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Increasing evidence suggests that dalbavancin is an effective long-term treatment for ventricular assist device (VAD) infections, with various prolonged dosing regimens currently in use. This retrospective study aimed to assess dalbavancin pharmacokinetics in VAD patients and identify optimal, feasible dosing regimens for long-term suppressive outpatient therapy. Data from Heidelberg University Hospital’s VAD register were analyzed using non-linear mixed-effects modeling for pharmacokinetic analysis and dosing simulations (Lixoft®). The probability of target attainment (PTA) and cumulative fraction of response (CFR) were calculated for different protein-binding scenarios considering the minimum inhibitory concentration (MIC) distribution of Staphylococcus aureus. Using data from 13 patients with 38 blood samples, a two-compartment model best described the dalbavancin pharmacokinetics, with a typical value for clearance of 0.050 L/h, central volume of distribution of 6.5 L, and peripheral volume of 15.4 L. No covariates significantly improved the model fit. The observed protein binding varied between 96 and 98%. Dosing simulations demonstrated that 1500 mg every 3 weeks ensured the target attainment for stasis at MIC values of 0.125 mg/L (PTA ≥ 90%) up to a protein binding of 99%. Considering the CRF, longer dosing intervals up to 5 weeks might be possible. Depending on individual MICs and protein binding, a dalbavancin regimen of 1500 mg every 3 to 5 weeks therefore appears to be a valuable option for outpatient therapy of VAD infections. Therapeutic drug monitoring should be considered to manage inter-individual variability and to support clinicians in long-term treatments of subacute and chronic infections.

Summary: Background: Anticipating the burden of intracerebral haemorrhage is crucial for proactive management and building resilience against future health challenges. Prior forecasts are based on population demography and to a lesser extent epidemiological trends. This study aims to utilise selected modifiable risk factors and socio-demographic indicators to forecast the incidence and mortality of intracerebral haemorrhage in Europe between 2019 and 2050. Methods: Three intracerebral haemorrhage risk factors identified in the Global Burden of Diseases, Injuries, and Risk Factors study (GBD 2019)—high systolic blood pressure, high fasting plasma glucose, and high body mass index—were utilised to predict the risk-attributable fractions between 2019 and 2050. Disease burden not attributable to these risk factors was then forecasted using time series models (autoregressive integrated moving average [ARIMA]), incorporating the Socio-demographic Index (SDI) as an external predictor. The optimal parameters of ARIMA models were selected for each age-sex-country group based on the Akaike Information Criterion (AIC). Different health scenarios were constructed by extending the past 85th and 15th percentiles of annualised rates of change in risk factors and SDI across all location-years, stratified by age and sex groups. A decomposition analysis was performed to assess the relative contributions of population size, age composition, and intracerebral haemorrhage risk on the projected changes. Findings: Compared with observed figures in 2019, our analysis predicts an increase in the burden of intracerebral haemorrhage in Europe in 2050, with a marginal rise of 0.6% (95% uncertainty interval [UI], −7.4% to 9.6%) in incident cases and an 8.9% (−2.8% to 23.6%) increase in mortality, reaching 141.2 (120.6–166.5) thousand and 144.2 (122.9–172.2) thousand respectively. These projections may fluctuate depending on trajectories of the risk factors and SDI; worsened trends could result in increases of 16.7% (8.7%–25.3%) in incidence and 31.2% (17.7%–48%) in mortality, while better trajectories may lead to a 10% (16.4%–2.3%) decrease in intracerebral haemorrhage cases with stabilised mortality. Individuals aged ≥80 years are expected to contribute significantly to the burden, comprising 62.7% of the cases in 2050, up from 40% in 2019, and 72.5% of deaths, up from 50.5%. Country-wide variations were noted in the projected changes, with decreases in the standardised rates across all nations but varying crude rates. The largest relative reductions in counts for both incidence and mortality are expected in Latvia, Bulgaria, and Hungary—ranging from −38.2% to −32.4% and −37.3% to −30.2% respectively. In contrast, the greatest increases for both measures were forecasted in Ireland (45.7% and 74.4%), Luxembourg (45% and 70.7%), and Cyprus (44.5% and 74.2%). The modelled increase in the burden of intracerebral haemorrhage could largely be attributed to population ageing. Interpretation: This study provides a comprehensive forecast of intracerebral haemorrhage in Europe until 2050, presenting different trajectories. The potential increase in the number of people experiencing and dying from intracerebral haemorrhage could have profound implications for both caregiving responsibilities and associated costs. However, forecasts were divergent between different scenarios and among EU countries, signalling the pivotal role of public health initiatives in steering the trajectories. Funding: The European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No. 754517. The National Institute for Health and Care Research (NIHR) under its Programme Grants for Applied Research (NIHR202339).

Introduction Up to 15% of adult patients in the clinical setting report to be allergic to penicillin. However, in most cases, penicillin allergy is not confirmed. Due to the negative aspects associated with erroneous penicillin allergy, the implementation of active delabelling processes for penicillin allergy is an important part of antibiotic stewardship programmes. Depending on the clinical setting, different factors need to be considered during implementation. This review examines the effectiveness of different delabelling interventions and summarises components and structures that facilitate, support or constrain structured penicillin allergy delabelling.Methods and analysis This review will adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The databases MEDLINE (via PubMed), EMBASE and Cochrane Library were searched for studies reporting on any intervention to identify, assess or rule out uncertain penicillin allergy. To improve completeness, two further databases are also searched for grey literature. Study design, intervention type, professional groups involved, effectiveness, limitations, barriers, facilitating factors, clinical setting and associated regulatory factors will be extracted and analysed. In addition, exclusion criteria for participation in the delabelling intervention and criteria for not delabelling penicillin allergy will be summarised. In case of failed protocols, these are highlighted and quantitatively analysed if possible. Two independent reviewers will perform the screening process and data extraction. Discordant decisions will be resolved through review by a third reviewer. Bias assessment of the individual studies will be performed using the Newcastle Ottawa Scale.Ethics and dissemination Because individual patient-related data are not analysed, an ethical approval is not required. The review will be published in a peer-reviewed scientific journal.

Abstract Glucocorticoids (GCs) are widely used in tumor therapy to reduce tumor growth, inflammation, edema, and other side effects. Controversially, GCs may also cause the progression of highly aggressive pancreatic ductal adenocarcinoma (PDAC). Because microRNA (miR) and autophagy signaling support the invasive growth of PDAC, we asked whether these mechanisms may be targeted by GCs. Six established human PDAC cell lines, tissue from patients who received GC medication (n = 35) prior to surgery, or not (n = 35), and tumor xenografts were examined by RT‒qPCR, transmission electron microscopy (TEM), monodansylcadaverine (MDC) staining, immunohistochemistry, in situ hybridization, gene array and Kaplan‒Meier analysis with bioinformatics, and MTT, western blot, colony, spheroid, migration, and invasion assays. We found that various GCs, including dexamethasone (DEX), induced typical features of macroautophagy with the appearance of autolysosomes, enhanced LC3-II, decreased SQSTM1/p62 expression and induced epithelial-mesenchymal transition (EMT) and gemcitabine resistance. The GC receptor (GR) antagonist mifepristone (RU486) counteracted DEX-induced autophagy features, suggesting that the GC-GR complex is involved in the induction of autophagy. The autophagy-related miR-378i and miR-378a-3p were selected as the top upregulated candidates, and their high expression in PDAC patient tissue correlated with low survival. siRNA-mediated downregulation of miR-378 inhibited DEX-induced autophagy, and tumor progression. Bioinformatics confirmed the contribution of miR-378 to the regulation of signaling networks involved in GC-induced autophagy and tumor progression. The construction of a molecular docking model revealed stable binding of miR-378 to the DEX-GR complex, suggesting direct regulation. These substantial, novel, in-depth data reveal that GCs favor autophagy-mediated cancer progression by inducing miR-378 and GR binding and implicate GR and miR-378 as new therapeutic targets.

Abstract Background It is known that drug shortages represent a major challenge for all stakeholders involved in the process, but there is little evidence regarding insights into patients′ awareness and perspectives. This study aimed to investigate the patients-perceived drug shortages experience and their view on outcomes in different European hospital settings. Furthermore, we wanted to explore information preferences on drug shortages. Methods A retrospective, cross sectional, a mixed method study was conducted in six European hospital settings. One hospital (H) from each of this country agreed to participate: Bosnia and Herzegovina (H-BiH), Croatia (H-CR), Germany (H-GE), Greece (H-GR), Serbia (H-SE) and Poland (H-PO). Recruitment and data collection was conducted over 27 months from November 2017 until January 2020. Overall, we surveyed 607 patients which completed paper-based questionnaire. Questions related to: general information (demographic data), basic knowledge on drug shortages, drug shortages experienced during hospitalization and information preferences on drug shortage. Differences between hospital settings were analyzed using Chi-squared test or Fisher’s exact test. For more complex contingency tables, Monte Carlo simulations (N = 2000) were applied for Fisher’s test. Post-hoc hospital-wise analyses were performed using Fisher’s exact tests. False discovery rate was controlled using the Bonferroni method. Analyses were performed using R: a language and environment for statistical computing (v 3.6.3). Results 6 % of patients reported experiences with drug shortages while hospitalized which led to a deterioration of their health. The majority of affected patients were hospitalized at hematology and/or oncology wards in H-BiH, H-PO and H-GE. H-BiH had the highest number of affected patients (18.1 %, N = 19/105, p

IntroductionWhile medicine shortages are complex, their mitigation is more of a challenge. Prospective risk assessment as a means to mitigate possible shortages, has yet to be applied equally across healthcare settings. The aims of this study have been to: 1) gain insight into risk-prevention against possible medicine shortages among healthcare experts; 2) review existing strategies for minimizing patient-health risks through applied risk assessment; and 3) learn from experiences related to application in practice.MethodologyA semi-structured questionnaire focusing on medicine shortages was distributed electronically to members of the European Cooperation in Science and Technology (COST) Action 15105 (28 member countries) and to hospital pharmacists of the European Association of Hospital Pharmacists (EAHP) (including associated healthcare professionals). Their answers were subjected to both qualitative and quantitative analysis (Microsoft Office Excel 2010 and IBM SPSS Statistics®) with descriptive statistics based on the distribution of responses. Their proportional difference was tested by the chi-square test and Fisher's exact test for independence. Differences in the observed ordinal variables were tested by the Mann-Whitney or Kruskal-Wallis test. The qualitative data were tabulated and recombined with the quantitative data to observe, uncover and interpret meanings and patterns.ResultsThe participants (61.7%) are aware of the use of risk assessment procedures as a coping strategy for medicine shortages, and named the particular risk assessment procedure they are familiar with failure mode and effect analysis (FMEA) (26.4%), root cause analysis (RCA) (23.5%), the healthcare FMEA (HFMEA) (14.7%), and the hazard analysis and critical control point (HACCP) (14.7%). Only 29.4% report risk assessment as integrated into mitigation strategy protocols. Risk assessment is typically conducted within multidisciplinary teams (35.3%). Whereas 14.7% participants were aware of legislation stipulating risk assessment implementation in shortages, 88.2% claimed not to have reported their findings to their respective official institutions. 85.3% consider risk assessment a useful mitigation strategy.ConclusionThe study indicates a lack of systematically organized tools used to prospectively analyze clinical as well as operationalized risk stemming from medicine shortages in healthcare. There is also a lack of legal instruments and sufficient data confirming the necessity and usefulness of risk assessment in mitigating medicine shortages in Europe.

The severe course of bloodstream infections with Gram-negative bacilli can lead to organ dysfunctions and compromise the integrity of the vascular barrier, which are the hallmarks of sepsis. This study aimed to investigate the potential effect of cefiderocol on the barrier function of vascular endothelial cells (vECs) in an in vitro experimental set-up. Human umbilical vein cells (HUVECs), co-cultured with erythrocyte-depleted whole blood for up to 48 h, were activated with tumor necrosis factor-alpha (TNF-α) or lipopolysaccharide (LPS) to induce endothelial damage in the absence or presence of cefiderocol (concentrations of 10, 40 and 70 mg/L). The endothelial integrity was quantified using transendothelial electrical resistance (TEER) measurement, performed at 0, 3, 24 and 48 h after stimulation. Stimulation with TNF-α and LPS increased the endothelial permeability assessed by TEER at 24 and 48 h of co-culture. Furthermore, cefiderocol reduces interleukin-6 (IL-6), interleukin-1β (IL-1β) and TNF-α release in peripheral blood mononuclear cells (PBMCs) following LPS stimulation in a dose-dependent manner. Collectively, the data suggest that cefiderocol may have an influence on the cellular immune response and might support the maintenance of vEC integrity during inflammation associated with infection with Gram-negative bacteria, which warrants further investigations.

Abstract Background Severe sepsis and septic shock remain a major challenge, even in modern intensive care. In Germany, about 68,000 patients die annually because of septic diseases, characterized by a complex systemic inflammatory response. Causal treatment of the underlying infection is essential for successful management of sepsis, but the course can be positively influenced by supportive and adjuvant measures. The cholinergic anti-inflammatory pathway (CAP) represents a new approach to adjunctive therapy of septic diseases and can be pharmacologically activated by the acetylcholinesterase inhibitor physostigmine (Anticholium®). Promising effects can be found in several in vitro and in vivo models of sepsis, such as a reduction in pro-inflammatory cytokines and improved survival. Methods Anticholium® per Se is a randomized, double-blind, placebo-controlled, monocentric trial to assess whether the CAP can be transferred from bench to bedside. In this pilot study, 20 patients with perioperative sepsis and septic shock as a result of intra-abdominal infection are enrolled. According to randomization, participants are treated with physostigmine salicylate (verum group) or 0.9% sodium chloride (placebo group) for up to 5 days. The mean Sequential Organ Failure Assessment (SOFA) score during treatment and subsequent intensive care of up to 14 days is used as surrogate outcome (primary endpoint). Secondary outcome measures include 30- and 90-day mortality. An embedded pharmacokinetics and pharmacodynamics study investigates plasma concentrations of physostigmine and its metabolite eseroline. Further analyses will contribute to our understanding of the role of various cytokines in the pathophysiology of human sepsis. A computer-generated list is used for block randomization. Discussion This randomized, controlled, monocentric trial investigates for the first time the adjunctive use of physostigmine (Anticholium®) in patients with perioperative sepsis and septic shock and may be a pivotal step toward the clinical use in this indication. Trial registration EudraCT Number: 2012-001650-26 (entered 14 August 2012), ClinicalTrials.gov identifier: NCT03013322 (registered on 1 Jan 2017).

Abstract   Objective Medication errors are frequent in a hospital setting and often caused by inappropriate drug handling. Systematic strategies for their prevention however are still lacking. We developed and applied a classification model to categorise medication handling errors and defined the urgency of correction on the basis of these findings. Setting Nurses on medical wards (including intensive and intermediate care units) of a 1,680-bed teaching hospital. Method In a prospective observational study we evaluated the prevalence of 20 predefined medication handling errors on the ward. In a concurrent questionnaire survey, we assessed the knowledge of the nurses on medication handling. The severity of errors observed in individual areas was scored considering prevalence, potential risk of an error, and the involved drug. These scores and the prevalence of corresponding knowledge deficits were used to define the urgency of preventive strategies according to a four-field decision matrix. Main outcome measure Prevalence and potential risk of medication handling errors, corresponding knowledge deficits in nurses committing the errors, and priority of quality improvement. Results In 1,376 observed processes 833 medication handling errors were detected. Errors concerning preparation (mean 0.88 errors per observed process [95% CI: 0.81–0.96], N = 645) were more frequent than administration errors (0.36 [0.32–0.41], N = 701, P N = 492) were more often involved in errors than enteral drugs (0.32 [0.28–0.36], N = 794, P Conclusion We successfully applied a newly developed classification model to prioritise medication handling errors for prevention strategies. [ABSTRACT FROM AUTHOR]

Objectives: Linezolid is an oxazolidinone antibiotic used in the treatment of infections caused by vancomycin-resistant enterococci. Resistance to linezolid has been associated with a G2576U mutation in domain V of the 23S rRNA.Patient and methods: We present clinical details and susceptibility data from multiple Enterococcus faecium strains isolated from a liver transplant patient over 13 months. MICs of linezolid, vancomycin and quinupristin/dalfopristin were determined using Etest. Molecular typing was performed by pulsed-field gel electrophoresis. Domain V of the 23S rRNA gene in the vancomycin-resistant Enterococcus faecium was amplified. Linezolid concentrations were analysed by HPLC.Results: We report the emergence of resistance to linezolid in a vancomycin-resistant Enterococcus faecium during linezolid treatment. After discontinuation of the linezolid therapy, the isolate reverted to susceptibility. However, after re-administration of linezolid the vancomycin-resistant Enterococcus faecium became resistant to linezolid again. The isolates that were resistant to linezolid had a G2576T mutation in their 23S rDNA.Conclusion: We describe a clinical case that shows the shift of a vancomycin-resistant Enterococcus faecium from linezolid resistance to susceptibility and then back to resistance again related to linezolid therapy. [ABSTRACT FROM AUTHOR]

Objective: Moxifloxacin is a recently developed fourth-generation methoxyquinolone with a broad spectrum of activity against both Gram-positive and Gram-negative aerobic bacteria and anaerobes. The aim of the present study was to assess the penetration of moxifloxacin into gastrointestinal (GI) mucosal tissues to evaluate its potential role as an antimicrobial drug in bacterial infections of the GI tract.Patients and methods: Twenty-eight patients undergoing GI-tract surgery received 400 mg of moxifloxacin twice pre-operatively [eight patients orally (po) and 20 patients intravenously (iv)], of whom 22 completed the study. Mucosal tissues (three stomach, three small bowel and 16 colon) and serum samples were collected and moxifloxacin concentrations were measured by HPLC.Results: The highest tissue concentrations were detected in the mucosa of the stomach (10.9 ± 5.1 mg/kg), followed by colon mucosa (7.8 ± 7.1 mg/kg after iv; 6.6 ± 3.6 mg/kg after po) and small bowel mucosa (5.4 ± 0.5 mg/kg). The tissue-to-serum ratio of moxifloxacin was 2.0 ± 1.6 in the small bowel mucosa, 5.8 ± 3.4 and 6.8 ± 3.9 in the colon mucosa after po and iv administration, respectively, and 9.7 ± 5.7 in the stomach mucosa.Conclusion: Moxifloxacin penetrates into and accumulates in the mucosa of the stomach, small bowel and colon. The clinical applicability of moxifloxacin administration for bacterial GI-tract infections should be investigated in controlled trials. [ABSTRACT FROM AUTHOR]

: Objectives Adequate antimicrobial therapy is crucial for the survival of critically ill patients with severe nosocomial infections. Tigecycline, the first available agent in the new class of glycylcyclines, is active against multiresistant Gram-positive and Gram-negative bacteria. The aim of this observational, retrospective evaluation was to assess tigecycline use patterns in a surgical intensive care unit (SICU) of a tertiary care centre. : Methods Data from 70 patients receiving tigecycline in the SICU were analysed. We reviewed tigecycline use in terms of demographic data and co-morbidities, disease severity, clinical indication, microbiology, therapy regimens and mortality. A logistic regression analysis was performed to identify prognostic factors for mortality. : Results The majority of patients had co-morbidities such as cancer (51%) or renal replacement therapy (57%). The mean Acute Physiology and Chronic Health Evaluation (APACHE) II score of patients at admission was 27. Intra-abdominal infection was most frequently diagnosed (50% of patients); intra-abdominal infection and pneumonia were diagnosed in 14%. Methicillin-resistant Staphylococcus aureus was found in 16% of patients (colonization; infection: 6%) and vancomycin-resistant enterococci in 27% (colonization; infection: 21%). The mean duration of tigecycline therapy was 9 ± 4 days; 76% of patients received tigecycline in combination, with 64% being treated second line. APACHE score and renal replacement were identified as predictive factors for mortality. SICU mortality was 30%. : Conclusions Tigecycline treatment of critically ill SICU patients with severe sepsis or septic shock appeared to result in remarkably low mortality. Tigecycline may be an important treatment option for septic patients with infections resistant to other available agents. [ABSTRACT FROM AUTHOR]