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      Optimization of the treatment with beta-lactam antibiotics in critically ill patients—guidelines from the French Society of Pharmacology and Therapeutics (Société Française de Pharmacologie et Thérapeutique—SFPT) and the French Society of Anaesthesia and Intensive Care Medicine (Société Française d’Anesthésie et Réanimation—SFAR)

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          Beta-lactam antibiotics (βLA) are the most commonly used antibiotics in the intensive care unit (ICU). ICU patients present many pathophysiological features that cause pharmacokinetic (PK) and pharmacodynamic (PD) specificities, leading to the risk of underdosage. The French Society of Pharmacology and Therapeutics (SFPT) and the French Society of Anaesthesia and Intensive Care Medicine (SFAR) have joined forces to provide guidelines on the optimization of beta-lactam treatment in ICU patients.


          A consensus committee of 18 experts from the two societies had the mission of producing these guidelines. The entire process was conducted independently of any industry funding. A list of questions formulated according to the PICO model (Population, Intervention, Comparison, and Outcomes) was drawn-up by the experts. Then, two bibliographic experts analysed the literature published since January 2000 using predefined keywords according to PRISMA recommendations. The quality of the data identified from the literature was assessed using the GRADE® methodology. Due to the lack of powerful studies having used mortality as main judgement criteria, it was decided, before drafting the recommendations, to formulate only “optional” recommendations.


          After two rounds of rating and one amendment, a strong agreement was reached by the SFPT-SFAR guideline panel for 21 optional recommendations and a recapitulative algorithm for care covering four areas: (i) pharmacokinetic variability, (ii) PK-PD relationship, (iii) administration modalities, and (iv) therapeutic drug monitoring (TDM). The most important recommendations regarding βLA administration in ICU patients concerned (i) the consideration of the many sources of PK variability in this population; (ii) the definition of free plasma concentration between four and eight times the Minimal Inhibitory Concentration (MIC) of the causative bacteria for 100% of the dosing interval as PK-PD target to maximize bacteriological and clinical responses; (iii) the use of continuous or prolonged administration of βLA in the most severe patients, in case of high MIC bacteria and in case of lower respiratory tract infection to improve clinical cure; and (iv) the use of TDM to improve PK-PD target achievement.


          The experts strongly suggest the use of personalized dosing, continuous or prolonged infusion and therapeutic drug monitoring when administering βLA in critically ill patients.

          Electronic supplementary material

          The online version of this article (10.1186/s13054-019-2378-9) contains supplementary material, which is available to authorized users.

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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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            Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T>MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections.

            The objective of this study was to evaluate the relationship of the predicted pharmacodynamic parameters 24-h area under the inhibitory curve (AUIC=area under the concentration-time curve for 24h of dosing/minimum inhibitory concentration (AUC0-24/MIC) and time above the minimum inhibitory concentration (T>MIC) with clinical and microbiological outcomes in patients with bacteraemia and sepsis treated with cefepime or ceftazidime. Pharmacokinetic and pharmacodynamic parameters were derived for 76 of 107 patients enrolled in two prospective, randomised, clinical trials comparing cefepime with ceftazidime for the treatment of sepsis with bacteraemia, lower respiratory tract infection or complicated urinary tract infection. The relationships between the pharmacodynamic parameters and outcomes were examined. Whilst no significant differences in clinical outcomes were observed between cefepime and ceftazidime, there were significant differences in the pharmacodynamic analysis. Patients with an AUIC> or =250 had significantly greater clinical cure (79% vs. 33%; P=0.002) and bacteriological eradication (96% vs. 44%; P MIC of 100% had significantly greater clinical cure (82% vs. 33%; P=0.002) and bacteriological eradication (97% vs. 44%; P MIC of MIC was <100%.
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              Drug dosing consideration in patients with acute and chronic kidney disease-a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO).

              Drug dosage adjustment for patients with acute or chronic kidney disease is an accepted standard of practice. The challenge is how to accurately estimate a patient's kidney function in both acute and chronic kidney disease and determine the influence of renal replacement therapies on drug disposition. Kidney Disease: Improving Global Outcomes (KDIGO) held a conference to investigate these issues and propose recommendations for practitioners, researchers, and those involved in the drug development and regulatory arenas. The conference attendees discussed the major challenges facing drug dosage adjustment for patients with kidney disease. In particular, although glomerular filtration rate is the metric used to guide dose adjustment, kidney disease does affect nonrenal clearances, and this is not adequately considered in most pharmacokinetic studies. There are also inadequate studies in patients receiving all forms of renal replacement therapy and in the pediatric population. The conference generated 37 recommendations for clinical practice, 32 recommendations for future research directions, and 24 recommendations for regulatory agencies (US Food and Drug Administration and European Medicines Agency) to enhance the quality of pharmacokinetic and pharmacodynamic information available to clinicians. The KDIGO Conference highlighted the gaps and focused on crafting paths to the future that will stimulate research and improve the global outcomes of patients with acute and chronic kidney disease.

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                +33 (0) 156 017 818 ,
                Crit Care
                Critical Care
                BioMed Central (London )
                29 March 2019
                29 March 2019
                : 23
                [1 ]ISNI 0000 0001 0407 1584, GRID grid.414336.7, AP-HM Hôpital de la Timone, Service de Pharmacologie Clinique et Pharmacovigilance, ; 264 rue Saint Pierre, 13005 Marseille, France
                [2 ]AP-HP Hôpital Cochin, Service de Pharmacologie, 27 rue du Faubourg St-Jacques, 75679 Paris Cedex 14, France
                [3 ]GRID grid.413858.3, CHU d’Amiens Picardie, Service de Pharmacologie Clinique, UPJV EA7517, ; Avenue Laennec, 80054 Amiens Cedex 1, France
                [4 ]ISNI 0000 0000 9336 4276, GRID grid.411162.1, CHU de Poitiers, Département d’Anesthésie Réanimation, ; 2 Rue de la Milétrie, 86021 Poitiers, France
                [5 ]ISNI 0000 0004 0472 0371, GRID grid.277151.7, CHU de Nantes, Département de Pharmacologie Clinique, ; 5 allée de l’île gloriette, 44093 Nantes Cedex 01, France
                [6 ]ISNI 0000 0001 1457 2980, GRID grid.411175.7, CHU de Toulouse, Laboratoire de Pharmacocinétique et Toxicologie Clinique, Institut Fédératif de Biologie, ; 330, avenue de Grande-Bretagne, 31059 Toulouse cedex 9, France
                [7 ]ISNI 0000 0001 2163 3825, GRID grid.413852.9, CHU de Lyon, Service de Pharmacie, Groupement Hospitalier Nord, Hôpital Pierre Garraud, ; 136 rue du Commandant Charcot, 69322 Lyon cedex 05, France
                [8 ]ISNI 0000 0004 1792 201X, GRID grid.413932.e, CHR d’Orléans, Laboratoire de Biochimie, ; 14 Avenue de l’Hôpital, 45067 Orléans, France
                [9 ]AP-HP Hôpital Henri Mondor, Département d’Anesthésie-Réanimation, 51 Avenue du Maréchal de Lattre de Tassigny, 94000 Créteil, France
                [10 ]ISNI 0000 0004 0593 8241, GRID grid.411165.6, CHU de Nîmes, Département d’anesthésie, réanimation, douleur et médicine d’urgence, ; Place du Pr Robert Debré, 30029 Nîmes cedex 9, France
                [11 ]ISNI 0000 0004 1765 1301, GRID grid.410527.5, CHRU de Nancy, Département de pharmacologie clinique et de toxicologie, ; 29 rue Lionnois, 54000 Nancy, France
                [12 ]GRID grid.414271.5, CHU Pontchaillou, Service de Pharmacologie Clinique et épidémiologique, ; 2 Rue Henri le Guilloux, 35000 Rennes, France
                [13 ]ISNI 0000 0001 2175 4109, GRID grid.50550.35, AP-HP Hôpital Tenon, Département d’Anesthésie et Réanimation, ; 4 rue de la Chine, 75020 Paris, France
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