Purpose: This Position Paper aims to review and discuss the available data on therapeutic drug monitoring (TDM) of antibacterials, antifungals and antivirals in critically ill adult patients in the intensive care unit (ICU). This Position Paper also provides a practical guide on how TDM can be applied in routine clinical practice to improve therapeutic outcomes in critically ill adult patients. Methods: Literature review and analysis were performed by Panel Members nominated by the endorsing organisations,

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appeared just over 7 months ago in Wuhan, China. Early reports from China indicated that although some cases are asymptomatic, 20% of COVID-19 cases follow a severe course, necessitating hospitalization, with a quarter of hospitalized patients requiring intensive care unit (ICU) facilities [1]. Later reports from China and other countries substantiated these data, although ICU admission rates, proportion of patients receiving invasive mechanical ventilation (IMV), and mortality rates differ considerably between studies [2]. The life-threatening form of respiratory failure, acute respiratory distress syndrome (ARDS) is a frequent complication in COVID-19 [3]. The severity of ARDS is classified into categories of mild, moderate, and severe, depending on the degree of hypoxemia [4]. Patients with moderate-tosevere ARDS require invasive mechanical ventilation (IMV) and have a poor prognosis [4]. The incidence of ARDS and specifically, moderate-to-severe ARDS, among COVID-19 patients is currently unknown [5]. We describe here the results of a survey of clinical studies reporting COVID-19-associated ARDS in hospitalized patients since the beginning of the COVID-19 pandemic in January until the end of July 2020. Our aim was to obtain a clearer picture of the incidence of COVID-19-associated ARDS in hospitalized patients on a global level, to better define the burden to healthcare

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ObjectivesSARS‐CoV‐2-induced COVID-19 has led to exponentially rising mortality, particularly in immunosuppressed patients, who inadequately respond to conventional COVID-19 vaccination.MethodsIn this blinded randomised clinical trial, we compare the efficacy and safety of an additional booster vaccination with a vector versus mRNA vaccine in non-seroconverted patients. We assigned 60 patients under rituximab treatment, who did not seroconvert after their primary mRNA vaccination with either BNT162b2 (Pfizer–BioNTech) or mRNA-1273 (Moderna), to receive a third dose, either using the same mRNA or the vector vaccine ChAdOx1 nCoV-19 (Oxford–AstraZeneca). Patients were stratified according to the presence of peripheral B cells. The primary efficacy endpoint was the difference in the SARS-CoV-2 antibody seroconversion rate between vector (heterologous) and mRNA (homologous) vaccinated patients by week 4. Key secondary endpoints included the overall seroconversion and cellular immune response; safety was assessed at week 1 and week 4.ResultsSeroconversion rates at week 4 were comparable between vector (6/27 patients, 22%) and mRNA (9/28, 32%) vaccines (p=0.6). Overall, 27% of patients seroconverted; specific T cell responses were observed in 20/20 (100%) vector versus 13/16 (81%) mRNA vaccinated patients. Newly induced humoral and/or cellular responses occurred in 9/11 (82%) patients. 3/37 (8%) of patients without and 12/18 (67%) of the patients with detectable peripheral B cells seroconverted. No serious adverse events, related to immunisation, were observed.ConclusionsThis enhanced humoral and/or cellular immune response supports an additional booster vaccination in non-seroconverted patients irrespective of a heterologous or homologous vaccination regimen.

Objectives: The aim was to characterize linezolid population pharmacokinetics in plasma and interstitial space fluid of subcutaneous adipose tissue (target site) of obese compared with non-obese patients and to determine dosing regimens enabling adequate therapy using Monte Carlo simulations. Methods: In this prospective, parallel group, open-label, controlled, single-centre trial, 30 surgery patients (15 obese, 15 non-obese) received 600 mg of intravenous linezolid. A population pharmacokinetic analysis characterizing plasma and microdialysis-derived target site pharmacokinetics was followed by Monte Carlo simulations using twice/thrice daily 600e1200 mg short-term and extended infusions of linezolid. Adequacy of therapy was assessed by the probability of pharmacokinetic/pharmacodynamic target attainment for time and exposure-related indices.Results: In the model, lean body weight and obesity status largely explained between-patient variability in linezolid PK parameters (12.0e44.9%). Both factors caused lower area under the concentrationetime curve in typical obese patients in plasma (e20.4%, 95% CI e22.0% to e15.9%) and at target-site (e37.7%, 95% CI e47.1% to e24.2%) compared with non-obese patients. Probability of target attainment showed improvement with increasing linezolid doses. Depending on lean body weight, adequate therapy was partially attained for 900-and 1200-mg linezolid doses and minimum inhibitory concentrations (MICs) 2 mg/L (probability of target attainment 62.5e100%) but could not be reached for MIC ¼ 4 mg/L (probability of target attainment 82.3%). Additionally, lower linezolid distribution into the target site in obese patients as described above might compromise the plasma-based probability of target attainment analysis. Discussion: This analysis revealed risks of linezolid underdosing in empirical antibiotic therapy of most resistant bacteria for obese and non-obese patients. Doubling the standard dose is associated with adequate probability of target attainment throughout most body masses for MIC 2 mg/L. Further clinical studies with adjusted dosing regimens in for example intensive care patients are needed.

Convalescent plasma is a suggested treatment for Coronavirus disease 2019 (Covid-19), but its efficacy is uncertain. We aimed to evaluate whether the use of convalescent plasma is associated with improved clinical outcomes in patients with Covid-19.In this systematic review and meta-analysis, we searched randomized controlled trials investigating the use of convalescent plasma in patients with Covid-19 in Medline, Embase, Web of Science, Cochrane Library, and medRxiv from inception to October 17th, 2021. Two reviewers independently extracted the data. The primary efficacy outcome was all-cause mortality. The Cochrane Risk of Bias Tool and GRADE (Grading of Recommendations Assessment, Development and Evaluation) method were used. This study was registered with PROSPERO, CRD42021284861. Of the 8874 studies identified in the initial search, sixteen trials comprising 16 317 patients with Covid-19 were included. In the overall population, the all-cause mortality was 23.8% (2025 of 8524) with convalescent plasma and 24.4% (1903 of 7769) with standard of care (risk ratio (RR) 0.97, 95% CI 0.90-1.04) (high-certainty evidence). All-cause mortality did not differ in the subgroups of noncritically ill (21.7% [1288 of 5929] vs. 22.4% [1320 of 5882]) and critically ill (36.9% [518 of 1404] vs. 36.4% [455 of 1247]) patients with Covid-19. The use of convalescent plasma in patients who tested negative for anti-SARS-CoV-2 antibodies at baseline was not associated with significantly improved survival (RR 0.94, 95% CI 0.87-1.02). In the overall study population, initiation of mechanical ventilation (RR 0.97, 95% CI 0.88-1.07), time to clinical improvement (HR 1.09, 95% CI 0.91-1.30), and time to discharge (HR 0.95, 95% CI 0.89-1.02) were similar between the two groups. In patients with Covid-19, treatment with convalescent plasma, as compared with control, was not associated with lower all-cause mortality or improved disease progression, irrespective of disease severity and baseline antibody status.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier PROSPERO (CRD42021284861).

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The antiemetic and gastroprokinetic drug metoclopramide is a weak substrate of the blood-brain barrier (BBB) efflux transporter P-gp and displays central nervous system (CNS) side effects (extrapyramidal symptoms, tardive dyskinesia), which occur with a higher incidence in elderly people. WHAT QUESTION DID THIS STUDY ADDRESS?  We performed [ 11 C]metoclopramide positron emission tomography scans in young and elderly healthy men, both after administration of a microdose and therapeutic dose of metoclopramide, to investigate whether differences in brain distribution of metoclopramide may explain its CNS side effects.