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Objectives: The aim of this study was to quantify the time delay between screening and initiation of contact isolation for carriers of extended-spectrum beta-lactamase (ESBL)–producing Enterobacterales (ESBL-E). Methods: This study was a secondary analysis of contact isolation periods in a cluster-randomized controlled trial that compared 2 strategies to control ESBL-E (trial no. ISRCTN57648070). Patients admitted to 20 non-ICU wards in Germany, the Netherlands, Spain, and Switzerland were screened for ESBL-E carriage on admission, weekly thereafter, and on discharge. Data collection included the day of sampling, the day the wards were notified of the result, and subsequent ESBL-E isolation days. Results: Between January 2014 and August 2016, 19,122 patients, with a length of stay ≥2 days were included. At least 1 culture was collected for 16,091 patients (84%), with a median duration between the admission day and the day of first sample collection of 2 days (interquartile range [IQR], 1–3). Moreover, 854 (41%) of all 2,078 ESBL-E carriers remained without isolation during their hospital stay. In total, 6,040 ESBL-E days (32% of all ESBL-E days) accrued for patients who were not isolated. Of 2,078 ESBL-E-carriers, 1,478 ESBL-E carriers (71%) had no previous history of ESBL-E carriage. Also, 697 (34%) were placed in contact isolation with a delay of 4 days (IQR, 2–5), accounting for 2,723 nonisolation days (15% of ESBL-E days). Conclusions: Even with extensive surveillance screening, almost one-third of all ESBL-E days were nonisolation days. Limitations in routine culture-based ESBL-E detection impeded timely and exhaustive implementation of targeted contact isolation.

Background Older age is associated with increased severity and death from respiratory infections, including coronavirus disease 2019 (COVID-19). The tuberculosis BCG vaccine may provide heterologous protection against nontuberculous infections and has been proposed as a potential preventive strategy against COVID-19. Methods In this multicenter, placebo-controlled trial, we randomly assigned older adults (aged ≥60 years; n = 2014) to intracutaneous vaccination with BCG vaccine (n = 1008) or placebo (n = 1006). The primary end point was the cumulative incidence of respiratory tract infections (RTIs) that required medical intervention, during 12 months of follow-up. Secondary end points included the incidence of COVID-19, and the effect of BCG vaccination on the cellular and humoral immune responses. Results The cumulative incidence of RTIs requiring medical intervention was 0.029 in the BCG-vaccinated group and 0.024 in the control group (subdistribution hazard ratio, 1.26 [98.2% confidence interval, .65–2.44]). In the BCG vaccine and placebo groups, 51 and 48 individuals, respectively tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with polymerase chain reaction (subdistribution hazard ratio, 1.053 [95% confidence interval, .71–1.56]). No difference was observed in the frequency of adverse events. BCG vaccination was associated with enhanced cytokine responses after influenza, and also partially associated after SARS-CoV-2 stimulation. In patients diagnosed with COVID-19, antibody responses after infection were significantly stronger if the volunteers had previously received BCG vaccine. Conclusions BCG vaccination had no effect on the incidence of RTIs, including SARS-CoV-2 infection, in older adult volunteers. However, it improved cytokine responses stimulated by influenza and SARS-CoV-2 and induced stronger antibody titers after COVID-19 infection. Clinical trials registration EU Clinical Trials Register 2020-001591-15 ClinicalTrials.gov NCT04417335.

Background The prospective identification of patients at high risk for hospital-acquired/ventilator-associated bacterial pneumonia may improve clinical trial feasibility and foster antibacterial development. In a prior study conducted in the United States, clinical criteria were used to prospectively identify these patients; however, these criteria have not been applied in a European population. Methods Adults considered high risk for pneumonia (treatment with ventilation or high levels of supplemental oxygen) in the intensive care units of 7 European hospitals were prospectively enrolled from June 12 to December 27, 2017. We estimated the proportion of high-risk patients developing pneumonia according to US Food and Drug Administration guidance and a subset potentially eligible for antibacterial trial enrollment. We compared patient characteristics, treatment exposures, and pneumonia incidence in a European cohort and a previously described US cohort. Results Of 888 high-risk patients, 211/888 (24%) were treated for possible pneumonia, and 150/888 (17%) met the Food and Drug Administration definition for hospital-acquired/ventilator-associated bacterial pneumonia. A higher proportion of European patients treated for possible pneumonia met the pneumonia definition (150/211 [71%] vs 537/1464 [37%]; P Conclusions Clinical criteria prospectively identified high-risk patients with high rates of pneumonia in the European cohort. Despite higher rates of established risk factors and incident pneumonia, European patients were significantly less likely to receive antibiotics for possible pneumonia than US patients. Different treatment practices may contribute to lower rates of antibacterial trial enrollment in the United States.

Rationale: Recent studies showed that biological subphenotypes in acute respiratory distress syndrome (ARDS) provide prognostic enrichment and show potential for predictive enrichment. Objectives: To determine whether these subphenotypes and their prognostic and potential for predictive enrichment could be extended to other patients in the ICU, irrespective of fulfilling the definition of ARDS. Methods: This is a secondary analysis of a prospective observational study of adult patients admitted to the ICU. We tested the prognostic enrichment of both cluster-derived and latentclass analysis (LCA)-derived biological ARDS subphenotypes by evaluating the association with clinical outcome (ICU-day, 30-day mortality, and ventilator-free days) using logistic regression and Cox regression analysis. We performed a principal component analysis to compare blood leukocyte gene expression profiles between subphenotypes and the presence of ARDS. Measurements and Main Results: We included 2,499 mechanically ventilated patients (674 with and 1,825 without ARDS). The cluster-derived "reactive"subphenotype was, independently of ARDS, significantly associated with a higher probability of ICU mortality, higher 30-day mortality, and a lower probability of successful extubation while alive compared with the "uninflamed"subphenotype. The blood leukocyte gene expression profiles of individual subphenotypes were similar for patients with and without ARDS. LCA-derived subphenotypes also showed similar profiles. Conclusions: The prognostic and potential for predictive enrichment of biological ARDS subphenotypes may be extended to mechanically ventilated critically ill patients without ARDS. Using the concept of biological subphenotypes for splitting cohorts of critically ill patients could add to improving future precision-based trial strategies and lead to identifying treatable traits for all critically ill patients.

The extent of non-coding RNA alterations in patients with sepsis and their relationship to clinical characteristics, soluble mediators of the host response to infection, as well as an advocated in vivo model of acute systemic inflammation is unknown. Here we obtained whole blood from 156 patients with sepsis and 82 healthy subjects among whom eight were challenged with lipopolysaccharide in a clinically controlled setting (human endotoxemia). Via next-generation microarray analysis of leukocyte RNA we found that long non-coding RNA and, to a lesser extent, small non-coding RNA were significantly altered in sepsis relative to health. Long non-coding RNA expression, but not small non-coding RNA, was largely recapitulated in human endotoxemia. Integrating RNA profiles and plasma protein levels revealed known as well as previously unobserved pathways, including non-sensory olfactory receptor activity. We provide a benchmark dissection of the blood leukocyte 'regulome' that can facilitate prioritization of future functional studies., peer-reviewed

The worldwide rapid increase in antibiotic resistance means that new therapeutic measures are urgently needed. Older antibiotics, such as colistin, fosfomycin, minocycline, mecillinam and temocillin, which had fallen from grace due to the development of more effective and less toxic drugs are now of renewed interest in the treatment of infections caused by multiresistant bacteria. Two new glycopeptides (oritavancin and dalbavancin) and a new oxazolidinone (tedizolid) are now registered for the treatment of acute skin and soft-tissue infections. In the treatment of infections caused by Gram-negative bacteria, cephalosporins are combined with beta-lactamase inhibitors which protect them from various beta-lactamases and also make them effective against extended spectrum beta-lactamase-producing bacteria. Examples of these are ceftolozane-tazobactam, ceftazidime-avibactam and meropenem-vaborbactam. Results of preclinical research on the effectiveness of new antibiotics are hopeful. There has been a great increase in investment in the development of new antimicrobials. Also, regulatory agencies have accelerated their assessment of these new - and urgently needed - drugs.

Rationale: Community-acquired pneumonia (CAP) accounts for a major proportion of intensive care unit (ICU) admissions for respiratory failure and sepsis. Diagnostic uncertainty complicates case management, which may delay appropriate cause-specific treatment. Objectives: To characterize the blood genomic response in patients with suspected CAP and identify a candidate biomarker for the rapid diagnosis of CAP on ICU admission. Methods: The study comprised two cohorts of consecutively enrolled patients treated for suspected CAP on ICU admission. Patients were designated CAP (cases) and no-CAP patients (control subjects) by post hoc assessment. The first (discovery) cohort (101 CAP and 33 no-CAP patients) was enrolled between January 2011 and July 2012; the second (validation) cohort (70 CAP and 30 no-CAP patients) between July 2012 and June 2013. Blood was collected within 24 hours of ICU admission. Measurements and Main Results: Blood microarray analysis of CAP and no-CAP patients revealed shared and distinct gene expression patterns. A 78-gene signature was defined for CAP, from which a FAIM3:PLAC8 gene expression ratio was derived with area under curve of 0.845 (95% confidence interval, 0.764-0.917) and positive and negative predictive values of 83% and 81%, respectively. Robustness of the FAIM3:PLAC8 ratio was ascertained by quantitative polymerase chain reaction in the validation cohort. The FAIM3:PLAC8 ratio outperformed plasma procalcitonin and IL-8 and IL-6 in discriminating between CAP and no-CAP patients. Conclusions: CAP and no-CAP patients presented shared and distinct blood genomic responses. We propose the FAIM3:PLAC8 ratio as a candidate biomarker to assist in the rapid diagnosis of CAP on ICU admission.

Objectives: Experimental studies suggest that calcium channel blockers can improve sepsis outcome. The aim of this study was to determine the association between prior use of calcium channel blockers and the outcome of patients admitted to the ICU with sepsis. Design: A prospective observational study. Setting: The ICUs of two tertiary care hospitals in the Netherlands. Patients: In total, 1,060 consecutive patients admitted with sepsis were analyzed, 18.6% of whom used calcium channel blockers. Interventions: None. Measurements and Main Results: Considering large baseline differences between calcium channel blocker users and nonusers, a propensity score matched cohort was constructed to account for differential likelihoods of receiving calcium channel blockers. Fifteen plasma biomarkers providing insight in key host responses implicated in sepsis pathogenesis were measured during the first 4 days after admission. Severity of illness over the first 24 hours, sites of infection and causative pathogens were similar in both groups. Prior use of calcium channel blockers was associated with improved 30-day survival in the propensity-matched cohort (20.2% vs 32.9% in non-calcium channel blockers users; p = 0.009) and in multivariate analysis (odds ratio, 0.48; 95% CI, 0.31–0.74; p = 0.0007). Prior calcium channel blocker use was not associated with changes in the plasma levels of host biomarkers indicative of activation of the cytokine network, the vascular endothelium and the coagulation system, with the exception of antithrombin levels, which were less decreased in calcium channel blocker users. Conclusions: Prior calcium channel blocker use is associated with reduced mortality in patients following ICU admission with sepsis.

Background Sepsis is a prominent reason for intensive care unit (ICU) admission in patients with HIV. We aimed to investigate the impact of HIV infection on presentation, outcome and host response in sepsis. Methods We performed a prospective observational study in the ICUs of two tertiary hospitals. For the current analyses, we selected all patients diagnosed with sepsis within 24 hours after admission. Host response biomarkers were analyzed in a more homogeneous subgroup of admissions involving HIV-positive patients with pneumosepsis, matched to admissions of HIV-negative patients for age, gender and race. Matching was done by nearest neighbor matching with R package “MatchIt”. Results We analyzed 2251 sepsis admissions including 41 (1.8 %) with HIV infection (32 unique patients). HIV-positive patients were younger and admission of HIV-positive patients more frequently involved pneumonia (73.2 % versus 48.8 % of admissions of HIV-negative patients, P = 0.004). Disease severity and mortality up to one year after admission did not differ according to HIV status. Furthermore, sequential plasma levels of host response biomarkers, providing insight into activation of the cytokine network, the vascular endothelium and the coagulation system, were largely similar in matched admissions of HIV-positive and HIV-negative patients with pneumosepsis. Conclusions Sepsis is more often caused by pneumonia in HIV-positive patients. HIV infection has little impact on the disease severity, mortality and host response during sepsis. Electronic supplementary material The online version of this article (doi:10.1186/s13054-016-1469-0) contains supplementary material, which is available to authorized users.