Background:This study evaluates the impact of a point-of-care (POC) testing strategy and subsequent treatments for respiratory tract infections (RTIs) on patients' health-related quality of life (QoL). Materials and Methods:The PRUDENCE trial, with a sample of 2639 patients, showed that a POC testing strategy for RTIs (C-reactive protein, group A streptococcus, and influenza A/B, with optional SARS-CoV-2 testing) did not reduce antibiotic prescribing nor had a measurable impact on time to patient recovery compared to usual care. However, differences in patient-reported QoL may still exist, as utility can capture more subtle changes in symptom burden and well-being. The EQ-5D-5L questionnaire was completed by PRUDENCE trial patients at days 1, 14, and 28 of follow-up. Quality-adjusted life-year (QALY) gains were estimated. Static and dynamic analyses were performed to assess changes in utility values. Results:No statistically significant differences in utility scores were observed between the usual care and POC testing groups at any time point during the 28-day study period. However, both groups demonstrated statistically significant improvements in patient-reported utility scores over the 28-day period, corresponding to gains of 0.00502 QALYs in the usual care group and 0.00525 QALYs in the POC testing group. These improvements were already apparent by day 14 of follow-up. Conclusion:Improvements in utility scores over time were similar in both groups and likely reflected the natural clinical recovery from RTIs rather than the effect of the diagnostic strategy itself. Measures such as symptom relief, full recovery and side effects may better capture the intervention's impact. Trial Registration Number:ISRCTN13336322.

Objective: To determine whether ivermectin improves outcomes for critically and noncritically ill hospitalized patients with COVID-19.Design: An ongoing international, multifactorial, adaptive platform, randomized, controlled trial.Setting: Hospitals in Pakistan, India, and Ireland between June 11, 2021, and September 9, 2022.Patients: Critically and noncritically ill patients.Interventions: Randomized to ivermectin or no ivermectin (control).Measurements and Main Results: The primary outcome was respiratory and cardiovascular organ support-free days, assessed on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support through day 21 in survivors. Analyses used a Bayesian cumulative logistic model. Enrollment was closed for operational futility, following external evidence suggesting no benefit with ivermectin in nonhospitalized patients with COVID-19. Among 61 critically ill patients, the median number of organ support-free days was -1, indicating death was the most common vital outcome (interquartile range [IQR], -1 to 17), for the ivermectin group and -1 (IQR, -1 to 17.25) for the control group (adjusted proportional odds ratio [OR], 0.94; 95% credible interval [CrI], 0.40-2.07) and the posterior probability of superiority to control was 44.2%. Among 89 noncritically ill patients, the median number of organ support-free days was 22 (IQR, 18.5-22) for ivermectin and 22 (IQR, 16-22) for control (adjusted proportional OR, 1.04; 95% CrI, 0.48-2.34) and the posterior probability of superiority was 53.7%. Among critically ill patients, hospital survival was 35.1% (13/37) for ivermectin and 37.5% (9/24) for control (adjusted OR, 1.00; 95% CrI, 0.39-2.32), posterior probability of superiority was 50.0%. Among noncritically ill patients, hospital survival was 84.1% (37/44) for ivermectin and 77.8% (35/45) for control (adjusted OR, 1.16; 95% CrI, 0.5-3.07), posterior probability of superiority was 63.3%.Conclusions: For critically and noncritically ill hospitalized patients with COVID-19, ivermectin was unlikely to improve the primary composite outcome of organ support-free days and hospital survival.

Antibiotic combination therapy is often used to broaden the antimicrobial spectrum, limit resistance and improve treatment efficacy. Several antibiotics show collateral effects where resistance to one antibiotic increases susceptibility to another. In intensive care units (ICUs), antibiotic treatments are frequently adjusted based on patient outcomes, without considering collateral effects. This provides a setting to study these effects in Pseudomonas aeruginosa (PA), a highly adaptable, multidrug-resistant (MDR), nosocomial pathogen. We compared longitudinal PA isolates from twenty-five ventilated ICU patients receiving various antibiotics to laboratory strains undergoing in vitro adaptive evolution under four antipseudomonal monotherapies. Prolonged exposure to certain antibiotics produced resistance with collateral effects. In vitro, increasing antibiotic pressure drove distinct mutational trajectories. In patients, the number of antibiotics administered did not correlate with resistance changes to those antibiotics, suggesting that switching may reduce persistence of resistance. Notably, an inverse correlation between resistance to non-administered antibiotics and the number of different antibiotic classes administered, aligns with the principles of collateral susceptibility driven by multi-class exposure. This study provides s real-world evidence that empirical antibiotic mixing in ICU patients leverages evolutionary trade-offs. Consequently, diversifying antibiotic pressure via multi-class exposure may attenuate the fixation and persistence of MDR phenotypes in critical care.

Unveiling the systemic effects of disease and health requires a holistic approach that has mainly revolved around well-established, determinable molecular relationships such as the protein synthesis cascade and epigenetic mechanisms. In this study, we integrate multi-modal data from a cohort of 394 individuals to identify direct linkage of branches spanning human biological functions often not studied in conjunction, using clinical data, gut microbial abundances, blood immune cell compositions, blood transcriptomic and blood T cell receptor data. Contrary to current paradigms, we demonstrate that immunotypes and enterotypes are orthogonal, likely fulfilling distinct roles in maintaining homeostasis, bridged via the blood transcriptome. We identify two distinct inflammatory profiles: the first driven by interferon signaling and the other characterized by non-viral, NF-kB and IL-6 markers. Lastly, we present compelling data showing strong associations of Ruminococcaceae and Christensenellaceae bacteria with healthy immunotype and transcriptomic patterns, highlighting their potential role in immune health.

In this study, we evaluated the performance of FT-IR spectroscopy for clonality assessment of Serratia marcescens by comparing its clustering output to that of whole-genome sequencing (WGS), using core genome single nucleotide polymorphism (cgSNP) analysis as reference. A genetically diverse set of Serratia marcescens clinical isolates was collected from different hospitals in Belgium and measured with FT-IR spectroscopy in biological triplicate to assess reproducibility and in turn build a robust reference set. WGS data of the isolates was available and used to assess the performance of FT-IR spectroscopy. FT-IR spectroscopy showed good overall concordance with WGS (Adjusted Rand Index [ARI] of 0.755), but the level of agreement was insufficient to support the use of a single fixed cut-off value (COV) for clinical outbreak interpretation. To address this, a standardized workflow was developed incorporating multiple COVs to interpret clustering with varying level of confidence. This approach was validated using three unrelated S. marcescens outbreak case studies in neonatal intensive care units. The workflow yielded clustering results that matched WGS-based analyses and allowed clonality assessments within 24 h after isolate recovery. In conclusion, FT-IR spectroscopy can serve as a first-line screening tool to rapidly identify clonal clusters of S. marcescens, reducing turnaround time and limiting the number of isolates requiring confirmatory WGS, thereby considerably lowering overall outbreak investigation costs.

Acute respiratory tract infections represent a significant burden in primary care, with antibiotics often prescribed unnecessarily. This contributes to the escalating threat of antimicrobial resistance (AMR) by increasing the burden of infectious diseases and mortality risk. This is a report from a joint European Society of Clinical Microbiology and Infectious Diseases/European Respiratory Society research seminar held in November 2023 to discuss the role of in vitro diagnostic tests to combat AMR in community-acquired respiratory tract infections. We review the diagnostic tools available and in development, and the challenges related to their assessment, implementation in clinical settings and their overall impact on AMR.

BACKGROUND:To determine long-term immunogenicity and reactogenicity of different SARS-CoV-2 messenger RNA (mRNA) vaccines in a population ≥75 years of age in a randomized trial. METHODS:Participants were randomized to receive either BNT162b2 30 µg or a double booster dose of mRNA-1273, i.e., 100 µg, as the third and fourth vaccinations (first and second booster). The primary endpoint was the rate of a two-fold geometric mean titer (GMT) antibody increase 14 days after vaccination targeting the receptor binding domain (RBD) region of wild-type SARS-CoV-2. Secondary endpoints included neutralizing capacity against wild-type and 25 variants at 14 days (D14) and 12 months (M12). Safety was assessed by monitoring adverse events (AEs) for 7 days after vaccination. FINDINGS:Between November 2021 and September 2022, 322 participants received a SARS-CoV-2 vaccine as a first (Part A) or second booster (Part B). Primary endpoint results have been published previously. In Part A, it was reached by 100% of participants in both vaccine arms, with a higher GMT increase in the mRNA-1273 arm (ratio, 1.64). At M12, the GMT of anti-RBD immunoglobulin G (IgG) was slightly higher than at D14 (9319.7 vs 8568.4 IU/mL) in the BNT162b2 arm, while in the mRNA-1273 arm, the GMT was equal (14,163.8 vs 14,266.7 IU/mL at D14). In Part B, the primary endpoint was reached by 78.5% of participants in the BNT162b2 and 87.2% in the mRNA-1273 arm (P = 0.056), respectively, with a higher GMT increase of anti-RBD IgG for mRNA-1273 (ratio, 1.38). At M12, GMT of anti-RBD IgG was markedly lower than at D14 (9962 vs 15,248.2 IU/mL) in the BNT162b2 arm as well as in the mRNA-1273 arm (12,024.3 vs 21,325.6 IU/mL). Higher neutralizing capacity in individuals who received a booster with mRNA-1273 was detected against wild-type and 15 of 25 tested variants. Fewer participants in the mRNA-1273 arm had vaccine-related AEs (29.6% vs 38.5%), but severity was more frequently grade 2 (n = 38, 28.1% vs n = 22, 16.3%). INTERPRETATION:Long-term serological immunogenicity and virus neutralization capacity in participants ≥75 years of age were numerically better with an mRNA-1273 100 µg booster, with a comparable safety profile.

Objective:To describe the prevalence, patterns, and quality indicators of antimicrobial use (AMU) in Burkinabe hospitals and identify priorities for stewardship. Design:Multicentre, cross-sectional point prevalence survey (PPS) following the Global Point Prevalence Survey protocol. Setting:Eight public hospitals across six cities in Burkina Faso (3 primary, 3 secondary, and 2 tertiary), February-June 2019. Participants:All inpatients present on the survey day at 8:00. Medical records were reviewed for those receiving systemic antimicrobial agents. Methods:Standardized ward- and patient-level data were collected on indications, agents, routes, and WHO AWaRe categories, alongside quality indicators (documented indication, stop/review date, guideline compliance, and targeted vs empirical therapy). Descriptive analyses compared hospital tiers. Results:Of 994 inpatients, 729 (73.3%) received ≥1 antimicrobial (range by tier: tertiary 69.7%, secondary 79.2%, primary 79.2%). Community-acquired infections accounted for 96.0% of therapeutic indications. Leading reasons were skin/soft tissue infections (12.2%), gastrointestinal infections (10.7%), and pneumonia (10.4%). Parenteral administration predominated. The most used agents were ceftriaxone (27.8%), metronidazole (15.7%), and gentamicin (9.4%). By AWaRe, Access agents comprised ∼ 50%, Watch agents ∼ 50% overall, with higher Watch use in tertiary hospitals; no Reserve antibiotics were recorded. Quality indicators were suboptimal: the indication was documented in 15.6%, the stop/review date was absent in 93.0%, and 41.1% of prescriptions were guideline-compliant. Therapy was largely empirical (98.5%). Prolonged surgical prophylaxis (>1 day) represented 86.8% of prophylaxis courses. Conclusions:Antimicrobial use (AMU) prevalence in Burkinabe hospitals is high, dominated by empirical therapy and Watch-class ceftriaxone. Deficits in prescribing quality and limited diagnostic use highlight urgent needs for context-adapted antimicrobial stewardship: enforce guideline-concordant care, curb prolonged prophylaxis and unnecessary Watch-class use, and expand affordable microbiology capacity to enable targeted therapy.

Antimicrobial resistance is a significant threat to healthcare worldwide. The appropriate use of antimicrobials could decrease the excess morbidity of respiratory infections and contribute to reducing the emergence of multidrug resistance. For this purpose, the European Union has funded the VALUE-Dx project to assess the value of rapid diagnostic tests in combatting antimicrobial resistance by optimizing antibiotic use in community-acquired lower respiratory tract infections (CA-LRTI). In this context, the current statement aims to review the literature and current practice regarding the role of rapid diagnostic tests in managing CA-LRTI for antibiotic stewardship purpose and combatting antimicrobial resistance. In particular, this paper evaluates the accuracy of rapid diagnostic tests for the aetiological diagnosis of CA-LRTI, the usefulness of biomarkers and clinical algorithms in the management of CA-LRTI, the differences in aetiology according to the diagnostic protocol and tests applied for CA-LRTI after the introduction of rapid diagnostic tests for a complete microbiological investigation and, finally, the role of rapid diagnostic tests in antibiotic stewardship protocols in improving clinical outcomes.

Background Point-of-care testing is widely promoted for reducing unnecessary antibiotic prescribing, but how best to implement this approach in primary care is unclear. The 13-country PRUDENCE trial found that, compared with usual care alone, the addition of a point-of-care testing strategy, which could include tests for C-reactive protein, group A Streptococcus, or influenza A/B depending on the season (influenza or not) and predominant symptoms, to usual care did not reduce antibiotic prescribing among clinicians for patients with respiratory tract infections for whom the clinician was considering or had planned to prescribe antibiotics. In this embedded qualitative process evaluation of the trial, we aimed to understand how the point-of-care testing strategy was used and viewed by clinicians and patients. Methods In this qualitative process evaluation of the PRUDENCE trial, we conducted semi-structured interviews, online or in person, with patients and clinicians who participated in the trial at primary care clinics in England (UK), Ireland, Belgium, Greece, Georgia, and Germany. Patients (aged ≥18 years) were eligible if they had received point-of-care testing, with purposive sampling used to achieve variation in age, symptom presentation, type of test, and whether an antibiotic was prescribed. Clinicians were eligible if they had recruited patients and used point-of-care testing during the trial, with sampling aimed at capturing variation in professional role and clinical experience. Data collection and analysis took place concurrently until data saturation. We adopted pragmatic qualitative methodological orientation, by use of a reflexive thematic analysis with iteration within the multidisciplinary study team, to analyse the interviews and understand local contexts. Findings Between Feb 15, 2022, and July 20, 2023, 56 patients (41 [73%] women and 15 [27%] men, aged 19·0–79·0 years) participated in an interview. Between Feb 11, 2022, and Feb 22, 2024, 33 clinicians (21 [64%] women and 12 [36%] men) participated in an interview. Clinicians reported that point-of-care testing often strengthened their initial intentions to prescribe antibiotics. Point-of-care testing also influenced clinician decisions not to prescribe antibiotics when they were considering prescribing but had not yet made a firm decision to do so. Point-of-care testing often changed clinician prescribing decisions in cases of ambiguous clinical presentation, such as when patients presented with non-specific symptoms or severe discomfort, or when bacterial and viral presentations were clinically indistinguishable. Nevertheless, the prescribing implications of point-of-care testing results were frequently over-ridden, particularly when they conflicted with clinicians’ experiential knowledge; when there were doubts over test accuracy; when both patients and clinicians perceived symptoms as severe, textbook-like, or both; when timing of presentation introduced prognostic uncertainty; or when (perceived) patient expectations exerted pressure. Interpretation The availability of point-of-care testing is unlikely to be a sufficient solution alone for reducing antibiotic prescribing; multiple, related clinical and social factors need to be addressed alongside the introduction of point-of-care testing in routine primary care. Complementary interventions used together with point-of-care testing could more effectively address the multiple clinical and non-clinical drivers of antibiotic prescribing to help mitigate antimicrobial resistance. Funding Innovative Medicines Initiative 2 Joint Undertaking.

Klebsiella pneumoniae sequence type 48 (Kp-ST48) is a globally distributed clone linked to antimicrobial resistance (AMR) yet lacks a comprehensive genomic analysis. Here, we investigated the persistence, transmission dynamics and global context of ST48 in a large tertiary hospital in Berlin, Germany. Between 2014 and 2022, 48 surveillance and 15 putative outbreak Kp-ST48 isolates were isolated in a tertiary care, multi-site hospital in Berlin, Germany. Genomic diversity was analysed by short- and long-read sequencing. Additionally, we included 223 publicly available Kp-ST48 genomes from five continents over 40 years (1982-2022) in the phylodynamic analysis. We identified two genetically distinct clades (A and B) within the global Kp-ST48 population. The global spread of Kp-ST48 was driven by clade B, which included all the genomes from the Berlin hospital. Two hospital-specific lineages (1 and 2) were identified with distinct population dynamics. Lineage 2 was transient and linked to a putative outbreak in 2019. Meanwhile, lineage 1 was first detected in 2014 and persisted for over 8 years until 2022, with multiple putative patient-to-patient and indirect transmission events identified. Carbapenem resistance determinants (ompK35/36 mutations, bla KPC, bla NDM, bla OXA-48, bla VIM) were present in 57% (n=163/286) of genomes, and up to three bla CTX-M-15 copies were found integrated into chromosomes. Although Kp-ST48 generally did not contain a high number of virulence genes, 19 genomes showed potential for AMR-hypervirulence convergence. This study reveals the endemic persistence with outbreak potentials of Kp-ST48 in a hospital over 8 years, characterized by high genome plasticity. Our results highlight the global distribution of this clone, which warrants continuous surveillance.

Antimicrobial resistance is a significant threat to healthcare worldwide. The appropriate use of antimicrobials could decrease the excess morbidity of respiratory infections and contribute to reducing the emergence of multidrug resistance. For this purpose, the European Union has funded the VALUE-Dx project to assess the value of rapid diagnostic tests in combatting antimicrobial resistance by optimising antibiotic use in community-acquired lower respiratory tract infections (CA-LRTI). In this context, the current statement aims to review the literature and current practice regarding the role of rapid diagnostic tests in managing CA-LRTI for antibiotic stewardship purpose and combatting antimicrobial resistance. In particular, the present paper evaluates the accuracy of rapid diagnostic tests for the aetiological diagnosis of CA-LRTI, the usefulness of biomarkers and clinical algorithms in the management of CA-LRTI, the differences in aetiology according to the diagnostic protocol and tests applied for CA-LRTI after the introduction of rapid diagnostic tests for a complete microbiological investigation and, finally, the role of rapid diagnostic tests in antibiotic stewardship protocols in improving clinical outcomes.

Background:Culture-independent molecular techniques could potentially be used to measure microbiological efficacy in response to antibiotic treatment and improve understanding of the role of the airway microbiota in determining response in patients with chronic respiratory disease. Methods:Using molecular methods, we analysed changes in the sputum microbiota in samples from 107 participants with bronchiectasis recruited to the iBEST-1 study, and defined community endotypes based on response to tobramycin inhalation powder (TIP) treatment. The relationship between microbiota metrics in these endotypes and clinical and inflammatory biomarkers were also determined. Results:There was a significant reduction in Pseudomonas aeruginosa density, measured by quantitative polymerase chain reaction (qPCR), between Days 1 and 29 for participants in the TIP treatment (n=63; p<0.0001) but not placebo (n=20; p>0.05) group. Based on decrease in P. aeruginosa density (oprL copies·mL-1) over 28 days, two clusters of participants receiving TIP were observed and stratified as either responders (≥2Log10; n=26) or non-responders (<2Log10; n=37). In responders, a shift to a microbial community structure less dominated (p=0.018) by a pathogen was apparent and associated with a greater improvement in inflammatory and fewer participant exacerbations in the following 6 months (27% versus 49%; p=0.117) when compared to non-responders. Lung function was higher at Day 1 in responders (median=64.6% predicted) than non-responders (μ̃median=50.3% predicted) and independently predicted response to treatment with TIP (p=0.013). Conclusions:qPCR may be a useful, culture-independent microbiological efficacy end-point in clinical trials. Using qPCR, participants with bronchiectasis were stratified into endotpyes which predicted response to antimicrobial treatment, potentially allowing for a more personalised approach to therapy.

BACKGROUND:Illness severity, comorbidity, fever, age, and symptom duration influence antibiotic prescribing for respiratory tract infections (RTI). Non-medical determinants, such as patient expectations, also impact prescribing. AIM:To quantify the effect of a GP's perception of a patient request for antibiotics on antibiotic prescribing for RTI and investigate effect modification by medical determinants and country. DESIGN & SETTING:Prospective audit of general practices in 18 European countries. METHOD:Consultation data were registered of 4982 patients presenting with acute cough and/or sore throat. A mixed-effect logistic regression model analysed the effect of GPs' perceptions of a patient request for antibiotics. Two-way interaction terms assessed effect modification. Relevant clinical findings were added to subgroups of lower RTI (LRTI), throat infection, and influenza-like-illness (ILI). RESULTS:A GP's perception of a request for antibiotics meant they were four times more likely to prescribe antibiotics (odds ratio [OR] 4.4, 95% confidence interval [CI] = 3.4 to 5.5). This effect varied by country: lower in Spain (OR 0.06), Ukraine (OR 0.15), and Greece (OR 0.22) compared with the lowest prescribing country. The effect was higher for ILI (OR 13.86, 95% CI = 5.5 to 35) and throat infection (OR 5.1, 95% CI = 3.1 to 8.4) than for LRTI (OR 2.9, 95% CI = 1.9 to 4.3). For ILI and LRTI, GPs were more likely to prescribe antibiotics with abnormal lung auscultation and/or increased or purulent sputum and for throat infection, with tonsillar exudate and/or swollen tonsils. CONCLUSION:GPs' perceptions of an antibiotic request and specific clinical findings influence antibiotic prescribing. Incorporating exploration of patient expectations, point-of-care testing, and discussing watchful waiting into the decision-making process will benefit appropriate prescribing of antibiotics.

Background Hospitals in low- and middle-income countries (LMIC) face context-specific challenges in implementing antimicrobial stewardship (AMS) programmes. The Global Point Prevalence Survey (Global-PPS) project has established a network of hospitals across 90 countries, using point prevalence surveys to monitor antimicrobial use and guide AMS activities. However, little is known about AMS implementation in these hospitals. Using qualitative research, we aim to explore the implementation process in LMIC hospitals within the Global-PPS network and the factors influencing it, identify potential implementation strategies, and evaluate the role of Global-PPS in this process. Methods A qualitative study was conducted using semi-structured online interviews with healthcare workers (HCWs) involved in AMS in LMIC hospitals within the Global-PPS network. Participants were selected using a combination of convenience and purposive sampling and included clinicians, microbiologists, pharmacists, and nurses. Interviews followed a topic guide based on the integrated checklist of determinants of practice (TICD Checklist). Transcripts were analysed using a combination of inductive and deductive thematic analyses. Findings Twenty-two HCWs from 16 countries were interviewed. Hospitals were in different stages of the AMS implementation process at the time of the study, from pre-implementation to institutionalisation of AMS as part of the continuous quality improvement process. While the Global-PPS provided a valuable tool for education and implementation, contextual barriers often hindered the translation of findings into targeted interventions. Four themes influenced AMS implementation, “institutional support and resource allocation”, “AMS team functioning, roles, and expertise”, “adoption and integration of AMS recommendations”, and “data-driven decision-making” as a cross-cutting theme. Key determinants included AMS team competencies, multidisciplinary teams, sustainable funding and leadership support, diagnostic capacity, and reliable data to inform interventions. We also identified various strategies employed by local AMS teams to enhance implementation. Conclusions This study examines AMS implementation in LMIC hospitals in the Global-PPS network and identifies key determinants. AMS teams address challenges through task shifting, local engagement and ownership. While empirical evidence on the effectiveness of these strategies is limited, these insights can guide future AMS interventions and studies within LMIC hospitals. Strengthening AMS requires bridging the gap between measurement and action and expanding research on behaviour change.

Objectives: Pseudomonas aeruginosa (PA) is a common causative pathogen of pneumonia acquired in the intensive care unit (ICU). The aim of this study was to determine the incidence of PA ICU pneumonia (PAIP) and to quantify its independent association with PA colonization at different body sites. Methods: Adult patients on mechanical ventilation at ICU admission were prospectively enrolled across 30 European ICUs. PA colonization in the perianal area and in the lower respiratory tract was assessed within 72 hours after ICU admission and twice weekly until ICU discharge. PAIP development was evaluated daily. Competing risk models with colonization as a time-varying exposure and ICU death and discharge as competing events were fitted and adjusted for confounders to investigate the association between PA carriage and PAIP. Results: A total of 1971 subjects were enrolled. The colonization prevalence with PA in the first 72 hours of ICU admission was 10.4% (179 perianal and 51 respiratory), whereas the acquisition incidence during the ICU stay was 7.0% (158 perianal and 47 respiratory). Of the 43 (1.8%) patients who developed PAIP, 11 (25.6%) were PA colonized on admission and 9 (20.9%) acquired colonization before PAIP onset. Both perianal (adjusted subdistribution hazard ratio, 4.4; 95% CI, 1.7-11.6) and respiratory colonization (adjusted subdistribution hazard ratio: 4.6, 95% CI, 1.9-11.1) were independently associated with PAIP development. Discussion: PAIP incidence was higher in PA colonized vs. non-colonized patients. Colonization of both the rectum and of the respiratory tract was associated with development of PAIP. The increased risk of PA colonization for subsequent infection provides an opportunity for targeted preventive interventions. (c) 2024 The Author(s). 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 license (http://creativecommons. org/licenses/by/4.0/).

INTRODUCTION:Tocilizumab improves outcomes in critically ill patients with COVID-19. Whether other immune-modulator strategies are equally effective or better is unknown. METHODS:We investigated treatment with tocilizumab, sarilumab, anakinra and no immune modulator in these patients. In this ongoing, adaptive platform trial in 133 sites in 9 countries, we randomly assigned patients with allocation ratios dependent on the number of interventions available at each site. The primary outcome was an ordinal scale combining in-hospital mortality (assigned -1) and days free of organ support to day 21 in survivors. The trial used a Bayesian statistical model with predefined triggers for superiority, inferiority, efficacy, equivalence or futility. RESULTS:Of 2274 critically ill participants enrolled between 25 March 2020 and 10 April 2021, 972 were assigned to tocilizumab, 485 to sarilumab, 378 to anakinra and 418 to control. Median organ support-free days were 7 (IQR -1, 16), 9 (IQR -1, 17), 0 (IQR -1, 15) and 0 (IQR -1, 15) for tocilizumab, sarilumab, anakinra and control, respectively. Median adjusted ORs were 1.46 (95% credible intervals (CrI) 1.13, 1.87), 1.50 (95% CrI 1.13, 2.00) and 0.99 (95% CrI 0.74, 1.35) for tocilizumab, sarilumab and anakinra relative to control, yielding 99.8%, 99.8% and 46.6% posterior probabilities of superiority, respectively, compared with control. All treatments appeared safe. CONCLUSIONS:In critically ill patients with COVID-19, tocilizumab and sarilumab have equivalent effectiveness at reducing duration of organ support and death. Anakinra is not effective in this population. TRIAL REGISTRATION NUMBER:NCT02735707.

Pneumococcal conjugate vaccines (PCVs) reduce Streptococcus pneumoniae infection and carriage. After switching from PCV13 to PCV10 in 2015-2016, Belgium switched back to PCV13 in 2019. Building on our systematic monitoring of childhood nasopharyngeal carriage since 2016, here, we analyze the serotypes of S. pneumoniae and other pathogens in children attending daycare centers (DCCs) from 2018 to 2021. From the period of 2018-2019 to 2020-2021, we included a total of 2,741 nasopharyngeal swabs collected from children aged 6 to 30 months. We identified S. pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus and conducted serotyping and antimicrobial susceptibility assessments of S. pneumoniae strains using culture methods and real-time PCR. S. pneumoniae carriage was frequent and quite stable over the three study years. H. influenzae and M. catarrhalis were more frequently carried than S. pneumoniae. Frequency of all PCV13-serotypes together among S. pneumoniae carriers decreased significantly from 19.4% in 2018-2019 to 9.9% in 2020-2021 (p < .001), largely due to the decreased serotype 19A carriage. Resistance of pneumococcal strains to penicillin increased significantly over the three study years. Two years after the second switch to PCV13 in 2019, pneumococcal serotype 19A carriage decreased again significantly in Belgian children attending daycare centers.

Serratia marcescens is an opportunistic pathogen with a propensity to cause nosocomial outbreaks, particularly in neonatal intensive care units (NICUs). We present a sustained outbreak spanning over 18 months (1 January 2022-29 August 2023) in a NICU in Antwerp, Belgium, affecting 61 neonates, identified through samples taken for diagnostic purposes and by rectal screening. Ten neonates were infected: five with lower respiratory tract infection, four with conjunctivitis and one fatal case with sepsis. In a logistic regression analysis, nursing in an incubator was significantly associated with acquisition of S. marcescens (odds ratio (OR): 2.99; 95% confidence interval (CI): 1.14-8.25; p < 0.05). Whole genome sequencing-based multilocus sequence typing (wgMLST) and core genome single nucleotide polymorphism (cgSNP) analysis of isolates from clinical (n = 4), screening (n = 52) and environmental samples (n = 8), identified eight clusters and five singletons not associated with the clusters. Although outbreak measures were successful in containing further spread within the ward during sudden surges when > 4 cases per week were identified (peak events), several peaks with different clonal clusters occurred. The emergence of similar outbreaks in Belgian hospitals underscores the need of continuous surveillance and NICU-specific infection prevention and control (IPC) measures.

Background Carbapenem-resistant Enterobacterales (CRE) bloodstream infections (BSIs) are a major threat to patients. To date, data on risk factors have been limited, with low internal and external validity. In this multicentre study, risk factors for CRE BSI were determined by comparison with two control groups: patients with carbapenem-susceptible Enterobacterales (CSE) BSI, and patients without Enterobacterales infection (uninfected patients).Methods A multicentre, case-control-control study was nested in a European prospective cohort study on CRE (EURECA). CRE BSI:CSE BSI matching was 1:1, CRE BSI:Uninfected patients matching was 1:3, based on hospital, ward and length of stay. Conditional logistic regression was applied.Results From March 2016 to November 2018, 73 CRE BSIs, 73 CSE BSIs and 219 uninfected patients were included from 18 European hospitals. For CRE versus CSE BSI, previous CRE colonization/infection [incidence rate ratio (IRR) 7.32; 95% CI 1.65-32.38) increased the risk. For CRE versus uninfected controls, independent risk factors included: older age (IRR 1.03; 95% CI 1.01-1.06), patient referral (long-term care facility: IRR 7.19; 95% CI 1.51-34.24; acute care hospital: IRR 5.26; 95% CI 1.61-17.11), previous colonization/infection with other MDR organisms (MDROs) (IRR 9.71; 95% CI 2.33-40.56), haemodialysis (IRR 8.59; 95% CI 1.82-40.53), invasive procedures (IRR 5.66; 95% CI 2.11-15.16), and beta-lactam/beta-lactamase inhibitor combinations (IRR 3.92; 95% CI 1.68-9.13) or third/fourth generation cephalosporin (IRR 2.75; 95% CI 1.06-7.11) exposure within 3 months before enrolment.Conclusions Evidence of previous CRE colonization/infection was a major risk factor for carbapenem resistance among Enterobacterales BSI. Compared with uninfected patients, evidence of previous MDRO colonization/infection and healthcare exposure were important risk factors for CRE BSI. Targeted screening, infection prevention and antimicrobial stewardship should focus on these high-risk patients.