Clinical epidemiology and case fatality due to antimicrobial resistance in Germany: a systematic review and meta-analysis, 1 January 2010 to 31 December 2021

Background Antimicrobial resistance (AMR) is of public health concern worldwide. Aim We aimed to summarise the German AMR situation for clinicians and microbiologists. Methods We conducted a systematic review and meta-analysis of 60 published studies and data from the German Antibiotic-Resistance-Surveillance (ARS). Primary outcomes were AMR proportions in bacterial isolates from infected patients in Germany (2016–2021) and the case fatality rates (2010–2021). Random and fixed (common) effect models were used to calculate pooled proportions and pooled case fatality odds ratios, respectively. Results The pooled proportion of meticillin resistance in Staphylococcus aureus infections (MRSA) was 7.9% with a declining trend between 2014 and 2020 (odds ratio (OR) = 0.89; 95% CI: 0.886–0.891; p  70%) across studies reporting resistance proportions. Conclusion Continuous efforts in AMR surveillance and infection prevention and control as well as antibiotic stewardship are needed to limit the spread of AMR in Germany.Peer Reviewe

Detection of pneumonia associated pathogens using a prototype multiplexed pneumonia test in hospitalized patients with severe pneumonia

Severe pneumonia remains an important cause of morbidity and mortality. Polymerase chain reaction (PCR) has been shown to be more sensitive than current standard microbiological methods--particularly in patients with prior antibiotic treatment--and therefore, may improve the accuracy of microbiological diagnosis for hospitalized patients with pneumonia. Conventional detection techniques and multiplex PCR for 14 typical bacterial pneumonia-associated pathogens were performed on respiratory samples collected from adult hospitalized patients enrolled in a prospective multi-center study. Patients were enrolled from March until September 2012. A total of 739 fresh, native samples were eligible for analysis, of which 75 were sputa, 421 aspirates, and 234 bronchial lavages. 276 pathogens were detected by microbiology for which a valid PCR result was generated (positive or negative detection result by Curetis prototype system). Among these, 120 were identified by the prototype assay, 50 pathogens were not detected. Overall performance of the prototype for pathogen identification was 70.6% sensitivity (95% confidence interval (CI) lower bound: 63.3%, upper bound: 76.9%) and 95.2% specificity (95% CI lower bound: 94.6%, upper bound: 95.7%). Based on the study results, device cut-off settings were adjusted for future series production. The overall performance with the settings of the CE series production devices was 78.7% sensitivity (95% CI lower bound: 72.1%) and 96.6% specificity (95% CI lower bound: 96.1%). Time to result was 5.2 hours (median) for the prototype test and 43.5 h for standard-of-care. The Pneumonia Application provides a rapid and moderately sensitive assay for the detection of pneumonia-causing pathogens with minimal hands-on time

Therapierelevante Antibiotikaresistenzen im One-Health-Kontext

„One Health“ bezeichnet ein Konzept, das die Gesundheit von Menschen, Tieren und der Umwelt miteinander verbindet. In Deutschland gibt es umfangreiche Daten zur Antibiotikaresistenz (AMR) und multiresistenten Erregern (MRE) in der Human- und Veterinärmedizin sowie aus Untersuchungen in verschiedenen Umweltkompartimenten (Boden, Wasser, Abwasser). Die Erhebung erfolgt nach unterschiedlichen Vorgaben und Standards, was den Vergleich von Daten erschwert. Ein Fokus auf humantherapeutisch wichtige AMR und MRE ist hilfreich, um eine gewisse Orientierung vorzugeben. Die meisten Daten liegen sektorübergreifend zu Methicillin-resistenten Staphylococcus aureus und multiresistenten Enterobacterales wie Escherichia coli und Klebsiella pneumoniae vor. Hier sind die Trends der Resistenzen heterogen. Der Einsatz von Antibiotika führt zur Selektion von MRE, was gut dokumentiert ist. Erfolge bei der Minimierung des Antibiotikaeinsatzes konnten in zurückliegenden Jahren für einzelne Sektoren dargestellt und z. T. mit Erfolgen in der Eindämmung von AMR und MRE korreliert werden (Rückgang MRSA in der Humanmedizin). Auch sektorspezifische Maßnahmen zur Senkung der Last durch MRE und AMR sind notwendig, da Resistenzprobleme nicht generell eine Verknüpfung mit anderen Sektoren aufweisen. Carbapenemresistenzen sind vor allem bei pathogenen Erregern vom Menschen nachweisbar. Colistinresistenzen kommen in verschiedenen Sektoren vor, zeigen aber dort jeweils verschiedene Mechanismen. Resistenzen gegen Reservesubstanzen wie Linezolid sind in Deutschland selten, sie zeigen aber einen konkreten One-Health-Bezug. Bestrebungen zur Harmonisierung von Methoden, z. B. im Bereich der antimikrobiellen Empfindlichkeitstestung und genombasierten Erreger- und AMR-Surveillance, sind ein wichtiger erster Schritt zu einer Vergleichbarkeit der verschiedenen Datenerhebungen.One Health refers to a concept that links human, animal, and environmental health. In Germany, there is extensive data on antibiotic resistance (AMR) and multidrug-resistant (micro)organisms (MDRO) in human and veterinary medicine, as well as from studies in various environmental compartments (soil, water, wastewater). All these activities are conducted according to different specifications and standards, which makes it difficult to compare data. A focus on AMR and MDRO of human therapeutic importance is helpful to provide some guidance. Most data are available across sectors on methicillin-resistant Staphylococcus aureus (MRSA) and multiresistant Enterobacterales such as Escherichia coli and Klebsiella pneumoniae. Here, the trends of resistance are heterogeneous. Antibiotic use leads to MRE selection, which is well documented. Success in minimizing antibiotic use has also been demonstrated in recent years in several sectors and could be correlated with success in containing AMR and MDRO (e.g., decrease in MRSA in human medicine). Sector-specific measures to reduce the burden of MDRO and AMR are also necessary, as not all resistance problems are linked to other sectors. Carbapenem resistance is still rare, but most apparent in human pathogens. Colistin resistance occurs in different sectors but shows different mechanisms in each. Resistance to antibiotics of last resort such as linezolid is rare in Germany, but shows a specific One Health correlation. Efforts to harmonize methods, for example in the field of antimicrobial susceptibility testing and genome-based pathogen and AMR surveillance, are an important first step towards a better comparability of the different data collections.Peer Reviewe

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

EBV miRNA expression profiles in different infection stages: A prospective cohort study.

The Epstein-Barr virus (EBV) produces different microRNAs (miRNA) with distinct regulatory functions within the infectious cycle. These viral miRNAs regulate the expression of viral and host genes and have been discussed as potential diagnostic markers or even therapeutic targets, provided that the expression profile can be unambiguously correlated to a specific stage of infection or a specific EBV-induced disorder. In this context, miRNA profiling becomes more important since the roles of these miRNAs in the pathogenesis of infections and malignancies are not fully understood. Studies of EBV miRNA expression profiles are sparse and have mainly focused on associated malignancies. This study is the first to examine the miRNA profiles of EBV reactivation and to use a correction step with seronegative patients as a reference. Between 2012 and 2017, we examined the expression profiles of 11 selected EBV miRNAs in 129 whole blood samples from primary infection, reactivation, healthy carriers and EBV seronegative patients. Three of the miRNAs could not be detected in any sample. Other miRNAs showed significantly higher expression levels and prevalence during primary infection than in other stages; miR-BHRF1-1 was the most abundant. The expression profiles from reactivation differed slightly but not significantly from those of healthy carriers, but a specific marker miRNA for each stage could not be identified within the selected EBV miRNA targets

The German Quality Network Sepsis: Evaluation of a Quality Collaborative on Decreasing Sepsis-Related Mortality in a Controlled Interrupted Time Series Analysis

Background Sepsis is one of the leading causes of preventable deaths in hospitals. This study presents the evaluation of a quality collaborative, which aimed to decrease sepsis-related hospital mortality. Methods The German Quality Network Sepsis (GQNS) offers quality reporting based on claims data, peer reviews, and support for establishing continuous quality management and staff education. This study evaluates the effects of participating in the GQNS during the intervention period (April 2016–June 2018) in comparison to a retrospective baseline (January 2014–March 2016). The primary outcome was all-cause risk-adjusted hospital mortality among cases with sepsis. Sepsis was identified by International Classification of Diseases (ICD) codes in claims data. A controlled time series analysis was conducted to analyze changes from the baseline to the intervention period comparing GQNS hospitals with the population of all German hospitals assessed via the national diagnosis-related groups (DRGs)-statistics. Tests were conducted using piecewise hierarchical models. Implementation processes and barriers were assessed by surveys of local leaders of quality improvement teams. Results Seventy-four hospitals participated, of which 17 were university hospitals and 18 were tertiary care facilities. Observed mortality was 43.5% during baseline period and 42.7% during intervention period. Interrupted time-series analyses did not show effects on course or level of risk-adjusted mortality of cases with sepsis compared to the national DRG-statistics after the beginning of the intervention period (p = 0.632 and p = 0.512, respectively). There was no significant mortality decrease in the subgroups of patients with septic shock or ventilation >24 h or predefined subgroups of hospitals. A standardized survey among 49 local quality improvement leaders in autumn of 2018 revealed that most hospitals did not succeed in implementing a continuous quality management program or relevant measures to improve early recognition and treatment of sepsis. Barriers perceived most commonly were lack of time (77.6%), staff shortage (59.2%), and lack of participation of relevant departments (38.8%). Conclusion As long as hospital-wide sepsis quality improvement efforts will not become a high priority for the hospital leadership by assuring adequate resources and involvement of all pertinent stakeholders, voluntary initiatives to improve the quality of sepsis care will remain prone to failure

Detection of pneumonia associated pathogens using a prototype multiplexed pneumonia test in hospitalized patients with severe pneumonia

Severe pneumonia remains an important cause of morbidity and mortality. Polymerase chain reaction (PCR) has been shown to be more sensitive than current standard microbiological methods--particularly in patients with prior antibiotic treatment--and therefore, may improve the accuracy of microbiological diagnosis for hospitalized patients with pneumonia. Conventional detection techniques and multiplex PCR for 14 typical bacterial pneumonia-associated pathogens were performed on respiratory samples collected from adult hospitalized patients enrolled in a prospective multi-center study. Patients were enrolled from March until September 2012. A total of 739 fresh, native samples were eligible for analysis, of which 75 were sputa, 421 aspirates, and 234 bronchial lavages. 276 pathogens were detected by microbiology for which a valid PCR result was generated (positive or negative detection result by Curetis prototype system). Among these, 120 were identified by the prototype assay, 50 pathogens were not detected. Overall performance of the prototype for pathogen identification was 70.6% sensitivity (95% confidence interval (CI) lower bound: 63.3%, upper bound: 76.9%) and 95.2% specificity (95% CI lower bound: 94.6%, upper bound: 95.7%). Based on the study results, device cut-off settings were adjusted for future series production. The overall performance with the settings of the CE series production devices was 78.7% sensitivity (95% CI lower bound: 72.1%) and 96.6% specificity (95% CI lower bound: 96.1%). Time to result was 5.2 hours (median) for the prototype test and 43.5 h for standard-of-care. The Pneumonia Application provides a rapid and moderately sensitive assay for the detection of pneumonia-causing pathogens with minimal hands-on time

Pathogen performance of the multiplexed prototype assay [including discrepant results resolution in brackets].

a<p>true positive: positive in microbiological standard-of-care testing and positive in the multiplexed assay.</p>b<p>false negative: positive in microbiological standard-of-care testing and negative in the multiplexed assay.</p>c<p>false positive: negative in microbiological standard-of-care testing and positive in the multiplexed assay.</p>d<p>true negative: negative in microbiological standard-of-care testing and negative in the multiplexed assay.</p>e<p>positive predictive value.</p>f<p>negative predictive value [confirmed FN and FP in brackets].</p><p>* confirmation of <i>Streptococcus</i>: only as "<i>Streptococcus</i> spp."</p><p>Additional pathogens not covered by the multiplexed assay: 114 yeasts (including 85 <i>Candida</i> spp.), 7 other fungi, 9 <i>Citrobacter</i> spp., 49 coagulase neg. staphylococci, 34 enterococci, 35 streptococci (mostly <i>viridans</i> group), 8 other Gram-positive bacteria (<i>Leuconostoc</i> spp., <i>Rothia</i> spp., <i>Corynebacterium</i> spp.), 3 <i>Pseudomonas</i> spp., 10 <i>Neisseria</i> spp., 3 <i>Haemophilus</i> spp., 10 <i>Citrobacter</i> spp., 7 other Gram-negative bacteria (<i>Ralstonia</i> spp., <i>Achromobacter</i> spp., <i>Burkholderia</i> spp., <i>Raoultella</i> spp., <i>Serratia</i> spp.).</p><p>Pathogen performance of the multiplexed prototype assay [including discrepant results resolution in brackets].</p