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      Failure of target attainment of beta-lactam antibiotics in critically ill patients and associated risk factors: a two-center prospective study (EXPAT)

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          Abstract

          Background

          Early and appropriate antibiotic dosing is associated with improved clinical outcomes in critically ill patients, yet target attainment remains a challenge. Traditional antibiotic dosing is not suitable in critically ill patients, since these patients undergo physiological alterations that strongly affect antibiotic exposure. For beta-lactam antibiotics, the unbound plasma concentrations above at least one to four times the minimal inhibitory concentration (MIC) for 100% of the dosing interval (100%ƒT > 1–4×MIC) have been proposed as pharmacodynamic targets (PDTs) to maximize bacteriological and clinical responses. The objectives of this study are to describe the PDT attainment in critically ill patients and to identify risk factors for target non-attainment.

          Methods

          This prospective observational study was performed in two ICUs in the Netherlands. We enrolled adult patients treated with the following beta-lactam antibiotics: amoxicillin (with or without clavulanic acid), cefotaxime, ceftazidime, ceftriaxone, cefuroxime, and meropenem. Based on five samples within a dosing interval at day 2 of therapy, the time unbound concentrations above the epidemiological cut-off (ƒT > MIC ECOFF and ƒT > 4×MIC ECOFF) were determined. Secondary endpoints were estimated multivariate binomial and binary logistic regression models, for examining the association of PDT attainment with patient characteristics and clinical outcomes.

          Results

          A total of 147 patients were included, of whom 63.3% achieved PDT of 100%ƒT > MIC ECOFF and 36.7% achieved 100%ƒT > 4×MIC ECOFF. Regression analysis identified male gender, estimated glomerular filtration rate (eGFR) ≥ 90 mL/min/1.73 m 2, and high body mass index (BMI) as risk factors for target non-attainment. Use of continuous renal replacement therapy (CRRT) and high serum urea significantly increased the probability of target attainment. In addition, we found a significant association between the 100%ƒT > MIC ECOFF target attainment and ICU length of stay (LOS), but no significant correlation was found for the 30-day survival.

          Conclusions

          Traditional beta-lactam dosing results in low target attainment in the majority of critically ill patients. Male gender, high BMI, and high eGFR were significant risk factors for target non-attainment. These predictors, together with therapeutic drug monitoring, may help ICU clinicians in optimizing beta-lactam dosing in critically ill patients.

          Trial registration

          Netherlands Trial Registry (EXPAT trial), NTR 5632. Registered on 7 December 2015.

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          Most cited references43

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          PKSolver: An add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel.

          This study presents PKSolver, a freely available menu-driven add-in program for Microsoft Excel written in Visual Basic for Applications (VBA), for solving basic problems in pharmacokinetic (PK) and pharmacodynamic (PD) data analysis. The program provides a range of modules for PK and PD analysis including noncompartmental analysis (NCA), compartmental analysis (CA), and pharmacodynamic modeling. Two special built-in modules, multiple absorption sites (MAS) and enterohepatic circulation (EHC), were developed for fitting the double-peak concentration-time profile based on the classical one-compartment model. In addition, twenty frequently used pharmacokinetic functions were encoded as a macro and can be directly accessed in an Excel spreadsheet. To evaluate the program, a detailed comparison of modeling PK data using PKSolver and professional PK/PD software package WinNonlin and Scientist was performed. The results showed that the parameters estimated with PKSolver were satisfactory. In conclusion, the PKSolver simplified the PK and PD data analysis process and its output could be generated in Microsoft Word in the form of an integrated report. The program provides pharmacokinetic researchers with a fast and easy-to-use tool for routine and basic PK and PD data analysis with a more user-friendly interface. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.
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            DALI: defining antibiotic levels in intensive care unit patients: are current β-lactam antibiotic doses sufficient for critically ill patients?

            Morbidity and mortality for critically ill patients with infections remains a global healthcare problem. We aimed to determine whether β-lactam antibiotic dosing in critically ill patients achieves concentrations associated with maximal activity and whether antibiotic concentrations affect patient outcome. This was a prospective, multinational pharmacokinetic point-prevalence study including 8 β-lactam antibiotics. Two blood samples were taken from each patient during a single dosing interval. The primary pharmacokinetic/pharmacodynamic targets were free antibiotic concentrations above the minimum inhibitory concentration (MIC) of the pathogen at both 50% (50% f T>MIC) and 100% (100% f T>MIC) of the dosing interval. We used skewed logistic regression to describe the effect of antibiotic exposure on patient outcome. We included 384 patients (361 evaluable patients) across 68 hospitals. The median age was 61 (interquartile range [IQR], 48-73) years, the median Acute Physiology and Chronic Health Evaluation II score was 18 (IQR, 14-24), and 65% of patients were male. Of the 248 patients treated for infection, 16% did not achieve 50% f T>MIC and these patients were 32% less likely to have a positive clinical outcome (odds ratio [OR], 0.68; P = .009). Positive clinical outcome was associated with increasing 50% f T>MIC and 100% f T>MIC ratios (OR, 1.02 and 1.56, respectively; P < .03), with significant interaction with sickness severity status. Infected critically ill patients may have adverse outcomes as a result of inadeqaute antibiotic exposure; a paradigm change to more personalized antibiotic dosing may be necessary to improve outcomes for these most seriously ill patients.
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              Sex differences in pharmacokinetics and pharmacodynamics.

              Significant differences that exist between the sexes affect the prevalence, incidence and severity of a broad range of diseases and conditions. Men and women also differ in their response to drug treatment. It is therefore essential to understand these reactions in order to appropriately conduct risk assessment and to design safe and effective treatments. Even from that modest perspective, how and when we use drugs can result in unwanted and unexpected outcomes. This review summarizes the sex-based differences that impact on pharmacokinetics, and includes a general comparison of clinical pharmacology as it applies to men, women and pregnant women. Sex-related or pregnancy-induced changes in drug absorption, distribution, metabolism and elimination, when significant, may guide changes in dosage regimen or therapeutic monitoring to increase its effectiveness or reduce potential toxicity. Given those parameters, and our knowledge of sex differences, we can derive essentially all factors necessary for therapeutic optimization. Since this is a rapidly evolving area, it is essential for the practitioner to review drug prescribing information and recent literature in order to fully understand the impact of these differences on clinical therapeutics.
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                Author and article information

                Contributors
                a.abdulla@erasmusmc.nl
                Journal
                Crit Care
                Critical Care
                BioMed Central (London )
                1364-8535
                1466-609X
                15 September 2020
                15 September 2020
                2020
                : 24
                : 558
                Affiliations
                [1 ]GRID grid.5645.2, ISNI 000000040459992X, Department of Hospital Pharmacy, , Erasmus University Medical Center, ; P.O. Box 2040, 3000 CA Rotterdam, the Netherlands
                [2 ]GRID grid.416213.3, ISNI 0000 0004 0460 0556, Department of Intensive Care, , Maasstad Hospital, ; Rotterdam, The Netherlands
                [3 ]GRID grid.5645.2, ISNI 000000040459992X, Department of Intensive Care, , Erasmus University Medical Center, ; Rotterdam, The Netherlands
                [4 ]GRID grid.5645.2, ISNI 000000040459992X, Department of Medical Microbiology and Infectious Diseases, , Erasmus University Medical Center, ; Rotterdam, The Netherlands
                [5 ]GRID grid.414842.f, ISNI 0000 0004 0395 6796, Department of Medical Microbiology, , Haaglanden Medical Center, ; The Hague, The Netherlands
                [6 ]GRID grid.10419.3d, ISNI 0000000089452978, Department of Clinical Pharmacy & Toxicology, , Leiden University Medical Center, ; Leiden, The Netherlands
                Author information
                http://orcid.org/0000-0002-2158-6376
                Article
                3272
                10.1186/s13054-020-03272-z
                7493358
                32933574
                140c75e5-41c7-4b9a-a3a7-6fbb9699d646
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 27 May 2020
                : 2 September 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100003061, Erasmus Medisch Centrum;
                Award ID: MRace Grant 2018
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2020

                Emergency medicine & Trauma
                beta-lactam,critically ill patients,pharmacokinetics,pharmacodynamics,target attainment,risk factors

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