Hitoshi Honda

BACKGROUND: Antimicrobial resistance (AMR) poses a major global health threat, with health-care-associated infections contributing substantially to mortality. Attributable disease burden remains poorly quantified by relying on cross-sectional and microbiology data. We aimed to characterise AMR epidemiology and disease burden associated with ventilator-associated pneumonia and bloodstream infection in a network of hospitals in Asia. METHODS: This large-scale, prospective, multinational, multicentre cohort study consecutively enrolled patients of any age with microbiologically-confirmed ventilator-associated pneumonia, hospital-acquired bloodstream infections, or health-care-associated bloodstream infections from 41 selected hospitals capable of standardised prospective data collection in 19 Asian countries and regions. Patients with pathogens typically associated with community-acquired infection or not recognised causes of health-care-associated infection were excluded according to predefined protocol criteria, and patients were followed for 28 days. The primary outcome was 28-day mortality from infection onset. Pathogen profiles, antimicrobial prescriptions, attributable mortality, and health-related quality-of-life outcomes were analysed. FINDINGS: Between Sept 1, 2022, and Feb 28, 2025, 10 111 patients were enrolled, and after exclusions, 9496 patients were included in the final analysis. 9642 infection episodes were analysed, comprising 6597 (68·4%) bloodstream infections and 3045 (31·6%) ventilator-associated pneumonia. Of these infections, 7102 (73·7%) of 9642 infection episodes were associated with AMR bacteria, and Gram-negative bacteria were predominant (7599 [78·8%]). Crude 28-day mortality was 2674 (37·7%) of 7102 AMR infection episodes and 1900 (40·6%) of 4683 multidrug resistance infection episodes, with the highest for carbapenem-resistant Acinetobacter spp (CRA; 51·3%) and carbapenem-resistant Enterobacterales (CRE; 48·4%). AMR-attributable mortality was the highest in ventilator-associated pneumonia (16·9%, 95% CI 13·0-20·9), individuals aged 5-14 years (11·7%, 95% CI 1·6-21·8), individuals aged 15-49 years (11·2%, 95% CI 7·2-15·2), and lower-middle-income countries (10·7%, 95% CI 7·0-14·4). By pathogens, CRA and CRE had the highest attributable mortality (19·4%, 95% CI 14·1-24·7 vs 16·2%, 95% CI 12·8-19·6) and also had the poorest quality-of-life outcomes. Most carbapenem-resistant Gram-negative infections were treated with carbapenems (57·8%) or polymyxins (35·6%). INTERPRETATION: AMR bacterial bloodstream infections and ventilator-associated pneumonia were common and associated with high mortality and reduced quality of life in Asia, particularly in infections due to carbapenem-resistant Acinetobacter spp and CRE, and among children and younger adults. The widespread use of suboptimal antimicrobial regimens highlights the urgent need for equitable access to effective therapies and context-specific evidence to guide antimicrobial stewardship. FUNDING: Wellcome Trust, National University of Singapore, Yong Loo Lin School of Medicine, Duke-NUS Medical School, Nanyang Technological University (Lee Kong Chian School of Medicine), Singapore National Centre for Infectious Diseases, and Singapore Medical Research Council.

BACKGROUND: Antivirals remain an important treatment strategy for persons who experience severe and life-threatening COVID-19. Ensitrelvir is an oral 3CL protease inhibitor with potent antiviral activity. METHODS: We conducted an international randomized, placebo-controlled trial of ensitrelvir with standard of care (SOC) among adults hospitalized for COVID-19. The primary outcome was clinical recovery assessed by the Days to Recovery Scale through Day 60 (DRS-60), analyzed using a Van Elteren test. RESULTS: From 2023 to 2025, 589 participants received blinded study treatment (293 ensitrelvir and 296 placebo). Median age was 69 years, 49% were female, 68% were White, and SOC commonly included corticosteroids (61% and 54%) and remdesivir (62% and 60%) in ensitrelvir and placebo groups, respectively. Median DRS-60 category was 6 (IQR: 3-15) in the ensitrelvir and 5.5 (IQR: 3-12) in the placebo group (p=0.19), and the OR was 0.82 (95% CI: 0.62-1.09) for a better DRS-60 category with ensitrelvir. Ensitrelvir participants had lower detectable viral antigen in plasma at Day 5 (13.4% vs 25.1%; p<0.001). There was no difference in secondary clinical outcomes or pre-specified safety outcomes, though the mortality rate was 6.1% vs 4.4% and the frequency of hemorrhagic events was 3.4% vs 0.3% among ensitrelvir and placebo groups, respectively. CONCLUSIONS: Ensitrelvir treatment did not improve clinical recovery in addition to SOC for adults hospitalized for COVID-19. The lower illness severity in the Omicron era compared to earlier periods in the COVID-19 pandemic, and high use of remdesivir and corticosteroids, may have contributed to the lack of clinical benefit.

OBJECTIVES: Advances in critical care have increased antimicrobial use in intensive care units (ICUs), often extending to end-of-life patients without clear clinical benefit. This systematic review and meta-analysis investigated antimicrobial use in critically ill ICU patients with end-of-life care status. METHODS: A comprehensive search of Medline (PubMed) and Embase identified articles published from January 2000 through August 2023. Interventional and observational studies focusing on antimicrobial use for critically ill ICU patients with end-of-life status were included. Study types, demographics, clinical characteristics, and antimicrobial use (i.e., continuation or discontinuation) were extracted. A meta-analysis was conducted to estimate the proportion of antimicrobial use, with subgroup analyses by region and national income status. RESULTS: From 13,542 publications, 26 studies met the inclusion criteria; no randomized or prospective studies were identified. Thirteen studies (50.0%) reported antimicrobial use and were included in the quantitative synthesis. The pooled proportion of antimicrobial prescriptions was 0.35 (95% CI, 0.18-0.54) with significant heterogeneity (I2=99.7%, P<0.01). Subgroup analysis revealed regional differences: 0.50 (95% CI, 0.11-0.89) in North America, 0.40 (95% CI, 0.10-0.76) in Europe, and 0.24 (95% CI, 0.10-0.76) in the Asia-Pacific region. CONCLUSIONS: Despite increasing emphasis on judicious antimicrobial use, studies comprehensively assessing antimicrobial prescribing in ICU patients with end-of-life care status remain scarce. Based on the limited available evidence, approximately one-third of such patients received antimicrobials. Regional differences in prescribing patterns were also observed, potentially influencing overall antimicrobial consumption in ICUs.