Search

Background Patients with hematological malignancies are at an increased risk of SARS‐CoV‐2 disease (COVID‐19) and adverse outcome. However, a low mortality rate has been reported in patients with chronic myeloid leukemia (CML). Preclinical evidence suggests that tyrosine kinase inhibitors (TKIs) may have a protective role against severe COVID‐19. Methods We conducted a cross‐sectional study of 564 consecutive patients with CML who were tested for anti‐SARS‐CoV‐2 IgG/IgM antibodies at their first outpatient visit between May and early November 2020 in five hematologic centers representative of three Italian regions. Results The estimated serological prevalence of SARS‐CoV‐2 infection in patients with CML after the first pandemic wave was similar to that in the general population (about 2%), both at national and regional levels. CML patients with positive anti‐SARS‐CoV‐2 serology were more frequently male (p = 0.027) and active workers (p = 0.012), while there was no significant association with TKI treatment type. Only 3 out of 11 IgG‐positive patients had previously received a molecular diagnosis of COVID‐19, while the remainders were asymptomatic or with mild symptoms. Conclusions Our data confirm that the course of SARS‐CoV‐2 infection in patients with CML is generally mild and reassure about the safety of continuing TKIs during the COVID‐19 pandemic. Furthermore, we suggest that patients with CML succeed to mount an antibody response after exposure to SARS‐CoV‐2, similar to the general population., The estimated serological prevalence of SARS‐CoV‐2 infection in patients with CML after the first pandemic wave was similar to that of the general population (about 2% in Italy). Our data reassure about the safety of continuing TKI treatment during the ongoing pandemic and suggest that patients with CML succeed to mount an antibody response against SARS‐CoV‐2 whether on TKI treatment or not.

Introduction To better define COVID-19 long-term impact we prospectively analysed patient-centred outcomes, including general health and symptom duration. Methods Barthel index (BI), St. George’s Respiratory Questionnaire adapted to patients with COVID-19 (aSGRQ) and WHO Clinical Progression Scale (CPS) were measured at enrolment and at 6 weeks from the onset of symptoms. Persistence of most frequently reported symptoms was assessed at 6 weeks and, among symptomatic patients, at 12 weeks from the onset of symptoms. Predictors of impaired general health over time were identified using an ordinal multilevel multivariate model. Results A total of 448 patients (55% men, median age 56 years) were enrolled. WHO-CPS showed mild, moderate and severe disease in 48%, 42% and 10% of patients at admission and mild disease in all patients at follow-up, respectively. BI and aSGRQ were normal in 96% and 93% patients before COVID-19 but only in 47% and 16% at COVID-19 diagnosis and in 87% and 65% at 6-week follow-up. Male gender was identified by all three assessments as a predictor of impaired general health (BI, OR 2.14, p

Background Management and control of coronavirus disease 2019 (COVID-19) relies on reliable diagnostic testing. Objectives To evaluate the diagnostic test accuracy (DTA) of nucleic acid amplification tests (NAATs) for the diagnosis of coronavirus infections. Data sources PubMed, Web of Science, the Cochrane Library, Embase, Open Grey and conference proceeding until May 2019. PubMed and medRxiv were updated for COVID-19 on 31st August 2020. Study eligibility Studies were eligible if they reported on agreement rates between different NAATs using clinical samples. Participants Symptomatic patients with suspected upper or lower respiratory tract coronavirus infection. Methods The new NAAT was defined as the index test and the existing NAAT as reference standard. Data were extracted independently in duplicate. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Confidence regions (CRs) surrounding summary sensitivity/specificity pooled by bivariate meta-analysis are reported. Heterogeneity was assessed using meta-regression. Results Fifty-one studies were included, 22 of which included 10 181 persons before COVID-19 and 29 including 8742 persons diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The overall summary sensitivity was 89.1% (95%CR 84.0–92.7%) and specificity 98.9% (95%CR 98.0–99.4%). Nearly all the studies evaluated different PCRs as both index and reference standards. Real-time RT PCR assays resulted in significantly higher sensitivity than other tests. Reference standards at high risk of bias possibly exaggerated specificity. The pooled sensitivity and specificity of studies evaluating SARS-COV-2 were 90.4% (95%CR 83.7–94.5%) and 98.1% (95%CR 95.9–99.2), respectively. SARS-COV-2 studies using samples from the lower respiratory tract, real-time RT-PCR, and tests targeting the N or S gene or more than one gene showed higher sensitivity, and assays based on reverse transcriptase loop-mediated isothermal amplification (RT-LAMP), especially when targeting only the RNA-dependent RNA polymerase (RdRp) gene, showed significantly lower sensitivity compared to other studies. Conclusions Pooling all studies to date shows that on average 10% of patients with coronavirus infections might be missed with PCR tests. Variables affecting sensitivity and specificity can be used for test selection and development.

Background The health impact of antimicrobial resistance (AMR) has not been included in the Global Burden of Disease (GBD) report, as reliable data have been lacking. AMR burden estimates have been derived from models combining incidence and/or prevalence data from national and/or international surveillance systems and mortality estimates from clinical studies. Depending on utilized empirical data, statistical methodology and applied endpoints, the validity and reliability of results can differ substantially. Objectives We assessed comprehensiveness, and internal and external validity of studies estimating the clinical impact of infections caused by the priority antibiotic resistant pathogens monitored by the WHO Global Antimicrobial Resistance Surveillance System. Data sources Ovid MEDLINE, January 1950 to March 2019, In-Process and other non-indexed citations were searched. Study eligibility criteria Studies reporting mortality, length of hospital stay, duration of the disease until remission and/or death, complications, hospital re-admissions, and follow-up beyond hospital discharge were eligible. Methods The literature was searched according to the Cochrane recommendations and reported according to Preferred Reporting Items for Systematic Reviews. Results Two-hundred and eighty-six studies out of 3529 were eligible. Studies derived mainly from high-income countries (215, 75%) and relied on data from retrospective (226, 79%), single-centre (201, 70%), cohort studies (243, 85%). The health impact was mostly limited to all-cause mortality (128, 45%) with heterogeneity in timing of assessment; attributable length of hospital stay was seldom adjusted for pre-infection admission time and a few studies had enough follow-up for assessing long-term sequelae. Overall, adjustment for confounding has shown a substantial improvement. Data on health state definitions and duration of diseases are generally lacking, precluding calculation of disability-adjusted life years, critical for application of the GBD study methodology. Conclusion Efforts to improve harmonization, representativeness, quality of AMR surveillance data and cohort studies to determine AMR attributable mortality and morbidity are urgently required. Policy makers need accurate and detailed burden estimates to inform prioritization of resource allocation, and to select the most effective intervention strategies to halt the AMR crisis.

Background The outpatient setting is a key scenario for the implementation of antimicrobial stewardship (AMS) activities, considering that overconsumption of antibiotics occurs mainly outside hospitals. This publication is the result of a joint initiative by the JPIAMR ARCH and COMBACTE-MAGNET EPI-Net networks, which is aimed at formulating a set of target actions for linking surveillance data with AMS activities in the outpatient setting. Methods A scoping review of the literature was carried out in three research areas: AMS leadership and accountability; antimicrobial usage and AMS; antimicrobial resistance and AMS. Consensus on the actions was reached through a RAND-modified Delphi process involving over 40 experts in infectious diseases, clinical microbiology, AMS, veterinary medicine or public health, from 18 low-, middle- and high-income countries. Results Evidence was retrieved from 38 documents, and an initial 25 target actions were proposed, differentiating between essential or desirable targets according to clinical relevance, feasibility and applicability to settings and resources. In the first consultation round, preliminary agreement was reached for all targets. Further to a second review, 6 statements were re-considered and 3 were deleted, leading to a final list of 22 target actions in the form of a practical checklist. Conclusions This White Paper is a pragmatic and flexible tool to guide the development of calibrated surveillance-based AMS interventions specific to the outpatient setting, which is characterized by substantial inter- and intra-country variability in the organization of healthcare structures, maintaining a global perspective and taking into account the feasibility of the target actions in low-resource settings.

Since the widespread of acute respiratory syndrome infection caused by Coronavirus-19 unenhanced computed tomography (CT) was considered an useful imaging tool commonly used in early diagnosis and monitoring of patients with complicated COVID-19 pneumonia. Many typical imaging features of this disease were described such as bilateral multilobar ground-glass opacification (GGO) with a prevalent peripheral or posterior distribution, mainly in the lower lobes, and sometimes consolidative opacities superimposed on GGO. As less common findings were mentioned septal thickening, bronchiectasis, pleural thickening, and subpleural involvement. After 3 months from the onset of COVID-19 pneumonia some studies published the evolution of imaging features of COVID-19 pneumonia such as an increase of GGOs and a progressive transformation of GGO into multifocal consolidative opacities, septal thickening, and development of a crazy-paving pattern. As far as we know bronchiectasis were described only as a possible aspecific imaging feature of COVID-19 pneumonia and no studies reporting the onset or evolution of bronchiectasis during imaging follow-up in patients with COVID-19 have been published. Here we describe two cases of rapid evolution of bronchiectasis documented at CT in patients with COVID-19 pneumonia. Further studies are necessary to determine predisposing factors to the onset of bronchiectasis and to evaluate clinical correlation with respiratory distress. Radiologists should always consider bronchial features when they report CT scans of patients with COVID-19 pneumonia.

Graphical abstract Unlabelled Image, Highlights • An association between COVID-19 and venous thromboembolism (VTE) is now recognized. • The prevalence of VTE is high in COVID-19 patients hospitalized in standard care units. • The prevalence of VTE is high even though thromboprophylaxis and in patients estimated at low risk. • A high index of suspicion for VTE is crucial in patients with SARS-CoV-2 infection.

ObjectivesTo analyse the rectal carriage rate and the molecular epidemiology of vancomycin-resistant Enterococcus faecium (VREfm) recovered from patients upon hospital admission.MethodsAdult patients were screened at six German university hospitals from five different federal states upon hospital admission for rectal colonization with VREfm between 2014 and 2018. Molecular characterization of VREfm was performed by WGS followed by MLST and core-genome MLST analysis.ResultsOf 16350 patients recruited, 263 were colonized with VREfm, with increasing prevalence rates during the 5 year study period (from 0.8% to 2.6%). In total, 78.5% of the VREfm were vanB positive and 20.2% vanA positive, while 1.2% harboured both vanA and vanB. The predominant ST was ST117 (56.7%) followed by ST80 (15%), ST203 (10.9%), ST78 (5.7%) and ST17 (3.2%). ST117/vanB VREfm isolates formed a large cluster of 96 closely related isolates extending across all six study centres and four smaller clusters comprising 13, 5, 4 and 3 isolates each. In contrast, among the other STs inter-regional clonal relatedness was rarely observed.ConclusionsTo our knowledge, this is the largest admission prevalence and molecular epidemiology study of VREfm. These data provide insight into the epidemiology of VREfm at six German university hospitals and demonstrate the remarkable inter-regional clonal expansion of the ST117/vanB VREfm clone.

Introduction: Haematological patients are at higher risk of bloodstream infections (BSI) after chemotherapy. The aim of this study was to develop a simulation model assessing the impact of selective digestive decontamination (SDD) of haematological patients colonised with extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E) on the incidence of ESBL-E BSI after chemotherapy.Methods: A patient population was created by a stochastic simulation model mimicking the patients' states of colonisation with ESBL-E during hospitalisation. A systematic literature search was performed to inform the model. All ESBL-E carriers were randomised (1:1) to either the intervention (targeted SDD) or the control group (placebo). ESBL-E BSI incidence was the outcome of the model. Sensitivity analyses were performed by prevalence of ESBL-E carriage at hospital admission (low: < 10%, medium: 10-25%, high: > 25%), duration of neutropenia after receiving chemotherapy, administration of antibiotic prophylaxis with quinolones, and time interval between SDD and chemotherapy.Results: The model estimated that the administration of targeted SDD before chemotherapy reduces the incidence of ESBL-E BSI in the hospitalised haematological population up to 27%. The greatest benefit was estimated in high-prevalence settings, regardless of the duration of neutropenia, the time interval before chemotherapy, and the administration of antibiotic prophylaxis with quinolones (p < 0.05). In medium-prevalence settings, SDD was effective in patients receiving quinolone prophylaxis, with either 1-day time interval before chemotherapy and a neutropenia duration > 6 days (p < 0.05) or 7-day time interval before chemotherapy and a neutropenia duration > 9 days (p < 0.05). No benefit was observed in low-prevalence settings.Conclusions: Our model suggests that targeted SDD could decrease the rate of ESBL-E BSI in haematological carriers before chemotherapy in the setting of high ESBL-E prevalence at hospital admission. These estimates require confirmation by well-designed multicentre RCTs, including the assessment of the impact on resistance/disruption patterns of gut microbiome.

Objectives: Optimal treatment of carbapenem-resistant Gram-negative bacteria (CR-GNB) infections is uncertain because of the lack of good-quality evidence and the limited effectiveness of available antibiotics. The aim of this survey was to investigate clinicians' prescribing strategies for treating CR-GNB infections worldwide. Methods: A 36-item questionnaire was developed addressing the following aspects of antibiotic prescribing: respondent's background, diagnostic and therapeutic availability, preferred antibiotic strategies and rationale for selecting combination therapy. Prescribers were recruited following the snowball sampling approach, and a post-stratification correction with inverse proportional weights was used to adjust the sample's representativeness. Results: A total of 1012 respondents from 95 countries participated in the survey. Overall, 298 (30%) of the respondents had local guidelines for treating CR-GNB at their facility and 702 (71%) had access to Infectious Diseases consultation, with significant discrepancies according to country economic status: 85% (390/502) in high-income countries versus 59% (194/283) in upper-medium-income countries and 30% (118/196) in lower-middle-income countries/lower-income-countries). Targeted regimens varied widely, ranging from 40 regimens for CR-Acinetobacter spp. to more than 100 regimens for CR-Enterobacteriaceae. Although the majority of respondents acknowledged the lack of evidence behind this choice, dual combination was the preferred treatment scheme and carbapenem-polymyxin was the most prescribed regimen, irrespective of pathogen and infection source. Respondents noticeably disagreed around the meaning of ‘combination therapy’ with 20% (150/783) indicating the simple addition of multiple compounds, 42% (321/783) requiring the presence of in vitro activity and 38% (290/783) requiring in vitro synergism. Conclusions: Management of CR-GNB infections is far from being standardized. Strategic public health focused randomized controlled trials are urgently required to inform evidence-based treatment guidelines.

Background A major limitation of current predictive prognostic models in patients with COVID-19 is the heterogeneity of population in terms of disease stage and duration. This study aims at identifying a panel of clinical and laboratory parameters that at day-5 of symptoms onset could predict disease progression in hospitalized patients with COVID-19. Methods Prospective cohort study on hospitalized adult patients with COVID-19. Patient-level epidemiological, clinical, and laboratory data were collected at fixed time-points: day 5, 10, and 15 from symptoms onset. COVID-19 progression was defined as in-hospital death and/or transfer to ICU and/or respiratory failure (PaO2/FiO2 ratio 65 years, dyspnoea, cardiovascular disease, and at least three abnormal laboratory parameters among CRP (> 80 U/L), ALT (> 40 U/L), NLR (> 4.5), LDH (> 250 U/L), and CK (> 80 U/L) was proposed. Discrimination power was assessed by computing area under the receiver operating characteristic (AUC) values. Results A total of 235 patients with COVID-19 were prospectively included in a 3-month period. The majority of patients were male (148, 63%) and the mean age was 71 (SD 15.9). One hundred and ninety patients (81%) suffered from at least one underlying illness, most frequently cardiovascular disease (47%), neurological/psychiatric disorders (35%), and diabetes (21%). Among them 88 (37%) experienced COVID-19 progression. The proposed model showed an AUC of 0.73 (95% CI 0.66–0.81) for predicting disease progression by day-11. Conclusion An easy-to-use panel of laboratory/clinical parameters computed at day-5 of symptoms onset predicts, with fair discrimination ability, COVID-19 progression. Assessment of these features at day-5 of symptoms onset could facilitate clinicians’ decision making. The model can also play a role as a tool to increase homogeneity of population in clinical trials on COVID-19 treatment in hospitalized patients.

The impact of inappropriate empirical antibiotic therapy (IEAT) on the outcome of severe infections due to extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-Ent) remains unclear. Current evidence is limited by study design and lack of confounder control. The main objective of this study was to define the outcome of severe infections due to ESBL-Ent according to clinical parameters and place of infection acquisition. Adult hospitalised patients with ESBL-Ent infections were included in a 3-year multicentre prospective study. Primary outcomes were IEAT rates and crude mortality of severe infections, adjusted by place of acquisition [community-acquired infection (CAI), healthcare-associated infection (HCAI) and hospital-acquired infection (HAI)]. Among 729 patients, 519 (71.2%) were diagnosed with HAI, 176 (24.1%) with HCAI and 34 (4.7%) with CAI. Moreover, 32.9% of patients received IEAT; higher rates of IEAT were observed in pneumonia (23%) and deep surgical site infections (19%). HCAIs were more frequently associated with IEAT than HAIs (48.3% vs. 27.9%; OR = 1.7, 95% CI 1.2–2.4). The overall mortality rate for severe infections (n = 264) was 12.1% and was significantly higher in HCAIs (20%) than HAIs (10%) (RR = 2.3, 95% CI 1.01–5.3). IEAT significantly increased the risk of mortality in bloodstream infections (RR = 8.3, 95% CI 2–46.3). Rates of IEAT and overall mortality of ESBL-Ent severe infections were higher in HCAIs than HAIs. Prompt diagnosis of patients with severe HCAIs due to ESBL-Ent is essential since these infections receive high rates of IEAT and significantly higher mortality than HAIs [ClinicalTrials.gov Identifier: NCT00404625].

Background Antimicrobial stewardship aims to optimise antibiotic use and minimise selection of antimicrobial resistance. The methodological quality of published studies in this field is unknown. Objectives Our objective was to perform a comprehensive systematic review of antimicrobial stewardship research design and identify features which limit validity and translation of research findings into clinical practice. Data sources The following online database was searched: PubMed. Study eligibility criteria:Studies published between January 1950 and January 2017, evaluating any antimicrobial stewardship intervention in the community or hospital setting, without restriction on study design or outcome. Methods We extracted data on pre-specified design quality features and factors that may influence design choices including: (1) clinical setting, (2) age group studied, (3) when the study was conducted, (4) geographical region and (5) financial support received. Results The initial search yielded 17,382 articles; 1,008 were selected for full-text screening, of which 825 were included. Most studies (675/825, 82%) were non-experimental and 104 (15%) used interrupted time series analysis, 41 (6%) used external controls and 19 (3%) used both. Studies in the community setting fulfilled a median of 5/10 quality features (IQR 3-7) and 3 (IQR 2-4) in the hospital setting. Community setting studies (25%, 205/825) were significantly more likely to use randomisation (OR 5.9 (95%CI 3.8-9.2)), external controls (OR 5.6 (95%CI 3.6-8.5)) and multiple centres (OR 10.5 (95%CI 7.1-15.7)). From all studies, only 48% (398/825) reported clinical and 23% (190/825) reported microbiological outcomes. Quality did not improve over time. Conclusions Overall quality of antimicrobial stewardship studies is low and has not improved over time. Most studies do not report clinical and microbiological outcome data. Studies conducted in the community setting were associated with better quality. These limitations should inform the design of future stewardship evaluations so that a robust evidence base can be built to guide clinical practice.

Background Effective treatment of sepsis due to carbapenem-resistant Gram-negative bacteria (CR-GNB) remains a challenge for clinicians worldwide. In recent years, the combination of antibiotics has become the preferred treatment strategy for CR-GNB infection. However, robust evidence to support this approach is lacking. This systematic review aimed at critically evaluating all available antibiotic options for CR-GNB sepsis with particular focus on combination. Methods We systematically searched published literature from January 1945 until December 2018 for observational comparative and non-comparative studies and randomized trials examining any antibiotic option for CR-GNB. Studies were included if reporting microbiologically-confirmed infection caused by Acinetobacter baumannii, Enterobacteriaceae/Klebsiella spp., or Pseudomonas aeruginosa, reporting at least one of the study outcomes, and definitive antibiotic treatment. Carbapenem-resistance was defined as phenotypically-detected in vitro resistance to at least one of the following carbapenems: doripenem, ertapenem, imipenem, meropenem. Each antibiotic regimen was classified as “defined” when at least the molecular class(es) composing the regimen was detailed. Primary outcomes were 30-day and attributable mortality. Bayesian network meta-analysis (NMA) approach was selected for quantitative synthesis to explore feasibility of pooling data on antibiotic regimens. Results A total of 6306 records were retrieved and 134 studies including 11,546 patients were included: 54 studies were on Acinetobacter, 52 on Enterobacteriaceae/Klebsiella, 21 on mixed Gram-negative, and 7 on Pseudomonas. Nine (7%) were RCTs; 19 prospective cohorts (14%), 89 (66%) retrospective, and 17 (13%) case series. Forty-one studies (31%) were multicentric. Qualitative synthesis showed an heterogeneous and scattered reporting of key-clinical and microbiological variables across studies. Ninety-two distinct antibiotic regimens were identified with 47 of them (51%, 5863 patients) not reporting any details on numbers, type, dosage and in vitro activity of the included antibiotic molecules. The NMAs could not be performed for any of the selected outcome given the presence of too many disconnected components. Conclusion The existing evidence is insufficient to allowing for the formulation of any evidence-based therapeutic recommendation for CR-GNB sepsis. Future studies must provide a standardized definition of antibiotic regimen to drive recommendations for using combination of antibiotics that can be reliably applied to clinical practice.

Background: A major limitation of current predictive prognostic models in patients with COVID-19 is the heterogeneity of population in terms of disease stage and duration. This study aims at identifying a panel of clinical and laboratory parameters that at day-5 of symptoms onset could predict disease progression in hospitalized patients with COVID-19.Methods: Prospective cohort study on hospitalized adult patients with COVID-19. Patient-level epidemiological, clinical, and laboratory data were collected at fixed time-points: day 5, 10, and 15 from symptoms onset. COVID-19 progression was defined as in-hospital death and/or ICU and/or respiratory failure (PaO2/FiO2 ratioResults: A total of 235 patients with COVID-19 were prospectively included in a 3-month period. The majority of patients were male (148, 63%) and the mean age was 71 (SD 15.9). One hundred and ninety patients (81%) suffered from at least one underlying illness, most frequently cardiovascular disease (47%), neurological/psychiatric disorders (35%), and diabetes (21%). Among them 88 (37%) experienced COVID-19 progression. A model assessed at day-5 of symptoms onset including male sex, age >65 years, dyspnea, cardiovascular disease, and at least three abnormal laboratory parameters among CRP (> 80 U/L), ALT (> 40 U/L), NLR (> 4.5), LDH (> 250 U/L), and CK (> 80 U/L) showed an AUC of 0.73 (95%CI: 0.66 - 0.81) for predicting disease progression by day-11. Conclusion: An easy-to-use panel of laboratory/clinical parameters computed at day-5 of symptoms onset predicts, with fair discrimination ability, COVID-19 progression. Assessment of these features at day-5 of symptoms onset could facilitate assessment of clinicians’ decision making. The model can also play a role as a tool to increase homogeneity of population in clinical trials on COVID-19 treatment in hospitalized patients.

Inflammatory responses rapidly detect pathogen invasion and mount a regulated reaction. However, dysregulated anti-pathogen immune responses can provoke life-threatening inflammatory pathologies collectively known as cytokine release syndrome (CRS), exemplified by key clinical phenotypes unearthed during the SARS-Cov-2 pandemic. The underlying pathophysiology of CRS remains elusive. We found that FLIP, a protein that controls caspase-8 death pathways, was highly expressed in myeloid cells of COVID-19 lungs. FLIP controlled CRS by fueling a STAT3-dependent inflammatory program. Indeed, constitutive expression of a viral FLIP homologue in myeloid cells triggered a STAT3-linked, progressive and fatal inflammatory syndrome in mice, characterized by elevated cytokine output, lymphopenia, lung injury and multiple organ dysfunctions that mimicked human CRS. As STAT3-targeting approaches relieved inflammation, immune disorders, and organ failures in these mice, targeted intervention towards this pathway could suppress the lethal CRS inflammatory state.One sentence summaryFLIP-expressing myeloid cells are key drivers of CRS through aberrant overexpression of STAT3 pathway. STAT3-targeting is effective in mitigating CRS like severe COVID-19.

Background: The combination of antibiotics has become the clinicians’ preferred strategy for the treatment of sepsis due to carbapenem-resistant Gram-negative bacteria (CR-GNB) although the evidence supporting its use is weak. This systematic review aimed at critically evaluating all available antibiotic options for CR-GNB sepsis with particular focus on combination. Methods: Comparative and non-comparative observational studies, randomized control trials (RCTs) and case series were considered eligible with no language restriction. Studies were included if reporting microbiologically-confirmed sepsis caused by Acinetobacter baumannii, Enterobacterales/Klebsiella spp., or Pseudomonas aeruginosa, reporting at least one of the study outcome and targeted antibiotic treatment. Carbapenem-resistance was defined as phenotypically-detected in vitro resistance to at least one of the following carbapenems: doripenem, ertapenem, imipenem, meropenem. Primary outcomes were 30-day and attributable mortality. Bayesian network meta-analysis (NMA) approach was selected to explore feasibility of pooling data on antibiotic regimens. Results: A total of 6306 records were retrieved and 134 studies (11546 patients) were included [54 studies on Acinetobacter, 52 on Enterobacterales/Klebsiella, 21 on mixed Gram-negative, and 7 on Pseudomonas]. Nine (7%) were RCTs; 19 prospective cohorts (14%), 89 (66%) retrospective and 17 (13%) case series. Forty-one studies (31%) were multicentric. Ninety-two distinct regimens were identified with 47 (51%, 5863 patients) not reporting any details on combination. 30-day mortality was assessed in 65 (48%) studies while attributable mortality was reported only in 19 (14%).The NMAs were not applicable for any of selected outcomes given the presence of too many disconnected components. Conclusion: The existing evidence is too weak for allowing formulating any evidence-based therapeutic recommendation for combination of antibiotics to treat CR-GNB sepsis. Future studies must clearly define number, type, dosages, and in vitro activity of each antibiotic included in the regimen to drive recommendations for using combination of antibiotics that might be reliably applied into clinical practice.

Antimicrobial resistance must be recognised as a global societal priority - even in the face of the worldwide challenge of the COVID-19 pandemic. COVID-19 has illustrated the vulnerability of our healthcare systems in co-managing multiple infectious disease threats as resources for monitoring and detecting, and conducting research on antimicrobial resistance have been compromised during the pandemic. The increased awareness of the importance of infectious diseases, clinical microbiology and infection control and lessons learnt during the COVID-19 pandemic should be exploited to ensure that emergence of future infectious disease threats, including those related to AMR, are minimised. Harnessing the public understanding of the relevance of infectious diseases towards the long-term pandemic of AMR could have major implications for promoting good practices about the control of AMR transmission., APR would like to acknowledge funding from the AMR Cross-Council Initiative through a grant from the Medical Research Council, a Council of UK Research and Innovation [grant number MR/S004793/1], the National Institute for Health Research [grant number NIHR200632] and the Joint Programming Initiative for Antimicrobial Resistance (JPIAMR) via the Medical Research Council in the UK [grant number MR/S037640/1]. JRB and RC acknowledge funding on AMR from Plan Nacional de I+D+i 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases [REIPI RD16/0016/0001 and RD16/0016/0011], co-financed by the European Regional Development Fund ‘A way to achieve Europe’, Operative Program Intelligence Growth 2014–2020. JRB also acknowledges the Joint Programming Initiative for Antimicrobial Resistance (JPIAMR) via Instituto de Salud Carlos III [grant number AC16/00076]. ET acknowledges funding on AMR from the Joint Programming Initiative for Antimicrobial Resistance (JPIAMR) via the German Federal Ministry of Education and Research (BMBF) [grant number 01KI1830], Innovative Medicines Initiative 1 and 2 Joint Undertaking [grants number 115737, 115523 and820755] and the Global Antibiotic Research and Development Partnership (GARDP). LP, PF and SL would like to acknowledge funding to the JPIAMR from the European Commission (EXEDRA, JPI-EC-AMR and JPIAMR-ACTION).

[Background] Pseudomonas aeruginosa bacteraemia is a common and serious infection. No consensus exists regarding whether definitive combination therapy is superior to monotherapy. We aimed to evaluate the impact of combination therapy on mortality., [Methods] This was a multicentre retrospective study (nine countries, 25 centres), including 1277 patients with P. aeruginosa bacteraemia during 2009–15. We evaluated the association between β-lactam plus aminoglycoside or quinolone combination therapy versus β-lactam monotherapy and mortality. The primary outcome was 30 day all-cause mortality. Univariate and multivariate Cox regression analyses were conducted, introducing combination as a time-dependent variable. Propensity score was conducted to adjust for confounding for choosing combination therapy over monotherapy., [Results] Of 1119 patients included, 843 received definitive monotherapy and 276 received combination therapy (59% aminoglycoside and 41% quinolone). Mortality at 30 days was 16.9% (189/1119) and was similar between combination (45/276; 16.3%) and monotherapy (144/843; 17.1%) groups (P = 0.765). In multivariate Cox regression, combination therapy was not associated with reduced mortality (HR 0.98, 95% CI 0.64–1.53). No advantage in terms of clinical failure, microbiological failure or recurrent/persistent bacteraemia was demonstrated using combination therapy. Likewise, adverse events and resistance development were similar for the two regimens., [Conclusions] In this retrospective cohort, no mortality advantage was demonstrated using combination therapy over monotherapy for P. aeruginosa bacteraemia. Combination therapy did not improve clinical or microbiological failure rates, nor affect adverse events or resistance development. Our finding of no benefit with combination therapy needs confirmation in well-designed randomized controlled trials.

Background and Aims Diabetes conveys an increased risk of infectious diseases and related mortality. We investigated risk of ascertained SARS-CoV-2 infection in diabetes subjects from the Veneto Region, Northeastern Italy, as well as the risk of being admitted to hospital or intensive care unit (ICU), or mortality for COVID-19. Methods and Results – Diabetic subjects were identified by linkage of multiple health archives. The rest of the population served as reference. Information on ascertained infection by SARS-CoV-2, admission to hospital, admission to ICU and mortality in the period from February 21 to July 31, 2020 were retrieved from the regional registry of COVID-19. Subjects with ascertained diabetes were 269,830 (55.2% men; median age 72 years). Reference subjects were 4,681,239 (men 48.6%, median age 46 years). Ratios of age- and gender-standardized rates (RR) [95% CI] for ascertained infection, admission to hospital, admission to ICU and disease-related death in diabetic subjects were 1.31 [1.19-1.45], 2.11 [1.83-2.44], 2.45 [1.96-3.07], 1.87 [1.68-2.09], all p

Background: A major limitation of predictive prognostic models in COVID-19 patients is the heterogeneity of disease stage and population. This study aims at identifying a panel of clinical and laboratory parameters that at day-5 of symptoms onset could predict disease progression within 11 days in hospitalized COVID-19 patients. Methods: Single-centre, prospective cohort study on hospitalized adult COVID-19 patients. Patient-level epidemiological, clinical, and laboratory data were collected at fixed time-points: day-5, -10, and -15 from symptoms onset and in case of intensive care unit (ICU) admission, discharge, or death. COVID-19 progression was defined as in-hospital death and/or ICU and/or respiratory failure (PaO2/FiO2 ratio65 years, cardiovascular disease, and at least three abnormal laboratory parameters among CRP > 80 U/L, AST > 45 U/L, ALT > 40 U/L, NLR > 4·5, LDH > 250 U/L, and CK > 80 U/L showed an AUC of 0·73 (95%CI: 0·66 - 0·81) for predicting disease progression. Conclusion: An easy-to-use panel of laboratory/clinical parameters computed at day-5 from symptoms onset predicts, with fair discrimination ability, COVID-19 progression. Assessment of these features at day-5 from symptoms onset could facilitate clinicians’ decision making and be used to increase patient population in clinical trials in hospitalized patients. Trial Registration: COVID 19-VR registry (ClinicalTrials.gov NCT04497194). Funding Statement: This study is part of React-COVID-19 project funded by Fondazione CARIVERONA. Declaration of Interests: The authors have no conflict of interests to be declared. Ethics Approval Statement: The study was approved by the hospital Institutional Review Board (IRB 2577CESC).

Background: Increasing antimicrobial resistance (AMR) is threatening our ability to effectively treat infections. People living with HIV (PLWH) may be at increased risk of infections with resistant organisms due to more frequent healthcare utilisation and antimicrobial prescriptions. This systematic review investigated the association between HIV and AMR. Methods: Studies reporting on AMR for colonisation or infection with bacterial pathogens excluding mycobacteria and bacteria causing sexual transmitted infections stratified by HIV status, species and antimicrobial tested were included. Pooled odds ratios were used to evaluate the association between HIV and resistance. The completeness of reporting was evaluated using the STROBE checklist. Findings: A total of 92 studies from 23 countries published between 1995 and 2020 were identified. The studies included the following organisms: Staphylococcus (n=47), Streptococcus pneumoniae (n=28), Escherichia coli (n=6) and other Gram-negative bacteria. PLWH had a 2·12 (95% CI 1·36-3·30) higher odds for colonization and 1·90 (95%CI 1·45-2·48) higher odds for infection with methicillin-resistant S. aureus; a 2·28 (95%CI 1·75-2·97) higher odds of infections with S. pneumoniae with decreased penicillin susceptibility and a 1·59 (95%CI 0·83-3·05) higher odds of resistance to third-generation cephalosporins in E. coli and Klebsiella pneumoniae. Overall, there was a high heterogeneity between studies. Interpretation: This review shows an increased risk of AMR in PLWH across a range of bacterial pathogens and multiple drug classes, which has important clinical implications for treatment. The lack of laboratory capacity for identifying AMR and limited access to alternative treatment options in countries with the highest burden of HIV highlights the need for more research on AMR in PLWH. This knowledge should translate into treatment guideline changes especially in settings where diagnostics are limited. Funding: IDO received funding though the Wellcome Trust Clinical PhD Programme awarded to the London School of Hygiene & Tropical Medicine (grant number 203905/Z/16/Z). Declaration of Interests: None of the authors have any competing interests.

Background Asymptomatic C. difficile colonization is believed to predispose to subsequent C. difficile infection (CDI). While emerging insights into the role of the commensal microbiota in mediating colonization resistance against C. difficile have associated CDI with specific microbial components, corresponding prospectively collected data on colonization with C. difficile are largely unavailable. Methods C. difficile status was assessed by GDH EIA and real-time PCR targeting the toxin A (tcdA) and B (tcdB) genes. 16S V3 and V4 gene sequencing results from fecal samples of patients tested positive for C. difficile were analyzed by assessing alpha and beta diversity, LefSe, and the Piphillin functional inference approach to estimate functional capacity. Results 1506 patients were recruited into a prospective observational study (DRKS00005335) upon admission into one of five academic hospitals. 936 of them provided fecal samples on admission and at discharge and were thus available for longitudinal analysis. Upon hospital admission, 5.5% (83/1506) and 3.7% (56/1506) of patients were colonized with toxigenic (TCD) and non-toxigenic C. difficile (NTCD), respectively. During hospitalization, 1.7% (16/936) acquired TCD. Risk factors for acquisition of TCD included pre-existing lung diseases, lower GI endoscopy and antibiotics. Species protecting against hospital-related C. difficile acquisition included Gemmiger spp., Odoribacter splanchnicus, Ruminococcus bromii and other Ruminococcus spp. Metagenomic pathway analysis identified steroid biosynthesis as the most underrepresented metabolic pathway in patients who later acquire C. difficile colonization. Conclusions Gemmiger spp., Odoribacter splanchnicus, Ruminococcus bromii and other Ruminococci were associated with a decreased risk of C. difficile acquisition. Clinical Trials Registration DRKS00005335.

The superiority of combination therapy for carbapenem-resistant Gram-negative bacilli (CR-GNB) infections remains controversial. In vitro models may predict the efficacy of antibiotic regimens against CR-GNB. A systematic review and meta-analysis was performed including pharmacokinetic/pharmacodynamic (PK/PD) and time-kill (TK) studies examining the in vitro efficacy of antibiotic combinations against CR-GNB [PROSPERO registration no. CRD42019128104]. The primary outcome was in vitro synergy based on the effect size (ES): high, ES ≥ 0.75, moderate, 0.35ES0.75; low, ES ≤ 0.35; and absent, ES = 0). A network meta-analysis assessed the bactericidal effect and re-growth rate (secondary outcomes). An adapted version of the ToxRTool was used for risk-of-bias assessment. Over 180 combination regimens from 136 studies were included. The most frequently analysed classes were polymyxins and carbapenems. Limited data were available for ceftazidime/avibactam, ceftolozane/tazobactam and imipenem/relebactam. High or moderate synergism was shown for polymyxin/rifampicin against Acinetobacter baumannii [ES = 0.91, 95% confidence interval (CI) 0.44-1.00], polymyxin/fosfomycin against Klebsiella pneumoniae (ES = 1.00, 95% CI 0.66-1.00) and imipenem/amikacin against Pseudomonas aeruginosa (ES = 1.00, 95% CI 0.21-1.00). Compared with monotherapy, increased bactericidal activity and lower re-growth rates were reported for colistin/fosfomycin and polymyxin/rifampicin in K. pneumoniae and for imipenem/amikacin or imipenem/tobramycin against P. aeruginosa. High quality was documented for 65% and 53% of PK/PD and TK studies, respectively. Well-designed in vitro studies should be encouraged to guide the selection of combination therapies in clinical trials and to improve the armamentarium against carbapenem-resistant bacteria.

Background: Point-of-care tests could be essential in differentiating bacterial and viral acute communityacquired lower respiratory tract infections and driving antibiotic stewardship in the community. Objectives: To assess diagnostic test accuracy of point-of-care tests in community settings for acute community-acquired lower respiratory tract infections. Data sources: Multiple databases (MEDLINE, EMBASE, Web of Science, Cochrane Library, Open Gray) from inception to 31 May 2021, without language restrictions. Study eligibility criteria: Diagnostic test accuracy studies involving patients at primary care, outpatient clinic, emergency department and long-term care facilities with a clinical suspicion of acute communityacquired lower respiratory tract infections. The comparator was any test used as a comparison to the index test. In order not to limit the study inclusion, the comparator was not defined a priori. Assessment of risk of bias: Four investigators independently extracted data, rated risk of bias, and assessed the quality using QUADAS-2. Methods of data synthesis: The measures of diagnostic test accuracy were calculated with 95% CI. Results: A total of 421 studies addressed at least one point-of-care test. The diagnostic performance of molecular tests was higher compared with that of rapid diagnostic tests for all the pathogens studied. The accuracy of stand-alone signs and symptoms or biomarkers was poor. Lung ultrasound showed high sensitivity and specificity (90% for both) for the diagnosis of bacterial pneumonia. Rapid antigen-based diagnostic tests for influenza, respiratory syncytial virus, human metapneumovirus, and Streptococcus pneumoniae had sub-optimal sensitivity (range 49%-84%) but high specificity (>80%). Discussion: Physical examination and host biomarkers are not sufficiently reliable as stand-alone tests to differentiate between bacterial and viral pneumonia. Lung ultrasound shows higher accuracy than chest X-ray for bacterial pneumonia at emergency department. Rapid antigen-based diagnostic tests cannot be considered fully reliable because of high false-negative rates. Overall, molecular tests for all the patho-gens considered were found to be the most accurate. Elisa Gentilotti, Clin Microbiol Infect 2022;28:13 (c) 2021 The Authors. Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

PRAISE network: Maaike S. M. van Mourik, Stephanie M.van Rooden, Mohamed Abbas, Olov Aspevall, Pascal Astagneau, Marc J. M. Bonten, Elena Carrara, Aina Gomila-Grange, Sabine C. de Greeff , Sophie Gubbels, Wendy Harrison, Hilary Humphreys, Anders Johansson, Mayke B. G. Koek, Brian Kristensen, Alain Lepape, Jean-Christophe Lucet, Siddharth Mookerjee, Pontus Naucler, Zaira R. Palacios-Baena, Elisabeth Presterl, Miquel Pujol, Jacqui Reilly, Christopher Roberts, Evelina Tacconelli, Daniel Teixeira, Thomas Tängdén, John Karlsson Valik, Michael Behnke, PetraGastmeier., [Introduction] Healthcare-associated infections (HAI) are a major public health concern. Monitoring of HAI rates, with feedback, is a core component of infection prevention and control programmes. Digitalization of healthcare data has created novel opportunities for automating the HAI surveillance process to varying degrees. However, methods are not standardized and vary widely between different healthcare facilities. Most current automated surveillance (AS) systems have been confined to local settings, and practical guidance on how to implement large-scale AS is needed., [Methods] This document was written by a task force formed in March 2019 within the PRAISE network (Providing a Roadmap for Automated Infection Surveillance in Europe), gathering experts in HAI surveillance from ten European countries., [Results] The document provides an overview of the key e-health aspects of implementing an AS system of HAI in a clinical environment to support both the infection prevention and control team and information technology (IT) departments. The focus is on understanding the basic principles of storage and structure of healthcare data, as well as the general organization of IT infrastructure in surveillance networks and participating healthcare facilities. The fundamentals of data standardization, interoperability and algorithms in relation to HAI surveillance are covered. Finally, technical aspects and practical examples of accessing, storing and sharing healthcare data within a HAI surveillance network, as well as maintenance and quality control of such a system, are discussed., [Conclusions] With the guidance given in this document, along with the PRAISE roadmap and governance documents, readers will find comprehensive support to implement large-scale AS in a surveillance network., This network has been supported under the 7th transnational call within the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR), Network Call on Surveillance (2018) and was thereby funded by ZonMw (grant 549007001). This project also received support from the COMBACTE MAGNET EPI-Net project funded by the Innovative Medicines Initiative Joint Undertaking under grant agreement 115523 | 115620 | 115737 | 777362, resources of which are composed of financial contribution from the European Union Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution. J.K.V. was supported by grants from Region Stockholm and Vinnova.

Hongchao Pan (University of Oxford. Nuffield Department of Population Health. Medical Research Council Population Health Research Unit. Oxford, United Kingdom); Richard Peto (University of Oxford. Nuffield Department of Population Health. Medical Research Council Population Health Research Unit. Oxford, United Kingdom); Ana-Maria Henao-Restrepo (World Health Organization. Geneva, Switzerland); Marie-Pierre Preziosi (World Health Organization. Geneva, Switzerland); Vasee Sathiyamoorthy (World Health Organization. Geneva, Switzerland); Quarraisha Abdool Karim (Centre for the AIDS Programme of Research in South Africa. Durban, South Africa); Marissa M. Alejandria (University of the Philippines. National Institutes of Health. Institute of National Epidemiology. Manila, Philippines); Cesar Hernandez Garcia (Spanish Agency of Medicines and Medical Devices. Madrid, Spain / Hospital Clinico San Carlos. Madrid, Spain); Marie-Paule Kieny (Institut National de la Sante et de la Recherche Medicale. Paris, France); Reza Malekzadeh (Tehran University of Medical Sciences. Digestive Disease Research Institute. Tehran, Iran); Srinivas Murthy (University of British Columbia. Vancouver, Canada); K. Srinath Reddy (Public Health Foundation of India. New Delhi, India); Mirta Roses Periago (National Academy of Sciences of Buenos Aires. Buenos Aires, Argentina); Pierre Abi Hanna (Rafic Hariri University Hospital. Beirut, Lebanon); Florence Ader (Hospices Civils de Lyon. Lyon, France); Abdullah M. Al-Bader (Ministry of Health. Kuwait City, Kuwait); Almonther Alhasawi (Infectious Diseases Hospital. Kuwait City, Kuwait); Emma Allum (University of Bristol. Bristol, United Kingdom); Athari Alotaibi (Ministry for Preventive Health. Riyadh, Saudi Arabia); Carlos A. Alvarez-Moreno (Universidad Nacional de Colombia. Bogota, Colombia / Clinica Colsanitas. Bogota, Colombia); Sheila Appadoo (University of Bern. Bern, Switzerland); Abdullah Asiri (Ministry for Preventive Health. Riyadh, Saudi Arabia); Pal Aukrust (Oslo University Hospital. Oslo, Norway); Andreas Barratt-Due (Oslo University Hospital. Oslo, Norway); Samir Bellani (University of Bristol. Bristol, United Kingdom); Mattia Branca (University of Bern. Bern, Switzerland); Heike B.C. Cappel-Porter (University of Bristol. Bristol, United Kingdom); Nery Cerrato (Secretaria de Salud de Honduras. Tegucigalpa, Honduras); Ting S. Chow (Penang Hospital. Penang, Malaysia); Najada Como (University Hospital Center "Mother Teresa". Tirana, Albania); Joe Eustace (University College Cork. HRB Clinical Research Facility. Cork, Ireland); Patricia J. Garcia (Universidad Peruana Cayetano Heredia. Lima, Peru); Sheela Godbole (Indian Council of Medical Research. New Delhi, India / National AIDS Research Institute. Pune, Maharashtra, India); Eduardo Gotuzzo (Universidad Peruana Cayetano Heredia. Lima, Peru); Laimonas Griskevicius (Vilnius University Hospital Santaros Klinikos. Vilnius, Lithuania); Rasha Hamra (Ministry of Public Health. Beirut, Lebanon); Mariam Hassan (Shaukat Khanum Memorial Cancer Hospital and Research Centre. Lahore, Pakistan); Mohamed Hassany (National Hepatology and Tropical Medicine Research Institute. Cairo, Egypt); David Hutton (University of Bristol. Bristol, United Kingdom); Irmansyah Irmansyah (National Institute of Health Research and Development. Jakarta, Indonesia); Ligita Jancoriene (Vilnius University. Faculty of Medicine. Institute of Clinical Medicine. Vilnius, Lithuania); Jana Kirwan (University of Bristol. Bristol, United Kingdom); Suresh Kumar (Sungai Buloh Hospital. Selangor, Malaysia / Jalan Hospital. Selangor, Malaysia); Peter Lennon (Department of Health and Children. Dublin, Ireland); Gustavo Lopardo (Fundacion del Centro de Estudios Infectologicos. Buenos Aires, Argentina); Patrick Lydon (World Health Organization. Geneva, Switzerland); Nicola Magrini (Italian Medicines Agency. Rome, Italy); Teresa Maguire (Department of Health and Children. Dublin, Ireland); Suzana Manevska (Ministry of Health. Skopje, North Macedonia); Oriol Manuel (Lausanne University Hospital. Lausanne, Switzerland); Sibylle McGinty (University of Bern. Bern, Switzerland); Marco T. Medina (Universidad Nacional Autonoma de Honduras. Tegucigalpa, Honduras); Maria L. Mesa Rubio (Ministry of Health. Bogota, Colombia); Maria C. Miranda-Montoya (World Health Organization. Geneva, Switzerland); Jeremy Nel (University of the Witwatersrand. Johannesburg, South Africa); Estevao Portela Nunes (Fundacao Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brasil); Markus Perola (National Institute for Health and Welfare of Finland. Helsinki, Finland / University of Finland. Helsinki, Finland); Antonio Portoles (Universidade Complutense de Madrid. Madrid, Spain / Spanish Clinical Research Network. Madrid, Spain / Hospital Clinico San Carlos. Instituto de Investigacion Sanitaria San Carlos. Madrid, Spain); Menaldi R. Rasmin (Rumah Sakit Umum Pusat Persahabatan. Jakarta, Indonesia); Aun Raza (Shaukat Khanum Memorial Cancer Hospital and Research Centre. Lahore, Pakistan); Helen Rees (Wits Reproductive Health and HIV Institute. Johannesburg, South Africa); Paula P. S. Reges (Fundacao Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brasil); Chris A. Rogers (University of Bristol. Bristol, United Kingdom); Kolawole Salami (World Health Organization. Geneva, Switzerland); Marina I. Salvadori (Public Health Agency of Canada. Ottawa, Canada); Narvina Sinani (National Agency for Medicines and Medical Devices. Tirana, Albania); Jonathan A. C. Sterne (University of Bristol. Bristol, United Kingdom); Milena Stevanovikj (University Clinic of Infectious Diseases and Febrile Conditions. Skopje, North Macedonia); Evelina Tacconelli (University of Verona. Verona, Italy); Kari A. O. Tikkinen (Helsinki University Hospital. Helsinki, Finland / South Karelian Central Hospital. Lappeenranta, Finland); Sven Trelle (University of Bern. Bern, Switzerland); Hala Zaid (Ministry of Health and Population. Cairo, Egypt); John-Arne Rottingen (Research Council of Norway. Oslo, Norway); Soumya Swaminathan (World Health Organization. Geneva, Switzerland).

Health-care workers are crucial to any health-care system. During the ongoing COVID-19 pandemic, health-care workers are at a substantially increased risk of becoming infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and could come to considerable harm as a result. Depending on the phase of the pandemic, patients with COVID-19 might not be the main source of SARS-CoV-2 infection and health-care workers could be exposed to atypical patients, infected family members, contacts, and colleagues, or live in communities of active transmission. Clear strategies to support and appropriately manage exposed and infected health-care workers are essential to ensure effective staff management and to engender trust in the workplace. These management strategies should focus on risk stratification, suitable clinical monitoring, low-threshold access to diagnostics, and decision making about removal from and return to work. Policy makers need to support health-care facilities in interpreting guidance during a pandemic that will probably be characterised by fluctuating local incidence of SARS-CoV-2 to mitigate the impact of this pandemic on their workforce.

Antibiotic-induced perturbation of the human gut flora is expected to play an important role in mediating the relationship between antibiotic use and the population prevalence of antibiotic resistance in bacteria, but little is known about how antibiotics affect within-host resistance dynamics. Here we develop a data-driven model of the within-host dynamics of extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae. We use blaCTX-M (the most widespread ESBL gene family) and 16S rRNA (a proxy for bacterial load) abundance data from 833 rectal swabs from 133 ESBL-positive patients followed up in a prospective cohort study in three European hospitals. We find that cefuroxime and ceftriaxone are associated with increased blaCTX-M abundance during treatment (21% and 10% daily increase, respectively), while treatment with meropenem, piperacillin-tazobactam, and oral ciprofloxacin is associated with decreased blaCTX-M (8% daily decrease for all). The model predicts that typical antibiotic exposures can have substantial long-term effects on blaCTX-M carriage duration., eLife digest Bacteria that are resistant to antibiotics are a growing global health crisis. One type of antibiotic resistance arises when certain bacteria that can produce enzymes called extended-spectrum beta-lactamases (or ESBLs for short) become more common in the gut. These enzymes stop important antibiotics, like penicillin, from working. However, exactly which antibiotics and treatment durations contribute to the emergence of this antibiotic resistance remain unknown. Now, Niehus et al. find certain antibiotics that are associated with an increase in the number of gut bacteria carrying antibiotic resistance genes for ESBL enzymes. First, rectal swabs collected from 133 patients from three European hospitals were analysed to measure the total gut bacteria and the number of genes for ESBL enzymes. These samples had been collected at several time points including when the patient was first admitted to hospital, then every two to three days during their stay, and finally when they were discharged. Combining the analysis of the samples with details of the patients’ charts showed that treatment with two antibiotics: cefuroxime and ceftriaxone, was linked to an increase in ESBL genes in the gut bacteria. Other antibiotics – namely, meropenem, piperacillin-tazobactam and oral ciprofloxacin – were associated with a decrease in the number of bacteria with ESBL genes. Niehus et al. then performed further analysis to see if different treatment regimens affected how long patients were carrying gut bacteria with ESBL genes. This predicted that a longer course of meropenem, 14 days rather than 5 days, would shorten the length of time patients carried ESBL-resistant bacteria in their guts by 70%, although this effect will likely depend on the location of the hospital and the local prevalence of other types of antibiotic resistance. This analysis reveals new details about how antibiotic treatment can affect ESBL resistance genes. More studies are needed to understand how antibiotics affect other antibiotic resistance genes and how resistant bacteria spread. This will help scientists understand how much specific antibiotic regimens contribute to antibiotic resistance. It may also help scientists develop new antibiotic treatment strategies that reduce antibiotic resistance.

Background: On February 23rd the first case of SARS-CoV-2 infection was diagnosed at the University Hospital Trust of Verona, Italy On March 13th, the Oncology Section was converted into a 22 inpatient beds COVID unit and we had to reshape our organization and personnel to face the SARS-CoV-2 epidemic, while maintaining our oncological activity Methods: We tracked down oncological activity from January 1st to March 31st, 2020, in relationship to the organizational changes implemented and in comparison to the same period of 2019 We also recorded cases of SARS-CoV-2 infections observed in oncology health professionals and hospital admissions of active oncology patients for SARS-CoV-2 infection Results: Progressive restrictions in patients', visitors', and caregivers' access to the inpatient and outpatient facilities of the Oncology section and organizational changes were adopted early on during the epidemic peak Since March 13th, segregated personnel teams were created, one dedicated to the COVID unit and a "clean" one dedicated to oncological patients, resulting in an overall 40% and 43% reduction in oncology-dedicated medical and nursing/auxiliary staff, respectively As compared with the same trimester in 2019, the overall reduction in total numbers of inpatient admissions, chemotherapy administrations, and specialty visits in the period January-March 2020 was 8%, 6%, and 3%, respectively;based on the weekly average of daily accesses, reduction in some of the oncological activities became statistically significant from week 11 Patient's acceptance of adopted measures was very high (see abstract by Tregnago D) Overall, 8/85 (9%) health professionals tested positive for SARS-CoV-2 (no hospital admissions and no treatment required) and 7/525 (1 3%) active oncology patients were admitted for SARS-CoV-2 infection (of whom, 2 died of infection-related complications) Conclusions: A minimal (

Since the beginning of the SARS-CoV-2 pandemic, COVID-19 appeared as a unique disease with unconventional tissue and systemic immune features. Here we show a COVID-19 immune signature associated with severity by integrating single-cell RNA-seq analysis from blood samples and broncho-alveolar lavage fluids with clinical, immunological and functional ex vivo data. This signature is characterized by lung accumulation of naïve lymphoid cells associated with a systemic expansion and activation of myeloid cells. Myeloid-driven immune suppression is a hallmark of COVID-19 evolution, highlighting arginase-1 expression with immune regulatory features of monocytes. Monocyte-dependent and neutrophil-dependent immune suppression loss is associated with fatal clinical outcome in severe patients. Additionally, our analysis shows a lung CXCR6+ effector memory T cell subset is associated with better prognosis in patients with severe COVID-19. In summary, COVID-19-induced myeloid dysregulation and lymphoid impairment establish a condition of ‘immune silence’ in patients with critical COVID-19., Integrated studies of matched tissue sites and cell types in COVID-19 patients are important to define the immune mechanisms of pathology. Here, the authors describe an immune signature in fatal COVID-19 patients harmonizing single-cell RNA sequencing of blood and matched BAL cells with deep clinical, immunological and functional data.

Objective: to compare COVID-19 patients’ vessel caliber with that of normal lungs and lungs interested by other inflammatory and thromboembolic processes. Methods: between March and April 2020, 42 patients affected by COVID-19 pneumonia [COV-P] underwent a CT scan of the lung at Verona University Hospital for clinical indications. Lung images were compared to 4 different groups of patients (normal lung [NL], distal thromboembolism [DTE], bacterial and fungal pneumonia [Bact-P, Fung-P]) by a 4-year-experienced radiologist. Results: COV-P patients’ segmental and subsegmental vessels, as evaluated as the ratio with the corresponding bronchial branch (V/B ratio) were larger with respect to NL, DTE in the apparently healthy parenchyma, a result confirmed in the zones of opacification with respect to Bact-P and Fung-P. Conclusions: This is the first study to comparatively showing that segmental and subsegmental COVID-19 patients’ vessel caliber is significantly enlarged. This is a distinctive feature of COVID-19 pneumonia suggesting distinct pathophysiology as compared to other inflammatory and thromboembolic diseases and alerting radiologists to consider it when evaluating CT scan of suspected patients.

Objective There is poor evidence to determine the superiority of combination regimens versus monotherapy against infections due to carbapenem-resistant (CR) Gram-negative bacteria. In vivo models can simulate the pathophysiology of infections in humans and assess antibiotic efficacy. We aim to investigate in vivo effects of antibiotic combination on mortality and disease burden for infections due to CR Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae and provide an unbiased overview of existing knowledge. The results of the study can help prioritising future research on the most promising therapies against CR bacteria. Methods and analysis This protocol was formulated using the Systematic Review Protocol for Animal Intervention Studies (SYRCLE) Checklist. Publications will be collected from PubMed, Scopus, Embase and Web of Science. Quality checklists adapted by Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies and SYRCLE’s risk of bias tool will be used. If the meta-analysis seems feasible, the ES and the 95% CI will be analysed. The heterogeneity between studies will be assessed by I2 test. Subgroup meta-analysis will be performed when possible to assess the impact of the studies on efficacy of the treatments. Funnel plotting will be used to evaluate the risk of publication bias. Dissemination This systematic review and meta-analysis is part of a wider research collaboration project, the COmbination tHErapy to treat sepsis due to carbapenem-Resistant bacteria in adult and paediatric population: EvideNCE and common practice (COHERENCE) study that includes also the analyses of in vitro and human studies. Data will be presented at international conferences and the results will be published in peer-reviewed journals. PROSPERO registration number CRD42019128104(available at: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42019128104).

Biomarkers to guide antibiotic treatment decisions have been proposed as an effective way to enhancing a more appropriate use of antibiotics. As a biomarker, procalcitonin (PCT) has been found to have good specificity to distinguish bacterial from non-bacterial inflammations. Decisions regarding antibiotic use in an individual patient are complex and should be based on the pre-test probability for bacterial infection, the severity of presentation and the results of PCT serum concentration. In the context of a high pre-test probability for bacterial infections and/or a high-risk patient with sepsis, monitoring of PCT over time helps to track the resolution of infection and decisions regarding early stop of antibiotic treatment. As outlined by the Evidence Based Laboratory Medicine (EBLM), not only the pre-test probability but also the positive likelihood ratio influence the performance of a test do be really diagnostic. This aspect should be taken into account in the interpretation of the results of clinical trials evaluating the performance of PCT in guiding antibiotic therapy.

Aim To study ground-glass opacities (GGO) not only from the coronavirus 2019 (COVID-19) pneumonia" perspective but also as a radiological presentation of other pathologies with comparable features. Methods We enrolled 33 patients admitted to Policlinico Universitario G. B. Rossi who underwent non-contrast-enhanced (NCE) or contrast-enhanced (CE) chest computed tomography (CT) between March 12 and April 12. All patients with CT-detected ground-glass opacity (GGO) were included. All patients resulted as COVID-19 negative at the reverse transcription-polymerase chain reaction (RT-PCR) assay. We studied the different pathologies underlying GGO features: neoplastic diseases and non-neoplastic diseases (viral pneumonias, interstitial pneumonias, and cardiopulmonary diseases) in order to avoid pitfalls and to reach the correct diagnosis. Results All CT scans detected GGOs. Symptomatic patients were 25/33 (75.7%). At the clinical presentation, they reported fever and dry cough; in six out of 25 cases, dyspnea was also reported (24%). Thirty-three (33; 100%) showed GGO at CT: 15/33 (45.45%) presented pure GGO, and 18/33 (54.54%) showed GGO with consolidation. The RT-PCR assay was negative in 100%. We investigated other potential underlying diseases to explain imaging features: neoplastic causes (8/33, 24.24%) and non-neoplastic causes, in particular, infectious pneumonias (16/33, 48,48 %, viral and fungal), interstitial pneumonias (4/33, 12,12%), and cardio-pulmonary disease (5/33, 15,15%). Conclusions GGO remains a diagnostic challenge. Although CT represents a fundamental diagnostic tool because of its sensitivity, it still needs to be integrated with clinical data to achieve the best clinical management. In the presence of typical imaging features (e.g. GGO and consolidation), the radiologist should focus on the pandemic and manage a suspect patient as COVID-19 positive until proven to be negative.

This study was presented as poster presentation at the European Society of Clinical Microbiology and Infectious Diseases annual conference, Madrid, Spain, 21–24 April 2018., [Background] The optimal antibiotic regimen for Pseudomonas aeruginosa bacteremia is controversial. Although β-lactam monotherapy is common, data to guide the choice between antibiotics are scarce. We aimed to compare ceftazidime, carbapenems, and piperacillin-tazobactam as definitive monotherapy. [Methods] A multinational retrospective study (9 countries, 25 centers) including 767 hospitalized patients with P. aeruginosa bacteremia treated with β-lactam monotherapy during 2009–2015. The primary outcome was 30-day all-cause mortality. Univariate and multivariate, including propensity-adjusted, analyses were conducted introducing monotherapy type as an independent variable. [Results] Thirty-day mortality was 37/213 (17.4%), 42/210 (20%), and 55/344 (16%) in the ceftazidime, carbapenem, and piperacillin-tazobactam groups, respectively. Type of monotherapy was not significantly associated with mortality in either univariate, multivariate, or propensity-adjusted analyses (odds ratio [OR], 1.14; 95% confidence interval [CI], 0.52–2.46, for ceftazidime; OR, 1.3; 95% CI, 0.67–2.51, for piperacillin-tazobactam, with carbapenems as reference in propensity adjusted multivariate analysis; 542 patients). No significant difference between antibiotics was demonstrated for clinical failure, microbiological failure, or adverse events. Isolation of P. aeruginosa with new resistance to antipseudomonal drugs was significantly more frequent with carbapenems (36/206 [17.5%]) versus ceftazidime (25/201 [12.4%]) and piperacillin-tazobactam (28/332 [8.4%] (P = .007). [Conclusions] No significant difference in mortality, clinical, and microbiological outcomes or adverse events was demonstrated between ceftazidime, carbapenems, and piperacillin-tazobactam as definitive treatment of P. aeruginosa bacteremia. Higher rates of resistant P. aeruginosa after patients were treated with carbapenems, along with the general preference for carbapenem-sparing regimens, suggests using ceftazidime or piperacillin-tazobactam for treating susceptible infection., This study was conducted with no external funding. In Sweden only, the research was funded by grants from the Stockholm County Council and Emil and Wera Cornell Foundation.

Background Using case-vignettes, we assessed the perception of European infection control (IC) specialists regarding the individual and collective risk associated with antimicrobial resistance (AMR) among inpatients. Methods In this study, sixteen case-vignettes were developed to simulate hospitalised patient scenarios in the field of AMR and IC. A total of 245 IC specialists working in different hospitals from 15 European countries were contacted, among which 149 agreed to participate in the study. Using an online database, each participant scored five randomly-assigned case-vignettes, regarding the perceived risk associated with six different multidrug resistant organisms (MDRO). The intra-class correlation coefficient (ICC), varying from 0 (poor) to 1 (perfect), was used to assess the agreement for the risk on a 7-point Likert scale. High risk and low/neutral risk scorers were compared regarding their national, organisational and individual characteristics. Results Between January and May 2017, 149 participants scored 655 case-vignettes. The perceptions of the individual (clinical outcome) and collective (spread) risks were consistently lower than other MDRO for extended spectrum beta-lactamase producing Enterobacteriaceae cases and higher for carbapenemase producing Enterobacteriaceae (CPE) cases. Regarding CPE cases, answers were influenced more by the resistance pattern (93%) than for other MDRO. The risk associated with vancomycin resistant Enterococci cases was considered higher for the collective impact than for the individual outcome (63% vs 40%). The intra-country agreement regarding the individual risk was globally poor varying from 0.00 (ICC: 0–0.25) to 0.51 (0.18–0.85). The overall agreement across countries was poor at 0.20 (0.07–0.33). IC specialists working in hospitals preserved from MDROs perceived a higher individual (local, p = 0.01; national, p Conclusions The perception of the risk associated with AMR varied greatly across IC specialists and countries, relying on contextual factors including the epidemiology. IC specialists working in high prevalence areas may underestimate both the individual and collective risks, and might further negatively promote the MDRO spread. These finding highlight the need to shape local and national control strategies according to risk perceptions and contextual factors.

This study aimed to evaluate risk factors for 30-day mortality among hospitalised patients with Pseudomonas aeruginosa bacteraemia, a highly fatal condition. A retrospective study was conducted between 1 January 2009 and 31 October 2015 in 25 centres (9 countries) including 2396 patients. Univariable and multivariable analyses of risk factors were conducted for the entire cohort and for patients surviving >= 48 h. A propensity score for predictors of appropriate empirical therapy was introduced into the analysis. Of the 2396 patients, 636 (26.5%) died within 30 days. Significant predictors (odds ratio and 95% confidence interval) of mortality in the multivariable analysis included patient-related factors: age (1.02, 1.01-1.03); female sex (1.34, 1.03-1.77); bedridden functional capacity (1.99, 1.24-3.21); recent hospitalisation (1.43, 1.07-1.92); concomitant corticosteroids (1.33, 1.02-1.73); and Charlson comorbidity index (1.05, 1.01-1.93). Infection-related factors were multidrug-resistant Pseudomonas (1.52, 1.15-2.1), nonurinary source (2.44, 1.54-3.85) and Sequential Organ Failure Assessment (SOFA) score (1.27, 1.18-1.36). Inappropriate empirical therapy was not associated with increased mortality (0.81, 0.49-1.33). Among 2135 patients surviving >= 48 h, hospital-acquired infection (1.59, 1.21-2.09), baseline endotracheal tube (1.63, 1.13-2.36) and ICU admission (1.53, 1.02-2.28) were additional risk factors. Risk factors for mortality among patients with P. aeruginosa were mostly irreversible. Early appropriate empirical therapy was not associated with reduced mortality. Further research should be conducted to explore subgroups that may not benefit from broad-spectrum antipseudomonal empirical therapy. Efforts should focus on prevention of infection, mainly hospital-acquired infection and multidrug-resistant pseudomonal infection. (C) 2019 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Objective:Automated surveillance of healthcare-associated infections reduces workload and improves standardization, but it has not yet been adopted widely. In this study, we assessed the performance and feasibility of an easy implementable framework to develop algorithms for semiautomated surveillance of deep incisional and organ-space surgical site infections (SSIs) after orthopedic, cardiac, and colon surgeries.Design:Retrospective cohort study in multiple countries.Methods:European hospitals were recruited and selected based on the availability of manual SSI surveillance data from 2012 onward (reference standard) and on the ability to extract relevant data from electronic health records. A questionnaire on local manual surveillance and clinical practices was administered to participating hospitals, and the information collected was used to pre-emptively design semiautomated surveillance algorithms standardized for multiple hospitals and for center-specific application. Algorithm sensitivity, positive predictive value, and reduction of manual charts requiring review were calculated. Reasons for misclassification were explored using discrepancy analyses.Results:The study included 3 hospitals, in the Netherlands, France, and Spain. Classification algorithms were developed to indicate procedures with a high probability of SSI. Components concerned microbiology, prolonged length of stay or readmission, and reinterventions. Antibiotics and radiology ordering were optional. In total, 4,770 orthopedic procedures, 5,047 cardiac procedures, and 3,906 colon procedures were analyzed. Across hospitals, standardized algorithm sensitivity ranged between 82% and 100% for orthopedic surgery, between 67% and 100% for cardiac surgery, and between 84% and 100% for colon surgery, with 72%–98% workload reduction. Center-specific algorithms had lower sensitivity.Conclusions:Using this framework, algorithms for semiautomated surveillance of SSI can be successfully developed. The high performance of standardized algorithms holds promise for large-scale standardization.

COACH working group.-- The paper is based on the discussion during the annual meeting of the EPI-Net project in Verona in September 2018., [Objectives] To systematically summarize the evidence on how to collect, analyse and report antimicrobial resistance (AMR) surveillance data to inform antimicrobial stewardship (AMS) teams providing guidance on empirical antibiotic treatment in healthcare settings., [Methods] The research group identified 10 key questions about the link between AMR surveillance and AMS using a checklist of 9 elements for good practice in health research priority settings and a modified 3D combined approach matrix, and conducted a systematic review of published original studies and guidelines on the link between AMR surveillance and AMS., [Results] The questions identified focused on AMS team composition; minimum infrastructure requirements for AMR surveillance; organisms, samples and susceptibility patterns to report; data stratification strategies; reporting frequency; resistance thresholds to drive empirical therapy; surveillance in high-risk hospital units, long-term care, outpatient and veterinary settings; and surveillance data from other countries. Twenty guidelines and seven original studies on the implementation of AMR surveillance as part of an AMS programme were included in the literature review., [Conclusions] The evidence summarized in this review provides a useful basis for a more integrated process of developing procedures to report AMR surveillance data to drive AMS interventions. These procedures should be extended to settings outside the acute-care institutions, such as long-term care, outpatient and veterinary. Without proper AMR surveillance, implementation of AMS policies cannot contribute effectively to the fight against MDR pathogens and may even worsen the burden of adverse events from such interventions.

The antibacterial agents currently in clinical development are predominantly derivatives of well-established antibiotic classes and were selected to address the class-specific resistance mechanisms and determinants that were known at the time of their discovery. Many of these agents aim to target the antibiotic-resistant priority pathogens listed by the WHO, including Gram-negative bacteria in the critical priority category, such as carbapenem-resistant Acinetobacter, Pseudomonas and Enterobacterales. Although some current compounds in the pipeline have exhibited increased susceptibility rates in surveillance studies that depend on geography, pre-existing cross-resistance both within and across antibacterial classes limits the activity of many of the new agents against the most extensively drug-resistant (XDR) and pan-drug-resistant (PDR) Gram-negative pathogens. In particular, cross-resistance to unrelated classes may occur by co-selection of resistant strains, thus leading to the rapid emergence and subsequent spread of resistance. There is a continued need for innovation and new-class antibacterial agents in order to provide effective therapeutic options against infections specifically caused by XDR and PDR Gram-negative bacteria. New antibacterial agents are urgently needed to address the global increase in resistance. In this Review, Theuretzbacher and colleagues critically review the current published literature and publicly available information on antibacterial agents in all phases of clinical development.

Supplemental Digital Content is available in the text., Objective: Pulmonary thrombosis is observed in severe acute respiratory syndrome coronavirus 2 pneumonia. Aim was to investigate whether subpopulations of platelets were programmed to procoagulant and inflammatory activities in coronavirus disease 2019 (COVID-19) patients with pneumonia, without comorbidities predisposing to thromboembolism. Approach and Results: Overall, 37 patients and 28 healthy subjects were studied. Platelet-leukocyte aggregates, platelet-derived microvesicles, the expression of P-selectin, and active fibrinogen receptor on platelets were quantified by flow cytometry. The profile of 45 cytokines, chemokines, and growth factors released by platelets was defined by immunoassay. The contribution of platelets to coagulation factor activity was selectively measured. Numerous platelet-monocyte (mean±SE, 67.9±4.9%, n=17 versus 19.4±3.0%, n=22; P

Integrase strand transfer inhibitors (INSTIs) are a class of antiretroviral drugs with high virologic efficacy and excellent tolerability. Recent evidence showed a possible link of dolutegravir-based regimens with weight gain, and a relationship between raltegravir use and changes in adipose tissue density and metabolic abnormalities, with an increased cardiovascular risk, has been suggested. We describe a case where dolutegravir monotherapy led to a decrease in adipose tissue density.

For the COMBACTE-MAGNET-EPI-Net Consortium. In Press., [Objectives] In 2017 the WHO published a global priority list of 12 antibiotic-resistant bacteria (ARB) in urgent need of new antibiotics. We aimed to identify and assess publicly accessible mandatory surveillance systems and outbreaks reporting for these pathogens in the 28 European Union and four European Free Trade Association member states. [Methods] Compulsory reporting was mapped by reviewing national documents without applying language restrictions and through expert consultation. Information on surveillance targets, indicators, metrics and dissemination modalities was extracted and a qualitative assessment was performed for open access systems only. [Results] Twenty-one countries (66%) had a mandate to survey at least one among the 12 WHO priority pathogens; 15 provided access to surveillance frameworks. These systems covered most frequently carbapenem-resistant Enterobacteriales (12; 38%), methicillin-resistant Staphylococcus aureus (12; 38%), and vancomycin-resistant enterococci (8; 25%). None of the European countries required reporting of resistance in Salmonella, Campylobacter, Helicobacter pylori and Neisseria gonorrhoeae. High heterogeneity was observed in data collection, reporting and dissemination among countries with clinical outcomes and risk factors being reported in less than half (22% and 25%). Only six countries (19%) implemented mandatory surveillance of outbreaks due to at least one WHO priority pathogen. [Conclusions] Our review shows that despite the increasing burden of ARB on the European population, very few countries implemented mandatory surveillance and outbreak reporting of the WHO priority pathogens. International efforts are needed to define the effectiveness of implementing mandatory reporting of these pathogens and to assess their role in reducing the spread of ARB in health-care and community settings., This research project receives support from the Innovative Medicines Initiative Joint Undertaking under grant agreement numbers 115737 (COMBACTE-MAGNET), resources of which are composed of financial contributions from the European Union Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution.

Background: The COVID-19 pandemic has resulted in many health systems worldwide facing an imbalance between patients’ need and available resources. No previous studies have developed explicit recommendations for selecting patients most likely to benefit from hospitalisation in settings with an unsolvable hospital-bed shortage. Methods: Multi-Criteria Decision Analysis (MCDA) was used to determine weights for criteria to prioritise COVID-19 patients for admission to hospital. The MCDA was applied in two main steps: specification of criteria for prioritising COVID-19 patients, and levels within each criterion; and determination of weights for the criteria based on experts’ knowledge and experience in managing COVID-19 patients, via an online survey. Criteria were selected based on available COVID-19 evidence with a focus on healthcare settings with limited resources. Findings: Eleven criteria for prioritising patients were specified, and 103 MDs caring for COVID-19 patients completed the survey to determine the criteria’s weights. The 11 criteria (and levels), in decreasing order of importance [mean weights, summing to 100%], are: PaO2 (>80, 70-80, and 96%, 92-96%, and 20 breaths/min) [9∙5%]; comorbidities (diabetes, respiratory/cardiovascular diseases, and onco-haematological diseases) [6.5%]; living with vulnerable people (people with comorbidities, pregnant women, and immunosuppressed patients) [6∙4%]; body mass index ( 40) [5∙6%]; duration of symptoms before hospital evaluation ( 7 days) [5∙4%]; CRP (normal / high based on local cut off) [5∙1%]; and age (18-50, 50-70, and >70) [3∙8%]. Interpretation: MCDA can be used for prioritising patients for hospitalisation when prioritisation is necessary and evidence for disease predictors is limited or unavailable. MCDA is likely to be especially useful in low- and middle-income countries where effective national contingency plans are difficult to establish. Funding Statement: This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 820755. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA and bioMerieux SA, Janssen Pharmaceutica NV, Accelerate Diagnostics S.L., Abbott, Bio-Rad Laboratories, BD Switzerland Sarl, and The Wellcome Trust Limited. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: There were no humans participating in the research project. Briefly, in the study a list of variables/criteria W ere selected from the scientific literature and the Multi-Criteria Decision Analysis (based on PAPRIKA method) was applied in order to give a weight/score (total 100%) to each criterion. For this reason, the study was exempted from ethical review/clearance.

[Background] The possibility of bloodstream infections caused by third-generation cephalosporin-resistant Enterobacterales (3GC-R-BSI) leads to a trade-off between empiric inappropriate treatment (IAT) and unnecessary carbapenem use (UCU). Accurately predicting 3GC-R-BSI could reduce IAT and UCU. We externally validate 2 previously derived prediction rules for community-onset (CO) and hospital-onset (HO) suspected bloodstream infections., [Methods] In 33 hospitals in 13 countries we prospectively enrolled 200 patients per hospital in whom blood cultures were obtained and intravenous antibiotics with coverage for Enterobacterales were empirically started. Cases were defined as 3GC-R-BSI or 3GC-R gram-negative infection (3GC-R-GNI) (analysis 2); all other outcomes served as a comparator. Model discrimination and calibration were assessed. Impact on carbapenem use was assessed at several cutoff points., [Results] 4650 CO infection episodes were included and the prevalence of 3GC-R-BSI was 2.1% (n = 97). IAT occurred in 69 of 97 (71.1%) 3GC-R-BSI and UCU in 398 of 4553 non–3GC-R-BSI patients (8.7%). Model calibration was good, and the AUC was .79 (95% CI, .75–.83) for 3GC-R-BSI. The prediction rule potentially reduced IAT to 62% (60/97) while keeping UCU comparable at 8.4% or could reduce UCU to 6.3% (287/4553) while keeping IAT equal. IAT and UCU in all 3GC-R-GNIs (analysis 2) improved at similar percentages. 1683 HO infection episodes were included and the prevalence of 3GC-R-BSI was 4.9% (n = 83). Here model calibration was insufficient., [Conclusions] A prediction rule for CO 3GC-R infection was validated in an international cohort and could improve empirical antibiotic use. Validation of the HO rule yielded suboptimal performance., J. R.-B. receives funds for research from Plan Nacional de I+D+i 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0001), co-financed by the European Development Regional Fund “A Way to Achieve Europe,” Operative Program Intelligent Growth 2014-2020.

[Introduction] Despite the increasing importance of infections due to multidrug-resistant organisms (MDROs), there is a lack of comprehensive information about the burden of disease and outcomes of key infections caused by these pathogens. The aim of the ABOUT-MDRO (A systematic review on the burden and outcomes of infections due to multidrug resitant organisms) project is to provide estimations of the burden of some key infections and their outcomes caused by the target MDROs., [Methods and analysis] A systematic literature search will be performed using MEDLINE/PubMed, Elsevier’s SCOPUS, Cochrane library, Clinical trials and Web of Science, as well as the Surveillance Systems from Public Health Institutions and Scientific Societies for Antimicrobial Resistance and Healthcare-Associated Infections in Europe database of European surveillance systems, for data on prevalence/incidence, mortality and length of stay of target infections in hospitalised patients (including ventilator-associated pneumonia, hospital-acquired pneumonia, complicated intra-abdominal infections, complicated urinary tract infections, skin and soft tissue infections and bloodstream infections) and in specific populations (children, hospital wards, neutropenic patients) caused by cephalosporin-resistant or carbapenem-resistant Enterobacteriaceae, carbapenem-resistant Pseudomonas aeruginosa and Acinetobacter spp., methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus spp. The information retrieved will be tabulated and pooled estimates and 95% CIs calculated of rates and outcomes, using random effects models. Relationships between rates and outcomes in randomised control trials and epidemiological studies, and data of proportions and incidence/prevalence rates will also be analysed. The information collected in this study will be useful for identifying gaps in our knowledge in terms of incidence/prevalence and clinical outcomes of infections caused by MDROs, and for informing priorities in infection control and the research and design of appropriate studies., [Ethics and dissemination] This study will be based on published data so we did not require ethical approval. Formal consent is not required. The results of this review will be reported according to the Preferred Reporting Items for Systematic Review and Meta-Analyses statement. Data will be presented at international conferences and published in peer-reviewed journals., [Registration details] PROSPERO (https://www.crd.york.ac.uk/prospero/) (CRD42019124185)., The ABOUT-MDRO Study is part of the COMBACTE-MAGNET project (Combatting Bacterial Resistance in Europe - Molecules against Gram-negative Infections), Innovative Medicines Initiative (IMI), European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in-kind contribution, Grant agreement 115737. ZRP-B and JR-B received funding for research from Plan Nacional de I+D+i 2013‐2016 and the Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0001), co-financed by the European Development Regional Fund 'A way to achieve Europe', Operative Programme Intelligent Growth 2014‐2020.

Objectives This case study addresses: (i) antibiotic treatment options for Staphylococcus aureus bacteraemia (SAB), for both empirical and targeted therapy; (ii) the current status of and priorities for the antibiotic pipeline to ensure access of effective antibiotics for SAB; and (iii) strategies for responsible antibiotic use relevant to the clinical management of SAB. Methods Evidence to address the aims was extracted from the following information sources: (i) EUCAST and CLSI recommendations, summaries of product characteristics (SPCs), antibiotic treatment guidelines and the textbook Kucers’ The Use of Antibiotics; (ii) the www.clinicaltrial.gov database; and (iii) quality indicators for responsible antibiotic use. Results Current monotherapy treatment options for SAB include only three drug classes (β-lactams, glycopeptides and lipopeptides), of which two also cover MRSA bacteraemia (glycopeptides and lipopeptides). The analysis of the antibiotic pipeline and ongoing clinical trials revealed that several new antibiotics with S. aureus (including MRSA) coverage were developed in the past decade (2009–19). However, none belonged to a new antibiotic class or had superior effectiveness and their added clinical value for SAB remains to be proven. Responsible antibiotic use for the treatment of SAB was illustrated using 11 quality indicators. Conclusions Awareness of the problem of a limited antibiotic arsenal, together with incentives (e.g. push incentives), is needed to steer the R&D landscape towards the development of novel and effective antibiotics for treating SAB. In the meantime, responsible antibiotic use guided by quality indicators should preserve the effectiveness of currently available antibiotics for treating SAB.

Key points: COVID-19 is a novel pandemic disease whose pathophysiology and clinical description are still not completely defined. Besides respiratory symptoms, gastrointestinal (GI) symptoms (especially including anorexia, diarrhea, and abdominal pain) represent the commonest clinical manifestations. Emerging data point out that severe SARS-CoV-2 infection causes an immune dysregulation, which in turn may favor other infections. Here we describe a patient with severe COVID-19 pneumonia who developed in the resolving phase abdominal pain associated to cytomegalovirus (CMV)-induced duodenitis with bleeding, and pancreatitis. A high level of suspicion toward multiple infections, including CMV, should be maintained in COVID-19 patients with heterogeneous clinical manifestations.

Antibiotic resistance is increasing worldwide. The implementation of antibiotic stewardship programmes (ASPs) is of utmost importance to optimize antibiotic use in order to prevent resistance development without harming patients. The emergency department (ED), cornerstone between hospital and community, represents a crucial setting for addressing ASP implementation; however, evidence data on ASP in ED are poor. In this study, a 4-year, non-restrictive, multi-faceted ASP was implemented in a general ED with the aim to evaluate its impact on antibiotic use and costs. Secondly, the study focused on assessing the impact on length of hospital stay (LOS), Clostridioides difficile infection (CDI) incidence rate, and mortality in the patients’ group admitted from ED to medical wards. The ASP implementation was associated with a reduction of antibiotic use and costs. A mild but sustained LOS decrease in all medical wards and a significant downward trend of CDI incidence rate were observed, while mortality did not significantly change. In conclusion, the implementation of our ED-based ASP has demonstrated to be feasible and safe and might clinically benefit the hospital admitted patients’ group. Further research is needed to identify the most suitable ASP design for ED and the key outcome measures to reliably assess its effectiveness.