The Janus kinase 1/2 inhibitor ruxolitinib in COVID-19 with severe systemic hyperinflammation.

A subgroup of patients with severe COVID-19 suffers from progression to acute respiratory distress syndrome and multiorgan failure. These patients present with progressive hyperinflammation governed by proinflammatory cytokines. An interdisciplinary COVID-19 work flow was established to detect patients with imminent or full blown hyperinflammation. Using a newly developed COVID-19 Inflammation Score (CIS), patients were prospectively stratified for targeted inhibition of cytokine signalling by the Janus Kinase 1/2 inhibitor ruxolitinib (Rux). Patients were treated with efficacy/toxicity guided step up dosing up to 14 days. Retrospective analysis of CIS reduction and clinical outcome was performed. Out of 105 patients treated between March 30th and April 15th, 2020, 14 patients with a CIS ≥ 10 out of 16 points received Rux over a median of 9 days with a median cumulative dose of 135 mg. A total of 12/14 patients achieved significant reduction of CIS by ≥25% on day 7 with sustained clinical improvement in 11/14 patients without short term red flag warnings of Rux-induced toxicity. Rux treatment for COVID-19 in patients with hyperinflammation is shown to be safe with signals of efficacy in this pilot case series for CRS-intervention to prevent or overcome multiorgan failure. A multicenter phase-II clinical trial has been initiated (NCT04338958).

Strategies to enhance rational use of antibiotics in hospital: a guideline by the German Society for Infectious Diseases.

INTRODUCTION: In the time of increasing resistance and paucity of new drug development there is a growing need for strategies to enhance rational use of antibiotics in German and Austrian hospitals. An evidence-based guideline on recommendations for implementation of antibiotic stewardship (ABS) programmes was developed by the German Society for Infectious Diseases in association with the following societies, associations and institutions: German Society of Hospital Pharmacists, German Society for Hygiene and Microbiology, Paul Ehrlich Society for Chemotherapy, The Austrian Association of Hospital Pharmacists, Austrian Society for Infectious Diseases and Tropical Medicine, Austrian Society for Antimicrobial Chemotherapy, Robert Koch Institute. MATERIALS AND METHODS: A structured literature research was performed in the databases EMBASE, BIOSIS, MEDLINE and The Cochrane Library from January 2006 to November 2010 with an update to April 2012 (MEDLINE and The Cochrane Library). The grading of recommendations in relation to their evidence is according to the AWMF Guidance Manual and Rules for Guideline Development. CONCLUSION: The guideline provides the grounds for rational use of antibiotics in hospital to counteract antimicrobial resistance and to improve the quality of care of patients with infections by maximising clinical outcomes while minimising toxicity. Requirements for a successful implementation of ABS programmes as well as core and supplemental ABS strategies are outlined. The German version of the guideline was published by the German Association of the Scientific Medical Societies (AWMF) in December 2013.

[Recent antibiotic use in German acute care hospitals - from benchmarking to improved prescribing and quality care]. / Antibiotika-Anwendung 2012/13 in 109 deutschen Akutkrankenhäusern.

BACKGROUND: In view of increasing rates of bacterial resistance and Clostridium difficile infections efforts to enhance appropriate and intelligent antibiotic prescribing have become important. A prerequisite is the availability of reliable antibiotic use data. So far antibiotic consumption data in this country had only a very limited coverage of acute care hospitals. METHODS: We obtained drug dispensing data from 109 German acute care hospital pharmacies and calculated yearly antibiotic use density values stratified for hospital size and type of service / department. Antibiotic use density was expressed as daily doses per 100 patient days (occupied bed days). For daily dose definition, both hospital adapted doses of antibiotics ("recommended daily dose", RDD) as well as the official WHO-defined daily doses (DDD) were used. RESULTS: The overall antibiotic use density was 43.5 RDD/100 patient days (median) with an interquartile range of 36-48 RDD/100 - corresponding to a median of 64.4 DDD/100 (interquartile range, 53-73 DDD/100). The antibiotic use levels in university hospitals were higher than in non-university hospitals that, in turn, showed similar antibiotic use density values across different hospital size categories. Antibiotic use density values for intensive care units were approximately twice as high as for normal wards but the proportion of antibiotic doses prescribed in intensive care per hospital-wide consumption was only 12 % (non-university hospitals) to 18 % (university hospitals). Extensive antibiotic use was also observed in university hospital hematology-oncology departments. Overall, cephalosporins were used slightly more frequently than penicillins, and fluoroquinolones were the third most frequently prescribed drug class. The proportion of first and second generation cephalosporins, and of third and fourth generation cephalosporins ranged between 5-37 % and between < 1 to 29 % of all dispensed antibiotic doses across the hospitals, respectively. The top five used drugs were cefuroxime, piperacillin-tazobactam, ceftriaxon, metronidazole und ciprofloxacin. CONCLUSIONS: Prescribing of antibiotics on almost every second day of hospitalization was extensive and highly variable, and the frequent use of cephalosporins is noteworthy. It is possible that the development of resistance and the rate of Clostridium difficile infection is associated with the diverse antibiotic use intensity and preferences for prescribing of cephalosporins and fluoroquinolones. Continuous antibiotic use surveillance and evaluation of prescribing patterns in acute care with feedback and benchmarking will help optimizing antibiotic use and better assessing strategies to minimize resistance and Clostridium difficile infection, and eventually improve patient safety.

[Surveillance of antibiotic consumption : clarification of the "definition of data on the nature and extent of antibiotic consumption in hospitals according to § 23 paragraph 4 sentence 2 of the IfSG"]. / Antibiotika-Verbrauchs-Surveillance : Ausführungen und Erläuterungen zur Bekanntmachung "Festlegung der Daten zu Art und Umfang des Antibiotika-Verbrauchs in Krankenhäusern nach § 23 Abs. 4 Satz 2 IfSG"

According to § 23 paragraph 4 of the German Infection Prevention Act (IfSG; July 2011), hospitals and clinics for ambulatory surgery are obliged to establish a continuous monitoring system of antibiotic consumption. This is aimed at contributing to an optimization of antibiotic prescription practices in order to confine the development and spread of resistant pathogens. The general requirements (restricted to hospitals) on the method and extent of data collection are provided by the national public health institution after discussion with representatives of various professional societies (Robert Koch-Institut, Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 59, 2013). The article aims to clarify these specifications and to provide background details. In agreement with national and European surveillance systems, the Anatomical Therapeutic Chemical (ATC)/Defined Daily Dose (DDD) classification system recommended by the WHO should be used as reference standard. Antibiotic consumption should be expressed as the number of DDDs per 100 patient days and per 100 admissions. The categories of antimicrobials and hospital organizational units to be monitored and the time intervals in which analyses should be conducted are determined. Furthermore, various approaches of data assessment are described.

Antibiotic use in non-university regional acute care general hospitals in southwestern Germany, 2001-2002.

BACKGROUND: A previous study from Germany showed high antibiotic use in university hospitals, particularly in intensive care units (ICU) and hematology-oncology services, but there has been no information about recent antibiotic use in non-university hospitals. In the present study, we collected data from 40 non-university regional general hospitals located in the southwestern part of the country, and analyzed use density in the medical and surgical services of these hospitals. MATERIALS AND METHODS: Hospital pharmacy records for the calendar years 2001 and 2002 were evaluated. The number of defined daily doses (DDD, definition according to the WHO/ATC 2001 index) and prescribed daily doses (PDD) per 100 patient days (DDD/100 or PDD/100, respectively) were calculated to compare antibiotic use densities in medical and surgical services. Data for surgery included various subspecialties and gynecology. RESULTS: Antibiotic use in the participating hospitals increased minimally between 2001 and 2002 both in medicine as well as in surgery. Use density in internal medicine (ICU areas excluded) in the year 2002 ranged between 13.5 and 93.7 DDD/100 with a weighted mean of 49.9 DDD/100 (corresponding to 28.6 PDD/100, respectively). Values for surgery were lower with a weighted mean of 43.4 DDD/100 (corresponding to 26.1 PDD/100, range, 10 to 65.4 DDD/100), respectively. Hospital size was not a strong predictor of use density, while large differences were observed between intensive care areas and normal wards. Mean use densities in intensive care areas in 2002 were 105.6 DDD/100 (or 49.7 PDD/100) in medical intensive care units, 116.9 DDD/100 (or 61.2 PDD/100) in surgical intensive care units, and 112.7 DDD/100 (or 66.7 PDD/100) in mixed, interdisciplinary intensive care units. Betalactams made up > 50% of all PDDs, while fluoroquinolones were the second most frequently prescribed drugs (15% of all PDDs). Fluoroquinolones were usually given orally. Overall glycopeptide and aminoglycoside use was < 1 PDD/100. CONCLUSION: This recent data from a large regional nonuniversity acute care hospital sample confirms that hospital antibiotic use density largely depends on patient care areas and less on hospital size. Surprisingly low use was observed for glycopeptides and aminoglycosides. The data may be useful as a benchmark for further pharmaco-epidemiologic evaluation and focused drug use control interventions.

Guidelines for anti-emetic therapy: acute emesis.

Anti-emetic therapy has become integral to the management of patients with cancer. Goals related to complete emesis control include providing treatment that reduces hospitalisation and time in the ambulatory setting, care that is convenient for the patient and therapy that enhances patients' quality of life. A panel of clinical, health economic and basic scientists with expertise in various oncology disciplines reviewed published literature to develop evidence-based consensus guidelines for the prevention and treatment of chemotherapy-induced emesis. Currently, serotonin receptor antagonists and corticosteroids are the two categories of anti-emetics that are most effective, have the fewest side-effects and are convenient to use. These agents are recommended in combination for highly emetogenic chemotherapy regimens and as single agents or in combination for moderately to highly emetogenic chemotherapy. When possible, these agents may be given orally in single doses; current evidence does not support dose escalation for either category of anti-emetics. In special situations, such as the use of high-dose chemotherapy combination regimens, the most emetogenic component of the regimen should dictate the choice of anti-emetic. Appropriate anti-emetic use described in these guidelines represents both good medical practice and a sensible economic approach to care.

Toxicodynamics of tumour promoters of mouse skin. II. Binding to protein kinase C of some new diterpene esters and induction of luminol-enhanced chemoluminescence in mouse peritoneal neutrophils.

In binding competition assays using a protein kinase C preparation from mouse brain (particulate fraction) 3H-labelled 12-O-tetradecanoylphorbol-13-acetate (TPA), for a series of new diterpene esters (DTE) the relative binding affinity [rba = Kia(TPA)/Kia(DTE)] in relation to TPA was determined. A wide range of values was noticed, some of the DTE binding more strongly than TPA (rba greater than 1), others binding less strongly than TPA (rba less than 1) In comparative terms, competition for specific binding sites appears to correlate better with irritant than with promoting activity of the DTE. Using mouse peritoneal neutrophils, binding of [3H]-TPA was determined by a modification of the "cold-acetone filter assay"; saturation of high-affinity sites (Kda = 0.2 nM) was obtained at concentrations less than or equal to 1 nM, but there was also evidence for specific binding at "low-affinity" sites (Kda = 26 nM). Induction of chemoluminescence in the presence of luminol in mouse peritoneal neutrophils with a set of DTE usually elecited two peaks; at concentrations greater than or equal to 10 nM DTE a short-lived, "spike-like" response lasting only from 0 to about 5 min (phase A) its followed by a "plateau" response from about 5-120 min (phase B). This latter phase of chemoluminescence stimulation with luminol correlated well with the irritant potential of the DTE used. The sequence of the two phases can be inverted partially by using first TPA at 2,5 nM followed by a quick concentration increase to 100 nM; this indicates two different concentration-dependent events. As regards the intensity of the chemoluminescent response, quantitative but not qualitative differences between DTE were observed, which show some correlation with strong and weak tumour-promoting activity. Inhibition studies suggest the involvement of the myeloperoxidase/H2O2/Cl- system in the luminogenic response; it is suggested that the release of hypochlorite or a closely related oxidant may be instrumental in tumour promotion.

Induction of Epstein-Barr virus early antigens by tumor promoters of the diterpene ester type in Raji cells and specific (receptor) binding as compared to irritant and promoting activities.

Sixteen new diterpene esters (DTE) of the tigliane, ingenane, daphnane, and 1 alpha-alkyldaphnane types were investigated in two in vitro assays: as inhibitors of specific binding of 3H-labeled 12-O-tetradecanoylphorbol 13-acetate (TPA) to protein kinase C in a receptor preparation from mouse brain, and as inducers of Epstein-Barr virus (EBV) early antigens in Raji cells. Inhibition of binding of [3H]TPA to the receptor preparation by tigliane and ingenane DTE correlates with irritant activity in vivo, while some daphnane and 1 alpha-alkyldaphnane DTE inhibit binding of [3H]TPA in a less pronounced manner but still are very irritant. Tumor-promoting activity does not correlate consistently with the receptor-binding data. To test the hypothesis that early antigen induction in Raji cells by DTE is coupled to functional DTE receptors (protein kinase C), the latter were searched on these Raji cells by a 'cold acetone-filter assay' and shown to be present. The dependence of the early antigen induction rate on the concentration of the DTE tested was demonstrated. At a given concentration of DTE, differences in the induction rate between various DTE are seen. However, a clear quantitative correlation either between early antigen induction and receptor binding data in vitro, or early-antigen-inducing activity in vitro versus irritancy and tumor-promoting activity in vivo was not observed.