Increased risk of acute stroke among patients with severe COVID-19: a multicenter study and meta-analysis.

BACKGROUND AND PURPOSE: Recent observations linked coronavirus disease 2019 (COVID-19) to thromboembolic complications possibly mediated by increased blood coagulability and inflammatory endothelial impairment. We aimed to define the risk of acute stroke in patients with severe and non-severe COVID-19. METHODS: We performed an observational, multicenter cohort study in four participating hospitals in Saxony, Germany to characterize consecutive patients with laboratory-confirmed COVID-19 who experienced acute stroke during hospitalization. Furthermore, we conducted a systematic review using PubMed/MEDLINE, Embase, Cochrane Library and bibliographies of identified papers following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines including data from observational studies of acute stroke in COVID-19 patients. Data were extracted by two independent reviewers and pooled with multicenter data to calculate risk ratios (RRs) and 95% confidence intervals (95% CIs) for acute stroke related to COVID-19 severity using a random-effects model. Between-study heterogeneity was assessed using Cochran's Q and I2 statistics. International Prospective Register of Systematic Reviews registration number: CRD42020187194. RESULTS: Of 165 patients hospitalized for COVID-19 (49.1% males, median age = 67 years [57-79 years], 72.1% severe or critical) included in the multicenter study, overall stroke rate was 4.2% (95% CI: 1.9-8.7). Systematic literature search identified two observational studies involving 576 patients that were eligible for meta-analysis. Amongst 741 pooled COVID-19 patients, overall stroke rate was 2.9% (95% CI: 1.9-4.5). Risk of acute stroke was increased for patients with severe compared to non-severe COVID-19 (RR = 4.18, 95% CI: 1.7-10.25; P = 0.002) with no evidence of heterogeneity (I2  = 0%, P = 0.82). CONCLUSIONS: Synthesized analysis of data from our multicenter study and previously published cohorts indicates that severity of COVID-19 is associated with an increased risk of acute stroke.

Mimicry of surgical site infection - Case report.

BACKGROUND CONTEXT: Calciphylaxis is a rare complication of secondary hyperparathyroidism caused by calcifications of small blood vessels in the skin and soft tissue. The disease occurs almost exclusively in patients with chronic kidney disease and has an incidence of approximately 50 cases per year in Germany [1]. PURPOSE: We present a case of a 61-year-old woman with calciphylaxis in connection with a primary knee endoprosthesis implantation. STUDY DESIGN: Case report. METHODS: A review of the medical records since the time of initial hospital admission throughout the entire hospitalization until the death of the patient was performed. RESULTS: Calciphylaxis caused severe soft tissue complications after total joint arthroplasty. Despite interdisciplinary therapy, including revision and plastic surgery as well as intensive care, the patient died 4 months after primary total knee arthroplasty due to septic multi-organ failure. CONCLUSION: Calciphylaxis may cause severe soft tissue complications after total joint arthroplasty and should be considered as potential differential diagnosis to surgical site infection. This is the first case report on calciphylaxis as direct complication of total joint replacement surgery.

[Antibiotic stewardship (ABS). Part 1: Basics]. / Antibiotic Stewardship (ABS). Teil 1: Grundlagen.

Against the background of increasing antimicrobial resistance, antibiotic stewardship (ABS) is an important measure to counteract the spread of resistant pathogens and multidrug resistance. For Germany and Austria, a comprehensive S3 guideline is available, which was last updated in 2018. The control of antibiotic or anti-infective use in hospitals should be guided by specialized ABS teams. At the hospital level, ABS also includes a structured ongoing analysis of local antibiotic use and resistance data. Recommendations for locally adapted therapy regimens should be derived and implemented from this data analysis. ABS consists of regular ward rounds ("ABS visits"), during which members of the ABS team review the indication, dosage, route of administration and duration of antimicrobial therapy at the bedside. Here, the key challenge is to save antibiotics without compromising the individual patient. Digitalization and artificial intelligence offer new options for ABS, while the adaption of inpatient concepts to outpatient care is also important.

[Antibiotic stewardship (ABS). Part 2: Application]. / Antibiotic Stewardship (ABS). Teil 2: Anwendung.

Antibiotic stewardship (ABS) is an important measure to counteract the spread of resistant pathogens and multidrug resistance. The most important ABS tools include the implementation of local guidelines, the development of a house-related list of anti-infective agents, regular ABS visits and practice-oriented internal training events. Effective strategies for therapy optimization include indication testing and therapy evaluation, dose optimization as well as determining an appropriate duration of therapy. Oralization of anti-infectives (sequence therapy) should be supported by consistent clinical criteria in in-house guidelines. The incidence of Clostridioides difficile infections (CDI) can be more than halved by restricting the so-called "4C antibiotics". Point-of-care tests help to minimize the use of antibiotics in the outpatient setting. Vaccination reduces the need for antibiotic therapy.

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.

[Antibiotic stewardship: Measures for optimization of antibacterial therapy]. / Antibiotic Stewardship: Maßnahmen zur Optimierung der antibakteriellen Therapie.

Because the development of resistance is steadily increasing, especially among Gram-negative pathogens and new developments in antibiotics are lacking, a rational antibiotic therapy is necessary now more than ever. A continuing uncritical and non-guideline-conform use of antibiotics leads to selection of multidrug-resistant pathogens, which can colonize patients and as instigators of infections make treatment more difficult. A prerequisite for targeted antibiotic therapy is a critical testing of the suspected infection diagnosis based on a guideline-conform microbiological preanalytical procedure. To promote a guideline-conform antibiotic therapy in hospitals with respect to choice of substance, dosage and duration, in December 2013 so-called antibiotic stewardship (ABS) measures were summarized in a so-called S3-guideline from the Association of the Scientific Medical Societies in Germany (AWMF) under the auspices of the German Society for Infectious Diseases (DGI). With a strategy of targeted antibiotic therapy and infection prevention it is possible to achieve optimum treatment results and to minimize the development of resistance.

[Can the antibiotic prescription practice in a hospital be influenced by in-house guidelines? An interventional study at the University Hospital Halle (Saale), Germany]. / Lässt sich die Antibiotikaverordnungspraxis im Krankenhaus durch hausinterne Richtlinien beeinflussen? Interventionsstudie am Universitätsklinikum Halle (Saale).

BACKGROUND: In-house guidelines are an essential tool of antibiotic stewardship (ABS) programs to guide antimicrobial therapy. We studied the effect of in-house guidelines adapted to the local pathogen and resistance epidemiology on prescribing behavior. METHODS: At the University Hospital Halle (Saale) guidelines for the antimicrobial therapy and essential microbiological diagnostics were introduced. Main objectives were reducing the use of third generation cephalosporines and fluoroquinolones, decreasing selection pressure for enterococci and multidrug-resistant Gram-negative bacteria, minimizing Clostridium difficile infections (CDI), and improving microbiological diagnostics to enhance de-escalation strategies. 12 months thereafter a comparison of antibiotic consumption, pathogen and resistance statistics and use of blood cultures was performed. RESULTS: There was a decrease of third-generation cephalosporines (-18.6%) and fluoroquinolones (-9.8%), while consumption of broad- and intermediate-spectrum penicillins (+23.8% and +37%) as well as carbapenems (+11.9%) increased. The total volume of prescribed anti-infectives remained unchanged. The number of enterococcal isolates (-18.3%) and CDI (-26.3%) decreased considerably. Gram-negatives, particulary ESBL-producing Enterobacteriaceae, were detected more frequently due to an expanded screening program. The rate of blood cultures/1000 patient-days was unaffected. CONCLUSION: In-house guidelines for the empiric antiinfective therapy appear to be suitable to influence the prescribing behavior and the selection pressure on individual pathogen groups. The total volume of antibiotic prescriptions was not affected in this study.

Selection of hospital antimicrobial prescribing quality indicators: a consensus among German antibiotic stewardship (ABS) networkers.

PURPOSE: Simple, valid, and evidence-based indicators to measure the quality of antimicrobial prescribing in acute-care hospitals are urgently needed and increasingly requested by policymakers. The aim of this study was to develop new consensus quality indicators (QIs) for hospital antibiotic stewardship (ABS) and infection management which will be further evaluated for internal quality management and external quality assessment in Germany. METHODS: Based on an extensive literature review, the Austrian-German hospital ABS Guideline Committee and selected members of the German ABS Expert Network discussed and drafted a list of 99 potential indicators for hospitals that reflect structural prerequisites for ABS (35 items), ABS core activities (18 items), additional ABS measures (5 items), and process of care indicators (both generic and disease-specific-12 and 29 items, respectively). Questionnaires were mailed to German ABS experts and healthcare professionals with further education in ABS. Participants scored (on a nine-point Likert scale) relevance (clinical, ecological/resistance, economical/expenses) and presumed practicability (six categories: clarity of definition, effort to collect data, barrier to implementation, verifiability, suitability for external quality assessment, quality gap), taking into account their local work environment. The scores were processed according to the RAND/UCLA appropriateness method, and QIs were judged relevant if the median (clinical + ecological and/or economical) scores were >6. The indicators thus assessed to be potentially relevant were then filtered according to their practicability. Highly relevant QIs with borderline practicability scores and items with disagreements and overlapping areas were re-discussed in a final multidisciplinary panel consensus workshop convened in November 2012. RESULTS: Of the 340 questionnaires that were mailed, 75 questionnaires were completed and returned. Of 99 initially proposed items, 32 were excluded due to insufficient scores. Of the remaining 67 items, 21 structural and 21 process of care QIs were finally selected, including four QIs with high clinical and ecological but limited economical relevance, and three QIs with high clinical and economical but limited ecological relevance. Among the selected QIs, efforts to collect data and implementation barriers were scored as suboptimal in many cases. CONCLUSIONS: A catalog of consensus structural and process of care ABS-QIs was established. These should undergo further pilot and feasibility studies in the German hospital healthcare sector. The panelists were most critical regarding resource use/complexity issues and presumed implementation barriers. How this may limit applicability of QIs remains to be determined.

[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.

[Rational antibiotic prescribing. Challenges and successes]. / Rationale Antibiotikaverordnung. Mehr Herausforderungen als Erfolge.

Rational and prudent antibiotic prescribing strategies are important both for the hospital sector as well as for ambulatory medicine. Prerequisites are the availability of antibiotic use and antibiotic resistance data and of infrastructure and trained personnel needed for implementing and evaluating antibiotic policies. Currently, these requirements are not being met sufficiently in Germany. A major challenge in this country is the lack of adequately trained and experienced personnel. On the other hand there are several projects and initiatives supported in part within the national antibiotic resistance control program which have produced some progress and success. One example is GERMAP, the national antibiotic use and resistance atlas covering both human medicine and the veterinary field. Other examples are the recently improved program for continuous hospital antibiotic use, surveillance and feedback and the Antibiotic Stewardship (ABS) training program with establishment of an ABS expert network. Future perspectives include programs for evaluation of practice guideline adherence and the development and evaluation of quality of care indicators. Intermediate and long-term investment is needed in specialty training and certification of a sufficient number of infectious disease physicians, medical microbiologists and infection control doctors/hospital epidemiologists and hospital pharmacists.

Comparison of defined versus recommended versus prescribed daily doses for measuring hospital antibiotic consumption.

BACKGROUND: Hospital antibiotic use is usually measured by calculating the volume as the number of daily doses defined by the World Health Organization/Anatomical Therapeutic Chemical (WHO/ATC) index (DDDs) divided by a denominator indicating clinical activity, such as the number of occupied bed days. Previous studies have found discrepancies between DDDs, daily doses as recommended in practice guidelines (recommended daily doses, RDDs), and truly prescribed daily doses (PDDs). Very few studies have quantified these discrepancies. METHODS: A point prevalence survey was carried out in defined acute care service areas of a large German state university hospital. Of the 941 adult inpatients present on the day of the survey for whom adequate information was available, 267 (28%) had 471 prescriptions for antimicrobial drugs on that specific day. A check for any additional antimicrobial drug prescriptions for these 267 patients during the six days immediately preceding the survey day yielded a total of 2,304 PDDs, of which 1,754 were antibacterial agents. The latter antibacterial drug PDDs constituted the basis for analysis. The proportion of PDDs different from RDDs and from DDDs was evaluated, and the deviations were calculated. RDD dose definitions corresponded to the local practice guideline recommendations of antibiotic therapy for adult hospitalized patients with normal renal function. RESULTS: Of the 1,754 PDDs, 625 were matching DDD dose definitions (36%), and 1,024 (58%) were matching RDD dose definitions (p < 0.01). Corresponding values for patients with impaired renal function (creatinine clearance < 50 ml/min) were 36% and 42%, respectively. Large DDD discrepancies (< 50% of prescribed doses matching DDD definitions) were noted for beta-lactams and macrolides, while large RDD discrepancies were observed for aminoglycosides. Compared with PDDs, the use of DDDs as the measurement of hospital antibiotic use overestimated antibiotic use volumes by 32%, while the use of RDD led to a slight underestimation (-9%). CONCLUSION: The use of DDDs as currently defined by WHO/ATC for measuring hospital antibiotic consumption may be associated with a substantial overestimation of antibiotic use density, while using practice guideline-derived RDDs may yield more valid antibiotic exposure estimates that would be helpful in cross-sectional and longitudinal analyses of antibiotic consumption.

Regional variation in outpatient antibiotic prescribing in Germany.

OBJECTIVE: According to recent surveys, outpatient antibiotic prescribing in Germany has been comparatively low among European countries. We assessed regional variation in outpatient antibiotic use within Germany both for overall use as well as for specific antibiotic drug classes. METHODS: Prescription data for the year 2003 covering approximately 90% of the total population were analysed using the ATC/WHO defined daily dose (DDD) methodology. Data were expressed in DDD per 1,000 persons covered by the insurance and day (DID). RESULTS: Outpatient antibiotic prescribing in 2003 was 13.6 DID and ranged between 9.2 and 17.9 DID in the different regions examined. Low consumption regions were eastern and southern states. High consumption areas were in the west near the French and Belgian border. This regional prescribing pattern was similar for children and adults. Penicillins were the most frequent prescribed drugs, but their use density showed a relatively large regional variation (factor 3.5), with relatively low prescription frequency in the eastern states. In almost all regions quinolones were used more often than trimethoprim-sulfamethoxazole. CONCLUSION: The regional variation in recent outpatient antibiotic prescribing in Germany is substantial. The relatively high antibiotic use in the western part of the country is remarkable, remains unexplained and requires further study.

Is there significant regional variation in hospital antibiotic consumption in Germany?

OBJECTIVE: Outpatient antibiotic use in Germany differs substantially between eastern and southern parts of the country (low use) and the western part (high use). Whether similar regional variation exists in hospital antibiotic consumption is not known. We investigated this issue using a convenience sample of 145 hospitals providing data for the year 2003. METHODS: Data on hospital consumption of systemic antibiotics in Anatomical Therapeutic Chemical (ATC) class J01 were obtained from acute care hospitals that participated in an IMS survey and had complete data (dispensed drugs and patient-days per year) for at least one non-pediatric, non-psychiatric department or ward. A total of 275 non-ICU surgical departments/wards, 229 non-ICU non-surgical (general medicine, haematology-oncology, neurology/stroke) departments/wards, and 184 ICUs were analysed. Data were expressed in DDD (WHO/ATC definition version 2003) or daily doses adapted for recommendations in hospitalized patients (RDD) per 100 patient days (DDD/100 and RDD/100). FINDINGS: The weighted mean over all departments/wards was 49.6 DDD/100 or 31.3 RDD/100, respectively. As expected, ICU antibiotic use density was much higher than use in non-ICU areas, and use in haematology-oncology was higher than in other non-surgical departments/wards. In univariate analyses, region, hospital bed-size category, university affiliation and haematology-oncology as specialty were associated with use density, but these associations were only partly confirmed in multivariate logistic regression analyses of factors associated with excess (> or = 75%) use density which showed university affiliation and haematology-oncology but not hospital location to be independently associated with comparatively high use. CONCLUSIONS: Antibiotic use density in German acute care hospitals does not appear to differ significantly between regions. Overall hospital consumption of antibiotics in this country appears to be similar to what has been described from other parts of Europe. In comparative analyses of hospital antibiotic consumption, data need to be adjusted at least for university affiliation and haematology-oncology.

Antibiotic use in two cohorts of German intensive care units.

Antibiotic use was evaluated in two cohorts of intensive care units (ICUs) in Germany. One cohort included ICUs participating in a surveillance programme (N=34) collecting antibiotic use and bacterial resistance data, with quarterly feedback. The second ICU cohort was from a cross-sectional study and represented a sample from hospitals in South-west Germany (N=58). Two dose definitions were used. These were the World Health Organization/Anatomical Therapeutic Chemical Classification (ATC) 2001 definition of defined daily dose (DDD), and a definition of recommended daily dose (RDD) that better reflected the currently prescribed dosages of parenteral drugs for hospitalized patients. Data were expressed as DDD or RDD per 100 patient-days. It was determined whether hospital size and affiliation, year of study and ICU type had an influence on overall use of antibiotics. Overall use differed between the two ICU cohorts irrespective of the dose definitions used. High use of antibiotics was primarily associated with hospital affiliation (university vs non-university) and hospital size. Mean overall use of antibiotics in non-university hospital ICUs ranged between 106 and 111 DDD/100 (59 and 67 RDD/100) for different hospital size categories, compared with 140 DDD/100 (87 RDD/100) in university hospital ICUs. In conclusion, in order to compare the use of antibiotics between ICU cohorts and to assess trends over time, data adjustment is required for hospital affiliation and size.

Trends in antibiotic use at a university hospital: defined or prescribed daily doses? Patient days or admissions as denominator?

BACKGROUND: Hospital antibiotic use can be measured by calculating daily doses as defined by the WHO/ATC index (DDD) divided by the number of patient or occupied bed days. We wondered whether changes in antibiotic use density over time at a university hospital using this data format are similar in order of magnitude when compared with a different, alternative dose definition and the number of admissions rather than the number of patient days as denominator. METHODS: Data obtained from the hospital pharmacy for the medical and surgical services of a 1,000-bed university hospital for the period 1992 through 2003 were expressed both in daily doses per 100 patient days and daily doses per admission. A PDD dose definition (prescribed daily doses), defining doses that reflect the usually prescribed dose in adult hospitalized patients with normal renal function was compared with the WHO/ATC 2001 DDD dose definitions. The percent changes using the different data formats between two 3-year averages (1992-1994 and 2001-2003) were calculated. RESULTS AND CONCLUSION: The DDD/100 patient days data format overestimated antibiotic use density changes in this hospital both in medicine (81% vs 48%) as well as in surgery (69% vs 39%) when compared with PDD/100 patient days. Due to changes in the number of admissions and length of stay over the years, the percent change between the two periods expressed in doses per 100 patient days in addition differed substantially from that estimated by using the DDD per admission or PDD per admission data format. Studies evaluating the evolution of hospital antibiotic use need to address the limitations and adequacy of the different data formats.