Predictors of clinical evolution of SARS-CoV-2 infection in hematological patients: A systematic review and meta-analysis.

Main aim of this systematic review is to quantify the risk and identify predictors of clinical evolution of SARS-CoV-2 in hematological patients compared to different control populations. Two independent reviewers screened the literature assessing clinical outcomes of SARS-CoV-2 infection in adult patients with active hematological malignancies published up to June 2021. Primary outcome was COVID-19 related mortality, secondary outcomes were hospital and intensive-care admission, mechanical ventilation (MV), and thromboembolic events. Variables related to study setting, baseline patients' demographic, comorbidities, underlying hematological disease, ongoing chemotherapy, COVID-19 presentation, and treatments were extracted. A total of 67 studies including 10,061 hematological patients and 111,143 controls were included. Most of the studies were retrospective cohorts (51 studies, 76%) and only 19 (13%) provided data for a control group. A significant increased risk of clinical progression in the hematological population compared to the controls was found in terms of COVID-19 related mortality (OR, 2.12; 95% CI, 1.77-2.54), hospitalization (OR, 1.98; 95% CI, 1.15-3.43), intensive-care admission (OR, 1.77; 95% CI, 1.38-2.26), and MV (OR, 2.17; 95% CI, 1.71-2.75). The risk remained significantly higher in the subgroup analysis comparing hematological patients versus solid cancer. Meta-regression analysis of uncontrolled studies showed that older age, male sex, and hypertension were significantly related to worse clinical outcomes of COVID-19 in hematological population. Older age and hypertension were found to be associated also to thromboembolic events. In conclusion, hematological patients have a higher risk of COVID-19 clinical progression compared to both the general population and to patients with solid cancer.

COVID-19 seroprevalence amongst healthcare workers: potential biases in estimating infection prevalence.

SARS-CoV-2 serological tests are used to assess the infection seroprevalence within a population. This study aims at assessing potential biases in estimating infection prevalence amongst healthcare workers (HCWs) when different diagnostic criteria are considered. A multi-site cross-sectional study was carried out in April-September 2020 amongst 1.367 Italian HCWs. SARS-CoV-2 prevalence was assessed using three diagnostic criteria: RT-PCR on nasopharyngeal swab, point-of-care fingerprick serological test (POCT) result and COVID-19 clinical pathognomonic presentation. A logistic regression model was used to estimate the probability of POCT-positive result in relation to the time since infection (RT-PCR positivity). Among 1.367 HCWs, 69.2% were working in COVID-19 units. Statistically significant differences in age, role and gender were observed between COVID-19/non-COVID-19 units. Prevalence of SARS-CoV-2 infection varied according to the criterion considered: 6.7% for POCT, 8.1% for RT-PCR, 10.0% for either POCT or RT-PCR, 9.6% for infection pathognomonic clinical presentation and 17.6% when at least one of the previous criteria was present. The probability of POCT-positive result decreased by 1.1% every 10 days from the infection. This study highlights potential biases in estimating SARS-CoV-2 point-prevalence data according to the criteria used. Although informative on infection susceptibility and herd immunity level, POCT serological tests are not the best predictors of previous COVID-19 infections for public health monitoring programmes.

The role of antimicrobial stewardship in preventing KPC-producing Klebsiella pneumoniae.

Antimicrobial stewardship programmes are widely considered to be a core component of the response to the antimicrobial resistance threat. However, a positive impact of these interventions in terms of microbiological outcomes remains difficult to demonstrate, especially when focusing on specific resistant phenotypes. The first part of this review aims to explore the complex relationship between antibiotic exposure and resistance development in KPC-producing Klebsiella pneumoniae. In the second part we aim to summarize published examples of antimicrobial stewardship interventions intended to impact on the epidemiology of KPC-producing K. pneumoniae. For this purpose, a literature search was performed and seven studies were included in the review. Both restrictive and non-restrictive interventions were associated with an overall reduction in antibiotic consumption, and a decrease in carbapenem resistance rates was observed in five studies. The overall quality of the evidence was low, mainly due to the poor reporting of microbiological outcomes, lack of a control group and suboptimal study design. Although the link between antibiotic use and resistance development is supported by strong evidence, demonstrating the impact of antimicrobial stewardship interventions on microbiological outcomes remains difficult. Studies with adequate design and appropriate outcome measures are needed to further promote antimicrobial stewardship and elucidate which interventions are more successful for controlling the spread of KPC-producing K. pneumoniae.

Role of new antibiotics for KPC-producing Klebsiella pneumoniae.

Klebsiella pneumoniae has accumulated a wide range of resistance determinants and has evolved into a difficult-to-treat pathogen that poses an increasing healthcare threat. KPC is an important marker for extensively drug-resistant (XDR) organisms with limited treatment options. In response to the medical need for new treatment options, several new antibiotics have been developed and registered recently. The ß-lactamase inhibitor (BLI) combinations ceftazidime/avibactam, meropenem/vaborbactam and imipenem/relebactam, the cephalosporin-siderophore conjugate cefiderocol, the aminoglycoside derivative plazomicin and the tetracycline derivative eravacycline, focus on carbapenem-resistant Enterobacterales. These modified agents from old antibiotic classes illustrate the challenges of this requirement to address class-specific resistance mechanisms while critical gaps and some cross-resistance within a class, or to unrelated antibiotic classes, remain. The diverse molecular mechanisms and increasing diversification of carbapenem resistance among Klebsiella isolates requires improved rapid molecular diagnostic capabilities and stringent stewardship programmes to preserve the efficacy of new antibiotics for as long as possible.

Platelets Promote Thromboinflammation in SARS-CoV-2 Pneumonia.

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<0.0001) and platelet-granulocyte conjugates (34.2±4.04% versus 8.6±0.7%; P<0.0001) were detected in patients. Resting patient platelets had similar levels of P-selectin (10.9±2.6%, n=12) to collagen-activated control platelets (8.7±1.5%), which was not further increased by collagen activation on patient platelets (12.4±2.5%, P=nonsignificant). The agonist-stimulated expression of the active fibrinogen receptor was reduced by 60% in patients (P<0.0001 versus controls). Cytokines (IL [interleukin]-1α, IL-1ß, IL-1RA, IL-4, IL-10, IL-13, IL, 17, IL-27, IFN [interferon]-α, and IFN-γ), chemokines (MCP-1/CCL2 [monocyte chemoattractant protein 1]), and growth factors (VEGF [vascular endothelial growth factor]-A/D) were released in significantly larger amounts upon stimulation of COVID-19 platelets. Platelets contributed to increased fibrinogen, VWF (von Willebrand factor), and factor XII in COVID-19 patients. Patients (28.5±0.7 s, n=32), unlike controls (31.6±0.5 s, n=28; P<0.001), showed accelerated factor XII-dependent coagulation. CONCLUSIONS: Platelets in COVID-19 pneumonia are primed to spread proinflammatory and procoagulant activities in systemic circulation.

The role of combination therapy in the treatment of severe infections caused by carbapenem resistant gram-negatives: a systematic review of clinical studies.

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.

White Paper: Bridging the gap between surveillance data and antimicrobial stewardship in long-term care facilities-practical guidance from the JPIAMR ARCH and COMBACTE-MAGNET EPI-Net networks.

BACKGROUND: In long-term care facilities (LTCFs) residents often receive inappropriate antibiotic treatment and infection prevention and control practices are frequently inadequate, thus favouring acquisition of MDR organisms. There is increasing evidence in the literature describing antimicrobial stewardship (AMS) activities in LTCFs, but practical guidance on how surveillance data should be linked with AMS activities in this setting is lacking. To bridge this gap, the JPIAMR ARCH and COMBACTE-MAGNET EPI-Net networks joined their efforts to provide practical guidance for linking surveillance data with AMS activities. MATERIALS AND METHODS: Considering the three main topics [AMS leadership and accountability, antimicrobial usage (AMU) and AMS, and antimicrobial resistance (AMR) and AMS], a literature review was performed and a list of target actions was developed. Consensus on target actions was reached through a RAND-modified Delphi process involving 40 experts from 18 countries and different professional backgrounds adopting a One Health approach. RESULTS: From the 25 documents identified, 25 target actions were retrieved and proposed for expert evaluation. The consensus process produced a practical checklist including 23 target actions, differentiating between essential and desirable targets according to clinical relevance and feasibility. Flexible proposals for AMS team composition and leadership were provided, with a strong emphasis on the need for well-defined and adequately supported roles and responsibilities. Specific antimicrobial classes, AMU metrics, pathogens and resistance patterns to be monitored are addressed. Effective reporting strategies are described. CONCLUSIONS: The proposed checklist represents a practical tool to support local AMS teams across a wide range of care delivery organization and availability of resources.

White Paper: Bridging the gap between surveillance data and antimicrobial stewardship in the outpatient sector-practical guidance from the JPIAMR ARCH and COMBACTE-MAGNET EPI-Net networks.

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.

White Paper: Bridging the gap between human and animal surveillance data, antibiotic policy and stewardship in the hospital sector-practical guidance from the JPIAMR ARCH and COMBACTE-MAGNET EPI-Net networks.

BACKGROUND: Antimicrobial surveillance and antimicrobial stewardship (AMS) are essential pillars in the fight against antimicrobial resistance (AMR), but practical guidance on how surveillance data should be linked to AMS activities is lacking. This issue is particularly complex in the hospital setting due to structural heterogeneity of hospital facilities and services. The JPIAMR ARCH and COMBACTE-MAGNET EPI-Net networks have joined efforts to formulate a set of target actions for linking surveillance data with AMS activities. METHODS: A scoping review of the literature was carried out addressing research questions on three areas: (i) AMS leadership and accountability; (ii) antimicrobial usage and AMS; (iii) AMR and AMS. Consensus on the target actions was reached through a RAND-modified Delphi process involving over 40 experts in different fields from 18 countries. RESULTS: Evidence was retrieved from 51 documents. Initially 38 targets were proposed, differentiated as essential or desirable according to clinical relevance, feasibility and applicability to settings and resources. In the first consultation round, preliminary agreement was reached for 32 targets. Following a second consultation, 27 targets were approved, 11 were deleted and 4 were suggested for rephrasing, leading to a final approved list of 34 target actions in the form of a practical checklist. CONCLUSIONS: This White Paper provides a pragmatic and flexible tool to guide the development of calibrated hospital-surveillance-based AMS interventions. The strength of this tool is that it is a comprehensive perspective that takes into account the hospital patient case-mix and the related epidemiology, which ultimately drives antimicrobial usage, and the feasibility in low-resource settings.

Prevalence of Antibiotic Resistance in Helicobacter pylori: A Systematic Review and Meta-analysis in World Health Organization Regions.

BACKGROUND & AIMS: In 2017, the World Health Organization (WHO) designated clarithromycin-resistant Helicobacter pylori a high priority for antibiotic research and development. However, there are no clear data on the global distribution of resistance or its clinical effects. We performed a systematic review and meta-analysis to assess the distribution of H pylori resistance to commonly used antibiotics and to measure the association between antibiotic resistance and treatment failure. METHODS: We searched publication databases for studies that assessed rates of H pylori resistance to clarithromycin, metronidazole, levofloxacin, amoxicillin, or tetracycline. Pooled estimates of primary and secondary resistance and 95% confidence intervals (CIs) were grouped by WHO region. The association between antibiotic resistance and treatment failure was measured by extracting data on treatment efficacy in patients with resistant and susceptible isolates and pooling odds ratios with 95% CIs. RESULTS: We identified 178 studies, comprising 66,142 isolates from 65 countries. Primary and secondary resistance rates to clarithromycin, metronidazole, and levofloxacin were ≥15% in all WHO regions, except primary clarithromycin resistance in the Americas (10%; 95% CI, 4%-16%) and South-East Asia region (10%; 95% CI, 5%-16%) and primary levofloxacin resistance in the European region (11%; 95% CI, 9%-13%). There was considerable heterogeneity (I2 > 75%) among all analyses-this might have resulted from the grouping of resistance rates by country. Increasing antibiotic resistance was observed in most WHO regions. Resistance to clarithromycin was significantly associated with failure of clarithromycin-containing regimens (odds ratio, 6.97; 95% CI, 5.23-9.28; P < .001). CONCLUSIONS: Resistance of H pylori to antibiotics has reached alarming levels worldwide, which has a great effect on efficacy of treatment. Local surveillance networks are required to select appropriate eradication regimens for each region.

Gross national income and antibiotic resistance in invasive isolates: analysis of the top-ranked antibiotic-resistant bacteria on the 2017 WHO priority list.

OBJECTIVES: To assess the association between country income status and national prevalence of invasive infections caused by the top-ranked bacteria on the WHO priority list: carbapenem-resistant (CR) Acinetobacter spp., Klebsiella spp. and Pseudomonas aeruginosa; third-generation cephalosporin-resistant (3GCR) Escherichia coli and Klebsiella spp.; and MRSA and vancomycin-resistant Enterococcus faecium (VR E. faecium). METHODS: Active surveillance systems providing yearly prevalence data from 2012 onwards for the selected bacteria were included. The gross national income (GNI) per capita was used as the indicator for income status of each country and was log transformed to account for non-linearity. The association between antibiotic prevalence data and GNI per capita was investigated individually for each bacterium through linear regression. RESULTS: Surveillance data were available from 67 countries: 38 (57%) were high income, 16 (24%) upper-middle income, 11 (16%) lower-middle income and two (3%) low income countries. The regression showed significant inverse association (P<0.0001) between resistance prevalence of invasive infections and GNI per capita. The highest rate of increase per unit decrease in log GNI per capita was observed in 3GCR Klebsiella spp. (22.5%, 95% CI 18.2%-26.7%), CR Acinetobacter spp. (19.2% 95% CI 11.3%-27.1%) and 3GCR E. coli (15.3%, 95% CI 11.6%-19.1%). The rate of increase per unit decrease in log GNI per capita was lower in MRSA (9.5%, 95% CI 5.2%-13.7%). CONCLUSIONS: The prevalence of invasive infections caused by the WHO top-ranked antibiotic-resistant bacteria is inversely associated with GNI per capita at the global level. Public health interventions designed to limit the burden of antimicrobial resistance should also consider determinants of poverty and inequality, especially in lower-middle income and low income countries.

Early discontinuation of antibiotics for febrile neutropenia versus continuation until neutropenia resolution in people with cancer.

BACKGROUND: People with cancer with febrile neutropenia are at risk of severe infections and mortality and are thus treated empirically with broad-spectrum antibiotic therapy. However, the recommended duration of antibiotic therapy differs across guidelines. OBJECTIVES: To assess the safety of protocol-guided discontinuation of antibiotics regardless of neutrophil count, compared to continuation of antibiotics until neutropenia resolution in people with cancer with fever and neutropenia, in terms of mortality and morbidity. To assess the emergence of resistant bacteria in people with cancer treated with short courses of antibiotic therapy compared with people with cancer treated until resolution of neutropenia. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 10) in the Cochrane Library, MEDLINE, Embase, and LILACS up to 1 October 2018. We searched the metaRegister of Controlled Trials and the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov for ongoing and unpublished trials. We reviewed the references of all identified studies for additional trials and handsearched conference proceedings of international infectious diseases and oncology and haematology conferences. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared a short antibiotic therapy course in which discontinuation of antibiotics was guided by protocols regardless of the neutrophil count to a long course in which antibiotics were continued until neutropenia resolution in people with cancer with febrile neutropenia. The primary outcome was 30-day or end of follow-up all-cause mortality. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed all studies for eligibility, extracted data, and assessed risk of bias for all included trials. We calculated risk ratios (RRs) with 95% confidence intervals (CIs) whenever possible. For dichotomous outcomes with zero events in both arms of the trials, we conducted meta-analysis of risk differences (RDs) as well. For continuous outcomes, we extracted means with standard deviations (SD) from the studies and computed mean difference (MD) and 95% CI. If no substantial clinical heterogeneity was found, trials were pooled using the Mantel-Haenszel fixed-effect model. MAIN RESULTS: We included eight RCTs comprising a total of 662 distinct febrile neutropenia episodes. The studies included adults and children, and had variable design and criteria for discontinuation of antibiotics in both study arms. All included studies but two were performed before the year 2000. All studies included people with cancer with fever of unknown origin and excluded people with microbiological documented infections.We found no significant difference between the short-antibiotic therapy arm and the long-antibiotic therapy arm for all-cause mortality (RR 1.38, 95% CI 0.73 to 2.62; RD 0.02, 95% CI -0.02 to 0.05; low-certainty evidence). We downgraded the certainty of the evidence to low due to imprecision and high risk of selection bias. The number of fever days was significantly lower for people in the short-antibiotic treatment arm compared to the long-antibiotic treatment arm (mean difference -0.64, 95% CI -0.96 to -0.32; I² = 30%). In all studies, total antibiotic days were fewer in the intervention arm by three to seven days compared to the long antibiotic therapy. We found no significant differences in the rates of clinical failure (RR 1.23, 95% CI 0.85 to 1.77; very low-certainty evidence). We downgraded the certainty of the evidence for clinical failure due to variable and inconsistent definitions of clinical failure across studies, possible selection bias, and wide confidence intervals. There was no significant difference in the incidence of bacteraemia occurring after randomisation (RR 1.56, 95% CI 0.91 to 2.66; very low-certainty evidence), while the incidence of any documented infections was significantly higher in the short-antibiotic therapy arm (RR 1.67, 95% CI 1.08 to 2.57). There was no significant difference in the incidence of invasive fungal infections (RR 0.86, 95% CI 0.32 to 2.31) and development of antibiotic resistance (RR 1.49, 95% CI 0.62 to 3.61). The data on hospital stay were too sparse to permit any meaningful conclusions. AUTHORS' CONCLUSIONS: We could make no strong conclusions on the safety of antibiotic discontinuation before neutropenia resolution among people with cancer with febrile neutropenia based on the existing evidence and its low certainty. Results of microbiological outcomes favouring long antibiotic therapy may be misleading due to lower culture positivity rates under antibiotic therapy and not true differences in infection rates. Well-designed, adequately powered RCTs are required that address this issue in the era of rising antibiotic resistance.

Combination versus monotherapy for the treatment of infections due to carbapenem-resistant Enterobacteriaceae.

PURPOSE OF REVIEW: Combination therapy is a common strategy for treatment of multidrug resistant infections. Despite the strong twin rationales of improving efficacy and reducing resistance development, the evidence supporting this strategy remains controversial. The aims of this review are to assess the most recent studies supporting the use of combination therapy for treating infections because of carbapenem-resistant Enterobacteriaceae (CRE) and to highlight relevant areas for further research. RECENT FINDINGS: Evidence supporting the use of combination therapy for the treatment of CRE remains limited to in-vitro experiments and observational studies with considerable risk of bias. Very few antibiotic combinations have been tested in well designed randomized controlled trials, making it difficult to draw general conclusions for clinical practice. SUMMARY: Further studies are urgently needed to test the most promising synergistic combinations. New drugs potentially active against CRE should also to be tested in studies with adequate sample size and truly representative of the general patient population.

Corticosteroids for pneumonia.

BACKGROUND: Pneumonia is a common and potentially serious illness. Corticosteroids have been suggested for the treatment of different types of infection, however their role in the treatment of pneumonia remains unclear. This is an update of a review published in 2011. OBJECTIVES: To assess the efficacy and safety of corticosteroids in the treatment of pneumonia. SEARCH METHODS: We searched the Cochrane Acute Respiratory Infections Group's Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS on 3 March 2017, together with relevant conference proceedings and references of identified trials. We also searched three trials registers for ongoing and unpublished trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that assessed systemic corticosteroid therapy, given as adjunct to antibiotic treatment, versus placebo or no corticosteroids for adults and children with pneumonia. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Two review authors independently assessed risk of bias and extracted data. We contacted study authors for additional information. We estimated risk ratios (RR) with 95% confidence intervals (CI) and pooled data using the Mantel-Haenszel fixed-effect model when possible. MAIN RESULTS: We included 17 RCTs comprising a total of 2264 participants; 13 RCTs included 1954 adult participants, and four RCTs included 310 children. This update included 12 new studies, excluded one previously included study, and excluded five new trials. One trial awaits classification.All trials limited inclusion to inpatients with community-acquired pneumonia (CAP), with or without healthcare-associated pneumonia (HCAP). We assessed the risk of selection bias and attrition bias as low or unclear overall. We assessed performance bias risk as low for nine trials, unclear for one trial, and high for seven trials. We assessed reporting bias risk as low for three trials and high for the remaining 14 trials.Corticosteroids significantly reduced mortality in adults with severe pneumonia (RR 0.58, 95% CI 0.40 to 0.84; moderate-quality evidence), but not in adults with non-severe pneumonia (RR 0.95, 95% CI 0.45 to 2.00). Early clinical failure rates (defined as death from any cause, radiographic progression, or clinical instability at day 5 to 8) were significantly reduced with corticosteroids in people with severe and non-severe pneumonia (RR 0.32, 95% CI 0.15 to 0.7; and RR 0.68, 95% CI 0.56 to 0.83, respectively; high-quality evidence). Corstocosteroids reduced time to clinical cure, length of hospital and intensive care unit stays, development of respiratory failure or shock not present at pneumonia onset, and rates of pneumonia complications.Among children with bacterial pneumonia, corticosteroids reduced early clinical failure rates (defined as for adults, RR 0.41, 95% CI 0.24 to 0.70; high-quality evidence) based on two small, clinically heterogeneous trials, and reduced time to clinical cure.Hyperglycaemia was significantly more common in adults treated with corticosteroids (RR 1.72, 95% CI 1.38 to 2.14). There were no significant differences between corticosteroid-treated people and controls for other adverse events or secondary infections (RR 1.19, 95% CI 0.73 to 1.93). AUTHORS' CONCLUSIONS: Corticosteroid therapy reduced mortality and morbidity in adults with severe CAP; the number needed to treat for an additional beneficial outcome was 18 patients (95% CI 12 to 49) to prevent one death. Corticosteroid therapy reduced morbidity, but not mortality, for adults and children with non-severe CAP. Corticosteroid therapy was associated with more adverse events, especially hyperglycaemia, but the harms did not seem to outweigh the benefits.

Follicular helper T-cells and virus-specific antibody response in primary and reactivated human cytomegalovirus infections of the immunocompetent and immunocompromised transplant patients.

Analysis of human cytomegalovirus (HCMV) primary infection in immunocompetent (n=40) and immunocompromised transplant patients (n=20) revealed that the median peak antibody titre neutralizing infection of epithelial cells was 16-fold higher in immunocompromised patients. The mechanism of this finding was investigated by measuring: (i) HCMV DNAemia; (ii) HCMV neutralizing antibodies; (iii) ELISA IgG antibody titre to HCMV glycoprotein complexes gHgLpUL128L, gHgLgO and gB; and (iv) HCMV-specific (IFN-γ+) CD4+ and CD8+ T-cells. Circulating CXCR5+ CD4+ (memory T follicular helper - TFH-cells) were identified as activated TFH (ICOS+PD-1++CCR7lo) and quiescent cells. In the early stages of primary infection, activated TFH cells increased in number. Concomitantly, both neutralizing and IgG antibodies to HCMV glycoproteins reached a peak, followed by a plateau. A stop in antibody rise occurred upon appearance of HCMV-specific CD4+ T-cells, HCMV clearance and progressive reduction in activated TFH cells. The main differences between healthy and transplant patients were that the latter had a delayed DNA peak, a much higher DNA load and delayed activated TFH cells and antibody peaks. Similar events were observed in clinically severe HCMV reactivations of transplant patients. A preliminary analysis of the specificity of the activated TFH cell response to viral proteins showed a major response to the pentamer gHgLpUL128L and gB. In conclusion, in the absence of T-cell immunity, one of the first lines of defence, during primary infection, is conferred by antibodies produced through the interaction of TFH cells and B-cells of germinal centres, resulting in differentiation of B-cells into antibody producing plasma cells.

Sepsis-related mortality: long-term trends in Northeastern Italy, including pandemic years.

BACKGROUND: Global estimates of sepsis mortality are based on multiple causes of death (MCOD, any mention of the condition on death certificates); however, MCOD data are sparse and mainly referring to the pre-pandemic period. OBJECTIVES: To investigate recent trends in sepsis-related mortality, associated sites of infection, and comorbidities in Veneto (Northeastern Italy). METHODS: Mortality records from 2008 to 2022 were extracted, and sepsis-related mortality was assessed based both on the underlying cause of death (UCOD) and on MCOD. The average annual percent change in age-standardised rates was estimated by join point regression through the whole study period. MCOD records were investigated to retrieve infection sites and comorbidities. RESULTS: Sepsis was mentioned in 63,479 death certificates, growing from 4.9% out of all deaths in 2008 to 12.9% in 2022. Age-standardised mortality rates increased yearly by 8.2% (95%CI 2.1-14.7%) based on the UCOD and by 5.9% (95%CI 5.3-6.5%) based on MCOD. Sharp peaks in monthly mortality were observed in correspondence with flu epidemics, COVID-19 pandemic waves, and periods of extreme heat. The percentage of sepsis-related deaths associated to urinary tract infections, and with mention of neurodegenerative disorders and chronic kidney disease increased over time. CONCLUSION: Raised awareness of physicians, ageing of the population, spread of antimicrobial resistance further fuelled by the COVID-19 pandemic are among reasons of increasing sepsis-related mortality in Italy. Continuous monitoring of sepsis by means of MCOD data and other surveillance tools is warranted.

How to tailor recommendations on the treatment of multi-drug resistant Gram-negative infections at country level integrating antibiotic stewardship principles within the GRADE-ADOLOPMENT framework.

Promoting the optimal use of antibiotics through evidence-based recommendations should be regarded as a crucial step in the global fight against antimicrobial resistance. Within this scope, several guidelines and guidance documents for antibiotic therapy have been published in recent years. All documents underline the limitations of existing evidence and remark on the need for tailoring recommendations at the national level, based on local epidemiology, availability of diagnostics and drugs, and antimicrobial stewardship principles. The GRADE-ADOLOPMENT methodology is an evidence-based methodology that allows the adoption, adaptation, and update of existing recommendations to specific settings without performing de novo systematic reviews and grading of the evidence. However, procedures to integrate this evidence with stewardship principles, countries' surveillance data, and capacity in terms of diagnostics and antibiotics' availability have never been defined. This Personal View provides the first example of a country's calibration of international evidence-based guidance documents on treating infections caused by multidrug-resistant bacteria. A panel of experts convened by the Italian Medicine Agency (AIFA) used the GRADE methodology for systematically extracting and evaluating 100 recommendations on the treatment of infections due to multidrug-resistant Gram-negative bacteria from 11 guidance documents and 24 systematic reviews. The ADOLOPMENT procedure was used to calibrate the existing recommendations to the national context, leading to the adoption of 64, the adaptation of 27, and the rejection of nine recommendations. We discuss the technical details of the GRADE-ADOLOPMENT application, the calibration process, and the human resources required to support such an effort. This Personal View also covers the challenges of integrating antibiotic stewardship principles in evidence-based recommendations for treating infections with very limited therapeutic and diagnostic options. The details presented here could support the easy transferability of the methodology to other countries and settings, particularly where the incidence of antibiotic-resistant infections is high.

European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines for Antimicrobial Stewardship in Emergency Departments (endorsed by European Association of Hospital Pharmacists).

SCOPE: This ESCMID guideline provides evidence-based recommendations to support a selection of appropriate antibiotic use practices for patients seen in the emergency department (ED) and guidance for their implementation. The topics addressed in this guideline are: 1) Do biomarkers or rapid pathogen tests improve antibiotic prescribing and/or clinical outcomes? 2) Does taking blood cultures in common infectious syndromes improve antibiotic prescribing and/or clinical outcomes? 3) Does watchful waiting without antibacterial therapy or with delayed antibiotic prescribing reduce antibiotic prescribing without worsening clinical outcomes in patients with specific infectious syndromes? 4) Do structured culture follow-up programs in patients discharged from the ED with cultures pending improve antibiotic prescribing? METHODS: An expert panel was convened by ESCMID and the guideline chair. The panel selected in consensus the four most relevant AMS topics according to pre-defined relevance criteria. For each main question for the four topics, a systematic review was performed, including randomized controlled trials and observational studies. Both clinical outcomes as well as stewardship process outcomes related to antibiotic use were deemed relevant. The literature searches were conducted between May 2021 and March 2022. In April 2022, the panel members were formally asked to suggest additional studies that were not identified in the initial searches. Data were summarized in a meta-analysis if possible or otherwise summarized narratively. The certainty of the evidence was classified according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. The guideline panel reviewed the evidence per topic critically appraising the evidence and formulated recommendations through a consensus-based process. The strength of the recommendations was classified as strong or weak. To substantiate the implementation process, implementation trials or observational studies describing facilitators/barriers for implementation were identified from the same searches and were summarized narratively. RECOMMENDATIONS: The recommendations on the use of biomarkers and rapid pathogen diagnostic tests focus on the initiation of antibiotics in patients admitted through the ED. Their effect on the discontinuation or de-escalation of antibiotics during hospital stay was not reported, neither was their effect on hospital infection prevention and control practices. The recommendations on watchful waiting (i.e., withholding antibiotics with some form of follow-up) focus on specific infectious syndromes for which the primary care literature was also included. The recommendations on blood cultures focus on the indication in three common infectious syndromes in the ED explicitly excluding patients with sepsis or septic shock. Most recommendations are based on very-low- and low-certainty of evidence, leading to weak recommendations or, when no evidence was available, to best practice statements. Implementation of these recommendations needs to be adapted to the specific settings and circumstances of the ED. The scarcity of high-quality studies in the area of antimicrobial stewardship in the ED highlights the need for future research in this field.

Modelling antimicrobial resistance transmission to guide personalized antimicrobial stewardship interventions and infection control policies in healthcare setting: a pilot study.

Infection control programs and antimicrobial stewardship have been proven effective in reducing the burden of diseases due to multidrug-resistant organisms, but quantifying the effect of each intervention is an open issue. For this aim, we propose a model to characterize the effect of interventions at single ward level. We adapted the Ross-Macdonald model to describe hospital cross-transmission dynamics of carbapenem resistant Klebsiella pneumoniae (CRKP), considering healthcare workers as the vectors transmitting susceptible and resistant pathogens among admitted patients. The model parameters were estimated from a literature review, further adjusted to reproduce observed clinical outcomes, and validated using real life data from a 2-year study in a university hospital. The model has been further explored through extensive sensitivity analysis, in order to assess the relevance of single interventions as well as their synergistic effects. Our model has been shown to be an effective tool to describe and predict the impact of interventions in reducing the prevalence of CRKP colonisation and infection, and can be extended to other specific hospital and pathological scenarios to produce tailored estimates of the most effective strategies.