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Key Points: Question: Is there a difference in mortality between continuous and intermittent infusions of β-lactam antibiotics in critically ill patients with sepsis? Findings: In this randomized clinical trial that included 7031 adult patients with sepsis, there was not a statistically significant difference in the proportion of patients who died within 90 days who received continuous (24.9%) compared with intermittent (26.8%) β-lactam antibiotic infusions (odds ratio, 0.91). Meaning: In critically ill patients with sepsis, continuous vs intermittent β-lactam antibiotic infusions did not significantly reduce 90-day mortality in the primary analysis. Importance: Whether β-lactam antibiotics administered by continuous compared with intermittent infusion reduces the risk of death in patients with sepsis is uncertain. Objective: To evaluate whether continuous vs intermittent infusion of a β-lactam antibiotic (piperacillin-tazobactam or meropenem) results in decreased all-cause mortality at 90 days in critically ill patients with sepsis. Design, Setting, and Participants: An international, open-label, randomized clinical trial conducted in 104 intensive care units (ICUs) in Australia, Belgium, France, Malaysia, New Zealand, Sweden, and the United Kingdom. Recruitment occurred from March 26, 2018, to January 11, 2023, with follow-up completed on April 12, 2023. Participants were critically ill adults (≥18 years) treated with piperacillin-tazobactam or meropenem for sepsis. Intervention: Eligible patients were randomized to receive an equivalent 24-hour dose of a β-lactam antibiotic by either continuous (n = 3498) or intermittent (n = 3533) infusion for a clinician-determined duration of treatment or until ICU discharge, whichever occurred first. Main Outcomes and Measures: The primary outcome was all-cause mortality within 90 days after randomization. Secondary outcomes were clinical cure up to 14 days after randomization; new acquisition, colonization, or infection with a multiresistant organism or Clostridioides difficile infection up to 14 days after randomization; ICU mortality; and in-hospital mortality. Results: Among 7202 randomized participants, 7031 (mean [SD] age, 59 [16] years; 2423 women [35%]) met consent requirements for inclusion in the primary analysis (97.6%). Within 90 days, 864 of 3474 patients (24.9%) assigned to receive continuous infusion had died compared with 939 of 3507 (26.8%) assigned intermittent infusion (absolute difference, −1.9% [95% CI, −4.9% to 1.1%]; odds ratio, 0.91 [95% CI, 0.81 to 1.01]; P =.08). Clinical cure was higher in the continuous vs intermittent infusion group (1930/3467 [55.7%] and 1744/3491 [50.0%], respectively; absolute difference, 5.7% [95% CI, 2.4% to 9.1%]). Other secondary outcomes were not statistically different. Conclusions and Relevance: The observed difference in 90-day mortality between continuous vs intermittent infusions of β-lactam antibiotics did not meet statistical significance in the primary analysis. However, the confidence interval around the effect estimate includes the possibility of both no important effect and a clinically important benefit in the use of continuous infusions in this group of patients. Trial Registration: ClinicalTrials.gov Identifier: NCT03213990 This clinical trial compares the efficacy of continuous vs intermittent infusion of a β-lactam antibiotic (piperacillin-tazobactam or meropenem) in decreasing all-cause mortality at 90 days in critically ill patients with sepsis. [ABSTRACT FROM AUTHOR]

Background: The β-Lactam Infusion Group (BLING) III study is a prospective, multicentre, open, phase 3 randomised controlled trial comparing continuous infusion with intermittent infusion of β-lactam antibiotics in 7000 critically ill patients with sepsis. Objective: To describe a statistical analysis plan for the BLING III study. Methods: The statistical analysis plan was designed by the trial statistician and chief investigators and approved by the BLING III management committee before the completion of data collection. Statistical analyses for primary, secondary and tertiary outcomes and planned subgroup analyses are described in detail. Interim analysis by the Data Safety and Monitoring Committee (DSMC) has been conducted in accordance with a pre-specified DSMC charter. Results and conclusions: The statistical analysis plan for the BLING III study is published before completion of data collection and unblinding to minimise analysis bias and facilitate public access and transparent analysis and reporting of study findings. Trial registration: ClinicalTrials.gov Registry NCT03212990., Competing Interests: Jeffrey Lipman has served as a board member for the Bayer ESICM and MSD Antibacterials Advisory Boards and given lectures with honoraria from Pfizer and MSD. Stephen Brett has received a speaker’s fee and attended an Advisory Board from Orion Pharma. Jan De Waele has attended Advisory Boards, acted as a consultant to, or given lectures with honoraria from Accelerate, Bayer Healthcare, Grifols, MSD and Pfizer. David Paterson has received research grants from AstraZeneca and has attended Advisory Boards, acted as a consultant to, or given lectures with honoraria from Three Rivers Pharmaceuticals, Merck, AstraZeneca, SanofiAventis, Pfizer, Johnson and Johnson, Shionogi, Sumitomo and Leo Pharmaceuticals. Jason Roberts has served as a consultant for MSD, Bayer, Astellas, bioMerieux and Accelerate Diagnostics and has received research grants from MSD, The Medicines Company, Pfizer, Astellas and Cardeas Pharma. Claire Roger has received speaker’s fees from Pfizer and MSD. Colman Taylor owns a company, Health Technology Analysts, which provides consulting services to pharmaceutical companies, medical device companies and the Australian Government., (© 2021 College of Intensive Care Medicine of Australia and New Zealand.)

Background: Nosocomial pneumonia in the critical care setting is associated with increased morbidity, significant crude mortality rates and high health care costs. Ventilator-associated pneumonia represents about 80% of nosocomial pneumonia cases in intensive care units (ICUs). Wide variance in incidence of nosocomial pneumonia and diagnostic techniques used has been reported, while successful treatment remains complex and a matter of debate. Objective: To describe the epidemiology, diagnostic strategies and treatment modalities for nosocomial pneumonia in contemporary ICU settings across multiple countries around the world. Design, setting and patients: PneumoINSPIRE is a large, multinational, prospective cohort study of adult ICU patients diagnosed with nosocomial pneumonia. Participating ICUs from at least 20 countries will collect data on 10 or more consecutive ICU patients with nosocomial pneumonia. Site-specific information, including hospital policies on antibiotic therapy, will be recorded along with patient-specific data. Variables that will be explored include: aetiology and antimicrobial resistance patterns, treatment-related parameters (including time to initiation of antibiotic therapy, and empirical antibiotic choice, dose and escalation or de-escalation), pneumonia resolution, ICU and hospital mortality, and risk factors for unfavourable outcomes. The concordance of ventilator-associated pneumonia diagnosis with accepted definitions will also be assessed. Results and conclusions: PneumoINSPIRE will provide valuable information on current diagnostic and management practices relating to ICU nosocomial pneumonia, and identify research priorities in the field. Trial registration: ClinicalTrials.gov identifier NCT02793141., Competing Interests: Jan De Waele has received a grant from the Flanders Research Foundation (Senior Clinical Investigator Grant) and has consulted for Accelerate, Bayer HealthCare, Cubist, Grifols, MSD, Pfizer (honoraria were paid to his institution). Jeffrey Lipman has given lectures with honoraria from Pfizer and MSD. David Paterson has received research grants from AstraZeneca and has attended advisory boards for, acted as a consultant to, or given lectures with honoraria from Three Rivers Pharmaceuticals, Merck, AstraZeneca, Sanofi-Aventis, Pfizer, Johnson and Johnson, Shionogi and Leo Pharmaceuticals. All other authors declare no relevant competing interests., (© 2021 College of Intensive Care Medicine of Australia and New Zealand.)