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      Clinically relevant pharmacokinetic knowledge on antibiotic dosing among intensive care professionals is insufficient: a cross-sectional study

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          Abstract

          Background

          Antibiotic exposure in intensive care patients with sepsis is frequently inadequate and is associated with poorer outcomes. Antibiotic dosing is challenging in the intensive care, as critically ill patients have altered and fluctuating antibiotic pharmacokinetics that make current one-size-fits-all regimens unsatisfactory. Real-time bedside dosing software is not available yet, and therapeutic drug monitoring is typically used for few antibiotic classes and only allows for delayed dosing adaptation. Thus, adequate and timely antibiotic dosing continues to rely largely on the level of pharmacokinetic expertise in the ICU. Therefore, we set out to assess the level of knowledge on antibiotic pharmacokinetics among these intensive care professionals.

          Methods

          In May 2018, we carried out a cross-sectional study by sending out an online survey on antibiotic dosing to more than 20,000 intensive care professionals. Questions were designed to cover relevant topics in pharmacokinetics related to intensive care antibiotic dosing. The preliminary pass mark was set by members of the examination committee for the European Diploma of Intensive Care using a modified Angoff approach. The final pass mark was corrected for clinical relevance as assessed for each question by international experts on pharmacokinetics.

          Results

          A total of 1448 respondents completed the survey. Most of the respondents were intensivists (927 respondents, 64%) from 97 countries. Nearly all questions were considered clinically relevant by pharmacokinetic experts. The pass mark corrected for clinical relevance was 52.8 out of 93.7 points. Pass rates were 42.5% for intensivists, 36.1% for fellows, 24.8% for residents, and 5.8% for nurses. Scores without correction for clinical relevance were worse, indicating that respondents perform better on more relevant topics. Correct answers and concise clinical background are provided.

          Conclusions

          Clinically relevant pharmacokinetic knowledge on antibiotic dosing among intensive care professionals is insufficient. This should be addressed given the importance of adequate antibiotic exposure in critically ill patients with sepsis. Solutions include improved education, intensified pharmacy support, therapeutic drug monitoring, or the use of real-time bedside dosing software. Questions may provide useful for teaching purposes.

          Electronic supplementary material

          The online version of this article (10.1186/s13054-019-2438-1) contains supplementary material, which is available to authorized users.

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          Most cited references11

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          Hospital deaths in patients with sepsis from 2 independent cohorts.

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            Risk factors for target non-attainment during empirical treatment with β-lactam antibiotics in critically ill patients.

            Risk factors for β-lactam antibiotic underdosing in critically ill patients have not been described in large-scale studies. The objective of this study was to describe pharmacokinetic/pharmacodynamic (PK/PD) target non-attainment envisioning empirical dosing in critically ill patients and considering a worst-case scenario as well as to identify patient characteristics that are associated with target non-attainment. This analysis uses data from the DALI study, a prospective, multi-centre pharmacokinetic point-prevalence study. For this analysis, we assumed that these were the concentrations that would be reached during empirical dosing, and calculated target attainment using a hypothetical target minimum inhibitory concentration (MIC), namely the susceptibility breakpoint of the least susceptible organism for which that antibiotic is commonly used. PK/PD targets were free drug concentration maintained above the MIC of the suspected pathogen for at least 50 % and 100 % of the dosing interval respectively (50 % and 100 % f T (>MIC)). Multivariable analysis was performed to identify factors associated with inadequate antibiotic exposure. A total of 343 critically ill patients receiving eight different β-lactam antibiotics were included. The median (interquartile range) age was 60 (47-73) years, APACHE II score was 18 (13-24). In the hypothetical situation of empirical dosing, antibiotic concentrations remained below the MIC during 50 % and 100 % of the dosing interval in 66 (19.2 %) and 142 (41.4 %) patients respectively. The use of intermittent infusion was significantly associated with increased risk of non-attainment for both targets; creatinine clearance was independently associated with not reaching the 100 % f T( >MIC) target. This study found that-in empirical dosing and considering a worst--case scenario--19 % and 41 % of the patients would not achieve antibiotic concentrations above the MIC during 50 % and 100 % of the dosing interval. The use of intermittent infusion (compared to extended and continuous infusion) was the main determinant of non-attainment for both targets; increasing creatinine clearance was also associated with not attaining concentrations above the MIC for the whole dosing interval. In the light of this study from 68 ICUs across ten countries, we believe current empiric dosing recommendations for ICU patients are inadequate to effectively cover a broad range of susceptible organisms and need to be reconsidered.
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              Augmented renal clearance in septic and traumatized patients with normal plasma creatinine concentrations: identifying at-risk patients

              Introduction Improved methods to optimize drug dosing in the critically ill are urgently needed. Traditional prescribing culture involves recognition of factors that mandate dose reduction (such as renal impairment), although optimizing drug exposure, through more frequent or augmented dosing, represents an evolving strategy. Elevated creatinine clearance (CLCR) has been associated with sub-therapeutic antibacterial concentrations in the critically ill, a concept termed augmented renal clearance (ARC). We aimed to determine the prevalence of ARC in a cohort of septic and traumatized critically ill patients, while also examining demographic, physiological and illness severity characteristics that may help identify this phenomenon. Methods This prospective observational study was performed in a 30-bed tertiary level, university affiliated, adult intensive care unit. Consecutive traumatized and septic critically ill patients, receiving antibacterial therapy, with a plasma creatinine concentration ≤110 μmol/L, were eligible for enrolment. Pulse contour analysis (Vigileo / Flo Trac® system, Edwards Lifesciences, Irvine, CA, USA), was used to provide continuous cardiac index (CI) assessment over a single six-hour dosing interval. Urinary CLCR measures were obtained concurrently. Results Seventy-one patients contributed data (sepsis n = 43, multi-trauma n = 28). Overall, 57.7% of the cohort manifested ARC, although there was a greater prevalence in trauma (85.7% versus 39.5%, P <0.001). In all patients, a weak correlation was noted between CI and CLCR (r = 0.346, P = 0.003). This was mostly driven by septic patients (r = 0.508, P = 0.001), as no correlation (r = -0.012, P = 0.951) was identified in trauma. Those manifesting ARC were younger (P <0.001), male (P = 0.012), with lower acute physiology and chronic health evaluation (APACHE) II (P= 0.008) and modified sequential organ failure assessment (SOFA) scores (P = 0.013), and higher cardiac indices (P = 0.013). In multivariate analysis, age ≤50 years, trauma, and a modified SOFA score ≤4, were identified as significant risk factors. These had greater utility in predicting ARC, compared with CI assessment alone. Conclusions Diagnosis, illness severity and age, are likely to significantly influence renal drug elimination in the critically ill, and must be regularly considered in future study design and daily prescribing practice. See related commentary by De Waele and Carlier, http://ccforum.com/content/17/2/130
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                Author and article information

                Contributors
                +31 20 444 7861 , l.fleuren@vumc.nl
                L.Roggeveen@vumc.nl
                T.Guo@vumc.nl
                petrwaldauf@gmail.com
                P.H.J.vanderVoort@olvg.nl
                R.J.Bosman@olvg.nl
                EL.Swart@vumc.nl
                ARJ.Girbes@vumc.nl
                P.Elbers@vumc.nl
                Journal
                Crit Care
                Critical Care
                BioMed Central (London )
                1364-8535
                1466-609X
                22 May 2019
                22 May 2019
                2019
                : 23
                : 185
                Affiliations
                [1 ]ISNI 0000 0004 1754 9227, GRID grid.12380.38, Department of Intensive Care Medicine, Research VUmc Intensive Care (REVIVE), Amsterdam Medical Data Science (AMDS), Amsterdam Cardiovascular Sciences (ACS), Amsterdam Infection and Immunity Institute (AI&II), , Amsterdam UMC, Location VUmc, Vrije Universiteit Amsterdam, ; Amsterdam, The Netherlands
                [2 ]ISNI 0000 0004 1937 116X, GRID grid.4491.8, Department of Anaesthesia and Intensive Care Medicine, Kralovske Vinohrady University Hospital and The Third Faculty of Medicine, , Charles University, ; Prague, Czech Republic
                [3 ]GRID grid.440209.b, Intensive Care, OLVG, ; Amsterdam, The Netherlands
                [4 ]ISNI 0000 0004 1754 9227, GRID grid.12380.38, Department of Clinical Pharmacology and Pharmacy, , Amsterdam UMC, Location VUmc, Vrije Universiteit Amsterdam, ; Amsterdam, The Netherlands
                Author information
                http://orcid.org/0000-0002-4056-1692
                Article
                2438
                10.1186/s13054-019-2438-1
                6532162
                31118061
                e979227b-e9b0-4223-8941-a3416c53806e
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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.

                History
                : 21 February 2019
                : 15 April 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001826, ZonMw;
                Award ID: 80-83600-98-40050
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2019

                Emergency medicine & Trauma
                antibiotics,intensive care,pharmacokinetics,drug dosing
                Emergency medicine & Trauma
                antibiotics, intensive care, pharmacokinetics, drug dosing

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