽

2002 ◽

Vol 97 (5) ◽

pp. 1218-1226 ◽

Cited By ~ 5

Author(s):

Diederik K. Van Sassenbroeck ◽

Peter De Paepe ◽

Frans M. Belpaire ◽

Paul A. Boon ◽

Walter A. Buylaert

Keyword(s):

Blood Pressure ◽

High Performance ◽

Compartment Model ◽

Volume Of Distribution ◽

Control Procedure ◽

Time Data ◽

Time Curve ◽

Concentration Time ◽

Gamma Hydroxybutyrate ◽

Significant Difference

Background Hypovolemia alters the effect of propofol in the rat by influencing the pharmacokinetics and the end organ sensitivity. We now studied the effect of hypovolemia on the anesthetic gamma-hydroxybutyrate (GHB) because in contrast with propofol it increases blood pressure. Methods Thirty-two rats were randomly assigned to undergo moderate hypovolemia or a control procedure. Each rat received either an infusion of sodium-GHB (390 mg x kg(-1) x 5 min(-1)) or the same volume of an equimolar solution of sodium chloride (6.9%). Plasma samples were taken for GHB assay (high-performance liquid chromatography) and the electroencephalography and blood pressure values were recorded. A two-compartment model with Michaelis-Menten elimination was fitted to the concentration-time data and a sigmoid E(max) model to the electroencephalographic effect effect site concentration curve allowing the study of the end organ sensitivity. Results Plasma concentration-time curves and the total volume of distribution in hypovolemic and normovolemic rats were comparable with only small but significant differences in central volume of distribution and the intercompartmental clearance. There was no significant difference either in the distribution from the plasma to the brain (k(e0)) or in the end organ sensitivity (EC50 = 335 +/- 76 microg/ml in control vs. 341 +/- 89 microg/ml in hypovolemic rats). GHB temporarily increased mean arterial pressure in both groups, which cannot be explained by the sodium salt alone. Conclusions Hypovolemia does not influence the overall concentration-time curve of GHB and induces no changes in the electroencephalographic effect of GHB in the rat. This difference with propofol may be due to the fact that it increases blood pressure but also due to its different pharmacokinetic properties.

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Combined Intravenous and Intraventricular Administration of Colistin Methanesulfonate in Critically Ill Patients with Central Nervous System Infection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01461-12 ◽

2013 ◽

Vol 57 (4) ◽

pp. 1938-1940 ◽

Cited By ~ 41

Author(s):

Mairi Ziaka ◽

Sophia L. Markantonis ◽

Marizoza Fousteri ◽

Paris Zygoulis ◽

Dimitris Panidis ◽

...

Keyword(s):

Central Nervous System ◽

Cerebrospinal Fluid ◽

Nervous System ◽

Critically Ill ◽

Intravenous Administration ◽

Critically Ill Patients ◽

External Ventricular Drain ◽

Central Nervous System Infection ◽

Intraventricular Administration ◽

Colistin Methanesulfonate

ABSTRACTColistin pharmacokinetics were prospectively studied after intravenous administration of colistin methanesulphonate in critically ill patients without central nervous system infection (controls,n= 5) and in patients with external ventricular drain-associated ventriculitis after intravenous administration (EVDViv,n= 3) or combined intravenous/intraventricular administration (EVDVcomb,n= 4). Cerebrospinal fluid (CSF)/serum colistin concentration ratios were higher in EVDViv than in control patients (11% versus 7%,P≤ 0.05) and in EVDVcomb compared to all other patients (P< 0.0001). CSF colistin concentrations above the MIC of 0.5 μg/ml were achieved only in EVDVcomb patients.

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Limited-Sampling Strategies for Anidulafungin in Critically Ill Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03375-14 ◽

2014 ◽

Vol 59 (2) ◽

pp. 1177-1181 ◽

Cited By ~ 5

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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