土井 洋平

INTRODUCTION: At the time of this study, no approved treatment for mpox was available in Japan, and data on the clinical course and virological changes during tecovirimat treatment were limited. METHODS: We conducted a prospective multicenter observational case series of patients with PCR-confirmed mpox between June 28, 2022, and March 31, 2025, to describe the clinical course and safety of a 14-day course of tecovirimat. Participants could choose treatment or no treatment. RESULTS: All 31 participants received tecovirimat; 24 completed a single 14-day course, and 2 received multiple courses plus vaccinia immune globulin. The median age was 39 years (range, 21-74), and all were men. Nineteen (61.3%) were people living with HIV, with a median CD4 count of 531 cells/μL (range, 50-830), including three with CD4 counts <200 cells/μL. Severe mpox occurred in 23 participants (74.2%), three of whom (9.7%) had risk factors for severe disease, all due to CD4 < 200 cells/μL. Skin lesions were present in 30 participants. At day 14, skin PCR results were available for 23 participants; 16 (69.6%) were negative. No deaths occurred within 14 or 30 days, although one patient with advanced HIV infection died following prolonged hospitalization. Adverse events occurred in 2 participants and were considered unrelated to treatment. DISCUSSION: This prospective multicenter case series describes the clinical course of mpox and temporal dynamics of skin PCR negativity in patients receiving tecovirimat in real-world practice.

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.

In response to the antimicrobial resistance (AMR) global health crisis, physicians have been forced to employ antibiotics of last resort such as colistin, which had previously been removed from clinics due to toxicity concerns. The increase in colistin usage has in turn resulted in the increased incidence of colistin-resistant isolates, making novel therapeutic options for infections caused by these pathogens a priority. We previously reported that sorafenib, a eukaryotic kinase inhibitor, is a colistin adjuvant, augmenting colistin activity against colistin-resistant Klebsiella pneumoniae and Acinetobacter baumannii. Herein, we describe the generation of a library of analogues based upon the sorafenib scaffold, lead compounds from which sensitize colistin-resistant K. pneumoniae, A. baumannii, and Pseudomonas aeruginosa to colistin, and exhibit reduced cytotoxicity compared to sorafenib. We also describe the standalone antimicrobial activity of these sorafenib analogues against methicillin-resistant Staphylococcus aureus (MRSA). Lead compound NDM-773 lowers the colistin minimum inhibitory concentration (MIC) against K. pneumoniae B9 from 512 μg mL-1 to 2 μg mL-1 at 1.5 μM, against A. baumannii 4106 from 1024 μg mL-1 to 1 μg mL-1 at 4 μM, and against P. aeruginosa TRPA162 from 8192 μg mL-1 to ≤0.125 μg mL-1 at 7.5 μM. NDM-773 acts as a standalone antibiotic against MRSA with an MIC of 0.781 μM (0.398 μg mL-1) and a frequency of mutation rate of <10-11 against MRSA BAA-1556. NDM-773 exhibits over three-fold reduction in HepG2 toxicity compared to sorafenib, and has therapeutic indices (TIs) up to 35.6 as a colistin adjuvant, and 68.4 as an MRSA antibiotic.

BACKGROUND: This study provides the first prospective, genomically validated dataset integrated into the global MultiDrug-Resistant Organism (MDRO) Network from the Middle East and North Africa region. To address the substantial gap in antimicrobial resistance (AMR) data, the American University of Beirut Medical Center (AUBMC) investigated carbapenem-resistant Enterobacterales (CRE), Acinetobacter baumannii (CRAB), and Pseudomonas aeruginosa (CRPA). METHODS: Consecutive, hospitalized patients whose clinical cultures were positive for CRE, CRAB, or CRPA were prospectively enrolled between June 2018 and November 2019. Data on demographics, hospitalization, outcomes, and antimicrobial susceptibility were collected. Whole-genome sequencing (WGS) characterized the isolates. The primary outcome was the Desirability of Outcome Ranking (DOOR). RESULTS: Ninety-four patients were included: 35 with CRE, 19 with CRAB, and 40 with CRPA. Overall, 30% of patients survived without adverse events, whereas 33% experienced two or more adverse events. Patients with CRAB had the poorest prognosis, with only 5% surviving without complications, and a significantly different DOOR distribution versus CRE or CRPA (p = 0.023). Adjusted DOOR probabilities confirmed the poorer outcomes associated with CRAB: when compared with CRE or CRPA, a randomly selected CRAB patient had only a 37.7% (95% CI, 24.9-52.6%) and 38.8% (95% CI, 26.5-52.7%) probability of achieving a more desirable outcome, respectively. WGS identified blaNDM-5 (24%) and blaOXA-48 (24%) as the most common genes in CRE, blaOXA-23 in all CRAB strains, and blaVIM-2 in 88% of CRPA strains. The dominant clones were CG383 K. pneumoniae (CRE), CG2 (CRAB), and CG111 (CRPA). CONCLUSIONS: MDRO infections in Lebanon have distinct molecular patterns compared to the US, Chinese, South American, and Australian cohorts, as well as poor outcomes, especially with CRAB. Ongoing surveillance, strengthening regional collaboration, and future clinical trials are essential to guide diagnostic and therapeutic strategies in settings with increasing AMR. TRIAL REGISTRY: ClinicalTrials.gov. TRIAL REGISTRATION NUMBER: NCT03646227. DATE OF REGISTRATION: 15-08-2018.

Novel β-lactam/β-lactamase inhibitors (βL/βLIs) are important therapies for carbapenem-resistant Pseudomonas aeruginosa (CRPA). However, the global extent of resistance to these agents and the impact of resistance on patient outcomes are unclear. We therefore evaluated patients with CRPA isolates at 35 hospitals (nine countries) from December 2018 to November 2019. Antimicrobial susceptibility testing was performed at a central laboratory by agar dilution for ceftolozane-tazobactam (C/T) and ceftazidime-avibactam (CZA) and by broth microdilution for imipenem-relebactam (I/R). Characteristics and outcomes, including desirability of outcome rankings (DOOR), were compared between patients infected with isolates not susceptible vs susceptible to each agent. Of 800 CRPA isolates, susceptibility to C/T, CZA, and I/R was 69%, 67%, and 33%, respectively. USA isolates (n = 526) were more frequently susceptible to these agents than isolates from other countries (n = 274; C/T: 83% vs 42%; CZA: 77% vs 47%; I/R: 37% vs 23%; P < 0.001 for each comparison) and isolates with carbapenemases (n = 157) were less frequently susceptible than isolates without carbapenemases (n = 643; C/T: 7% vs 84%; CZA: 24% vs 77%; I/R: 6% vs 39%; P < 0.001 for each comparison). Thirty-day mortality and DOOR were similar overall in patients infected with isolates not susceptible vs susceptible to each βL/βLI. However, the adjusted probability of a better DOOR outcome for a randomly selected patient with bacteremia due to a C/T-not susceptible vs -susceptible isolate was 38.2% (95% confidence interval, 25.6%-52.7%). Resistance to novel βL/βLIs, especially I/R, is common in CRPA, particularly outside the USA and in carbapenemase-producing isolates. Additional treatment options are needed for CRPA infections.

The development of novel therapeutic approaches to combat infections that stem from extensively drug-resistant (XDR) gram-negative bacteria remains an area of significant unmet need. One such approach is the use of antibiotic adjuvants. Currently, colistin (polymyxin E) is used as the antibiotic of last resort for the treatment of XDR gram-negative bacterial infections. However, resistance to this antibiotic is on the rise. We previously reported that IMD-0354 (an IκB kinase-β inhibitor) and related salicylanilide adjuvants overcome colistin resistance in several gram-negative pathogens. However, this scaffold exhibits unfavorable eukaryotic toxicity, thought to arise from the salicyl moiety. Herein, we investigate the structure-activity relationship (SAR) of second-generation m-hydroxybenzanilide analogs of IMD-0354, to uncover compounds with reduced eukaryotic toxicity and IκB kinase-β inhibitory properties, while maintaining colistin adjuvant activity. We have identified new leads that lower the colistin minimum inhibitory concentration (MIC) upwards of 2048-fold against highly colistin-resistant Acinetobacter baumannii and Klebsiella pneumoniae. In particular, NDM-622 exhibits reduced HepG2 toxicity compared to IMD-0354, with an IC50 of 125 ± 8.0 μM (59.4 ± 3.8 μg/mL) and a therapeutic index of ≥50. In a murine peritonitis model using a highly a colistin-resistant K. pneumoniae strain, NDM-622 and colistin together effect a decrease in colony forming units (CFUs) compared to treatment with colistin alone or vehicle controls. Preliminary mechanism-of-action (MoA) studies suggest that m-hydroxybenzanilides, including NDM-622, likely act via a mechanism distinct from IMD-0354.

Carbapenem-resistant Enterobacterales (CRE) pose a global threat due to limited treatment options and high mortality. Difficult-to-treat resistance (DTR), defined as non-susceptibility to all conventional β-lactams and fluoroquinolones, has primarily been applied to Pseudomonas aeruginosa. However, its relevance for Enterobacterales remains unclear, particularly in regions with a distinct carbapenemase landscape, such as Japan where IMP-type metallo-β-lactamases predominate. We analyzed the MultiDrug-Resistant organisms clinical research network (MDRnet) cohort, a multicenter prospective study conducted at 13 Japanese hospitals between April 2019 and March 2024. This analysis included patients with clinically indicated cultures yielding CRE. Clinical characteristics and outcomes assessed using the desirability of outcome ranking (DOOR) framework and genomic epidemiology characterized by whole-genome sequencing were compared between DTR and non-DTR groups. Among 196 CRE cases, 64 (32.7%) represented infections, including 12 DTR cases (18.8%). Carbapenemase genes were detected in 34/64 infections (53.1%), with similar prevalence in the DTR and non-DTR groups (50.0% vs 53.8%). blaIMP-1 was the most frequently identified carbapenemase gene (n = 28). The overall 30-day mortality rate was 21.9%, with 16.7% (95% confidence interval [CI], 2.1%-48.4%) in the DTR group and 23.1% (95% CI, 12.5%-36.8%) in the non-DTR group. DOOR outcomes were similar between groups. Appropriate empiric and definitive therapy was less frequently administered in the DTR group. In this cohort, where IMP-type carbapenemases and non-DTR CRE are prevalent, DTR classification did not appear to correlate with 30-day mortality or DOOR outcomes. These findings underscore the importance of regional molecular epidemiology when interpreting clinical outcomes of CRE infections.IMPORTANCEDifficult-to-treat resistance (DTR) is increasingly used to assess the clinical impact of antimicrobial resistance, but its significance in carbapenem-resistant Enterobacterales (CRE) may vary across molecular epidemiologic settings. In this prospective multicenter study from Japan, where IMP-type carbapenemases predominated, most CRE infections were classified as non-DTR. Whole-genome sequencing also revealed a distinct local clonal structure. DTR was not associated with 30-day mortality or desirability of outcome ranking despite lower rates of appropriate empiric and definitive therapy. Our study highlights the importance of interpreting DTR in CRE within the context of regional molecular epidemiology and supports the need for continued regional multicenter studies to evaluate its clinical utility.

OBJECTIVES: Nacubactam is a novel diazabicyclooctane carbapenemase inhibitor that, in combination with cefepime or aztreonam, has been submitted for regulatory approval in Japan for treating serious Gram-negative infections. This study aimed to evaluate the in vitro activity of nacubactam combined with cefepime or aztreonam against a nationwide collection of clinical carbapenem-resistant Enterobacterales (CRE) isolates in Japan. METHODS: Minimum inhibitory concentration (MIC) values of 376 CRE isolates from 6 medical institutions in Japan were determined according to the Clinical and Laboratory Standards Institute (CLSI) methods. Results were interpreted using clinical breakpoints of the CLSI document M100 (2025) and the European Committee on Antimicrobial Susceptibility Testing clinical breakpoints, version 15.0 (2025). RESULTS: The predominant CRE isolates were Klebsiella pneumoniae (n = 98), Klebsiella aerogenes (n = 62) and Escherichia coli (n = 43), with the Enterobacter cloacae complex accounting for 117 isolates. Carbapenemase-producing Enterobacterales (CPE) accounted for 48.9% (n = 184), with the predominant carbapenemases being IMP-1 (n = 70), IMP-6 (n = 43) and NDM (n = 17). Cefepime-nacubactam and aztreonam-nacubactam exhibited potent antibacterial activity against CRE isolates with MIC50/90 of 1/4 and 0.5/2 mg/L, respectively. Cefepime-nacubactam and aztreonam-nacubactam demonstrated potent activity against CPE, with MIC50/90 of 2/4 and 0.5/2 mg/L, respectively, which were lower than those for ceftazidime-avibactam (64/>64 mg/L) and imipenem-relebactam (2/16 mg/L). Both combinations exhibited potent antibacterial activity against non-carbapenemase-producing carbapenem-resistant Enterobacterales (non-CP-CRE), with MIC50/90 of 0.25/4 and 0.5/4 mg/L, respectively. CONCLUSIONS: Cefepime-nacubactam and aztreonam-nacubactam have excellent antibacterial activities against CPE and non-CP-CRE, supporting their potential as therapeutic options for CRE infections.

Carbapenem-resistant bacteria represent a significant challenge for patients with cancer; however, the characteristics and prognoses of carbapenem-resistant Gram-negative bacilli (CRGNB) infections in Japanese patients with cancer remain unclear. Therefore, we aimed to investigate the features and outcomes of CRGNB infections in this population. This multicenter prospective observational cohort study prospectively enrolled 167 patients with CRGNB infections, with or without cancer from April 2019 to March 2022. The 30-day mortality rate was numerically higher, although not significantly (18.2% vs. 14.0%, p = 0.45), in the cancer group than in the non-cancer group. The average length of hospital stay was similar (44.6 days vs. 51.0 days, p = 0.55). Similarly, the incidence of the composite outcome-defined as the 30-day mortality or events associated with worsening clinical course-was also not significantly different (56.1% vs. 43.6%, p = 0.12). Propensity score analysis using inverse probability weighting showed no significant difference in the 30-day mortality and average length of hospital stay (p = 0.25 and 0.66). However, the incidence of the composite outcome was significantly higher in the cancer group (odds ratio, 2.36; p = 0.02). Patients with cancer and CRGNB infection experienced worse composite outcomes than those without cancer, highlighting the need for preventive measures for CRGNB infections in this population.

BACKGROUND: Nacubactam (OP0595) is a newly developed diazabicyclooctane β-lactamase inhibitor used in combination with cefepime or aztreonam. We assessed the efficacy and safety of cefepime-nacubactam and aztreonam-nacubactam versus imipenem-cilastatin in complicated urinary tract infection (cUTI) or acute uncomplicated pyelonephritis. METHODS: The Integral-1 global, phase 3, multicentre, randomised, double-blind study recruited adults (aged ≥18 years) with cUTI or acute uncomplicated pyelonephritis at 79 sites in Bulgaria, China, Czech Republic, Estonia, Georgia, Japan, Latvia, Lithuania, and Slovakia. Patients were randomly assigned (2:1:1) to receive intravenous cefepime (2 g) plus nacubactam (1 g), aztreonam (2 g) plus nacubactam (1 g), or imipenem (1 g) plus cilastatin (1 g) every 8 h for 5-14 days. Randomisation was stratified by diagnosis and geographical region. The primary endpoint was the proportion of patients achieving composite clinical and microbiological success at test of cure in the microbiological modified intention-to-treat population-all patients who were randomly assigned, received any amount of the study drug, and had a baseline qualifying pathogen that was susceptible to imipenem and meropenem. The prespecified non-inferiority margin was more than 15 percentage points difference; the superiority margin was more than zero percentage points difference, for the lower bound of the two-sided 95% CI for imipenem-cilastatin. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT05887908. FINDINGS: Between May 22, 2023, and Nov 26, 2024, 614 patients were randomly assigned and 431 were included in the primary efficacy analysis (cefepime-nacubactam [n=214], aztreonam-nacubactam [n=112], or imipenem-cilastatin [n=105]); 228 patients (53%) were male and 203 (47%) were female. The primary endpoint was achieved by 176 (82%) of 214, 81 (72%) of 112, and 64 (61%) of 105 patients in the cefepime-nacubactam, aztreonam-nacubactam, and imipenem-cilastatin groups, respectively. The percentage difference in the success rate versus imipenem-cilastatin was 21·3% (95% CI 10·9 to 32·0) for cefepime-nacubactam (non-inferior and superior), and 11·4% (-1·2 to 23·7) for aztreonam-nacubactam (non-inferior). Treatment-emergent adverse events were reported in 100 (33%) of 306, 45 (30%) of 152, and 65 (43%) of 150 patients in the cefepime-nacubactam, aztreonam-nacubactam, and imipenem-cilastatin groups, respectively. No treatment-related deaths occurred. INTERPRETATION: Cefepime-nacubactam and aztreonam-nacubactam are potential treatment options for Gram-negative cUTI and acute uncomplicated pyelonephritis, including infections caused by antimicrobial-resistant strains. FUNDING: Meiji Seika Pharma and Japan Agency for Medical Research and Development.

Intrinsic Acinetobacter-derived cephalosporinases (ADCs) in Acinetobacter baumannii are AmpC-type β-lactamases that confer resistance to β-lactam agents, typically through insertion sequence (IS) element-driven overexpression. However, the contribution of ADCs to resistance against advanced β-lactam agents has not been systematically investigated. Given the increasing clinical use of these agents, including cefiderocol, we analyzed the diversity and function of ADC variants in a global collection of carbapenem-resistant A. baumannii (CRAb) isolates. We identified 52 distinct ADC variants in a collection of 428 CRAb clinical isolates from the United States. Among these, variants carrying both a valine substitution at position 292 in the R2 loop and an alanine duplication (ADUP) in the Ω loop consistently conferred stable resistance to cefiderocol. Biochemical and crystallographic analyses demonstrated that ADC-227, which harbors a V292W substitution with an ADUP at position 218a in the Ω loop, exhibits enhanced catalytic efficiencies for ceftazidime and cefiderocol and moderately reduced inhibition by avibactam, leading to resistance not only to cefiderocol but also to ceftazidime-avibactam. Structural studies revealed conformational flexibility of the R2 loop, allowing dynamic accommodation of substrates. Collectively, the findings identify Val292, in combination with an ADUP in the Ω loop, as a mutational "hot spot" for ADCs evolution that may undermine the efficacy of newer β-lactams, including cefiderocol. These results underscore the need for ongoing molecular surveillance of A. baumannii isolates to detect and track the emergence of such variants in clinical settings.IMPORTANCECarbapenem-resistant Acinetobacter baumannii (CRAb) has been designated as a critical priority pathogen by the World Health Organization (WHO). Cefiderocol has been introduced as a novel therapy against CRAb; however, recent clinical data highlight concerning treatment failures and excess mortality. Understanding resistance mechanisms is therefore essential to preserve the clinical utility of this agent. This study addresses a critical knowledge gap by investigating the role of intrinsic Acinetobacter-derived cephalosporinases (ADCs), which are ubiquitous in A. baumannii and diverse in sequence. By defining specific mutational patterns that endanger cefiderocol activity, this work highlights how chromosomally encoded enzymes can evolve to erode the effectiveness of newer β-lactams such as cefiderocol. These insights underscore the importance of integrating molecular surveillance into clinical practice and antimicrobial stewardship to ensure timely detection of emerging resistance in clinical A. baumannii isolates, ultimately informing treatment strategies and guiding future drug development.

This challenging clinical case highlights the impact of PBP3 insertions in Escherichia coli, which reduce susceptibility to key β-lactam agents and complicate treatment, particularly in the setting of NDM production (C. Fabrizio, F. Valzano, S. Giuliano, E. Morelli, et al., Antimicrob Agents Chemother 70:e00887-25, 2026, https://doi.org/10.1128/aac.00887-25). Clinical improvement was achieved with imipenem-relebactam plus aztreonam, supporting the idea that targeting multiple penicillin-binding proteins can overcome functional redundancy. These findings emphasize the clinical relevance of PBP3-mediated resistance and the need for treatment strategies that address complex β-lactam resistance in Gram-negative pathogens.

Despite the increasing number of reports on hypervirulent and extended-spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae infections, data on the distribution of these pathogens in the community are limited. To address this knowledge gap, we investigated the carriage rates of K. pneumoniae complex in the stools of community-dwelling individuals in Japan. From 627 stool samples submitted to a commercial diagnostic laboratory, 407 Klebsiella strains were identified from 368 samples, corresponding to a colonization rate of 58.7%. Based on whole-genome sequencing, K. pneumoniae was the most prevalent species (n = 218, 53.6%), followed by Klebsiella variicola (n = 137, 33.7%). The detection rate of K. variicola was higher than previously reported in studies from other Asian countries. The overall distribution of sequence types (STs) was similar to those observed in previous studies of clinical isolates. However, hypervirulent K. pneumoniae clones, specifically ST23-K1 and ST412-K57, and ESBL-producing strains were rare, each accounting for less than 1% of the strains. These findings suggest that, while carriage of K. pneumoniae complex species is common in the community, healthcare settings may represent a more significant reservoir of hypervirulent and ESBL-producing K. pneumoniae strains in this epidemiological setting.IMPORTANCEKlebsiella pneumoniae complex species are bacteria that can cause serious infections, especially in hospital settings. Some types have become more dangerous because they are resistant to antibiotics or highly virulent. To better understand where these harmful clones come from, this study looked for Klebsiella species in healthy people living in the community in Japan. The results showed that these bacteria are commonly found in the gut, particularly K. pneumoniae and K. variicola. While some strains with traits linked to antibiotic resistance or severe infections were identified, they were rare. These findings suggest that most people carry Klebsiella strains as commensals and that the more dangerous forms of Klebsiella are likely spreading mainly in healthcare settings.

PURPOSE: The aim of this study was to evaluate the effectiveness of remdesivir among vulnerable patients hospitalized with a primary diagnosis of coronavirus disease 2019 (COVID-19). METHODS: In this retrospective study, data from the Premier Healthcare Database compiled from December 2021 to December 2024 were examined. Four cohorts were analyzed: overall (≥18 years of age), elderly (≥65 years of age), those with pneumonia due to COVID-19, and those with chronic obstructive pulmonary disease (COPD). Analyses were stratified by supplemental oxygen requirements upon admission. Patients treated with remdesivir within the first 2 days of hospitalization were matched to those not treated with remdesivir during hospitalization, using 1:1 propensity score matching without replacement. Outcomes of interest were 14- and 28-day all-cause inpatient mortality. RESULTS: A total of 220,677 patients met the eligibility criteria; of these, 123,388 (55.9%) were treated with remdesivir within the first 2 days of hospitalization. Overall, treatment with remdesivir was associated with significantly lower 14- and 28-day mortality rates compared to rates in patients who did not receive remdesivir (adjusted hazard ratio [95% CI], 0.76 [0.73-0.79] and 0.78 [0.75-0.81], respectively; P < 0.0001). Similar results were observed across all patient groups irrespective of supplemental oxygen requirements and across early (December 2021-December 2022) and later (January 2023-December 2024) Omicron periods. CONCLUSIONS: These results build on previous research highlighting the effectiveness of early treatment initiation with remdesivir in vulnerable patients hospitalized due to SARS-CoV-2 infection.

Evidence regarding the diagnostic value of quantitative interferon-gamma release assay (IGRA) results in elderly populations is limited, and large-scale data for QuantiFERON-TB Gold Plus (QFT-Plus) are scarce. We evaluated QFT-Plus and T-SPOT.TB (T-SPOT) for distinguishing active tuberculosis (ATB) from latent infection (LTBI) in elderly individuals in Japan, a super-aged country. We conducted a retrospective, cross-sectional diagnostic accuracy study of patients ≥65 years who underwent IGRA testing between 2015 and 2024 at two hospitals: a tuberculosis referral center (QFT-Plus and T-SPOT) and a tertiary hospital (T-SPOT only). ATB was defined as microbiologically confirmed TB. Quantitative IGRA values were compared between ATB and LTBI in all patients and in IGRA-positive subsets. Receiver operating characteristic (ROC) curves assessed discriminatory performance. Among 10,745 elderly patients (ATB: n = 310; LTBI: n = 1,158), values showed substantial overlap. For T-SPOT, the area under the curves (AUCs) improved at Tosei General Hospital (TGH) (ESAT-6: 0.679, CFP-10: 0.670) in IGRA-positive cases. In contrast, all-patient AUCs at Fujita Health University Hospital (FHUH) were low (ESAT-6: 0.367, CFP-10: 0.362), demonstrating an inverse association, though they improved (ESAT-6: 0.607 and CFP-10: 0.554) in IGRA-positive cases. For QFT-Plus, all-patient AUCs were low (TB1 antigen: 0.462, TB2 antigen: 0.470), but improved in the IGRA-positive cohort (TB1 antigen: 0.630, TB2 antigen: 0.645). The optimal quantitative cutoffs in IGRA-positive cases provided modest diagnostic accuracy. In elderly individuals, quantitative IGRA values alone have limited ability to distinguish ATB from LTBI, but QFT-Plus and T-SPOT show modest improvement in IGRA-positive cases. Although not suitable as a stand-alone diagnostic, quantitative IGRA may assist risk stratification and decision-making in selected scenarios.IMPORTANCETuberculosis remains a major health concern in aging societies, such as Japan, where most patients are elderly adults with impaired immune function. Interferon-gamma release assays (IGRA) are widely used for detecting infection, but the role of their quantitative values in differentiating active tuberculosis from latent tuberculosis infection has been uncertain. Our study is the first to evaluate the quantitative performance of the latest QuantiFERON-TB Gold Plus and T-SPOT.TB specifically in elderly patients, across both a tuberculosis referral hospital and a university hospital. Although absolute separation between active and latent disease was not achieved, we found that, in test-positive individuals, active cases tended to yield higher values, particularly with T-SPOT.TB. This indicates that quantitative information, when interpreted within the clinical context, can assist physicians in assessing risk and guiding further diagnostic steps, offering practical value for improving decision-making in the care of vulnerable elderly patients.

INTRODUCTION: Carbapenem-resistant Gram-negative bacteria (CRGNB) pose a major clinical threat. This study evaluated the in vitro activity of cefiderocol and other recently approved β-lactam/β-lactamase inhibitor combinations against major CRGNB. MATERIALS AND METHODS: A total of 292 CRGNB clinical isolates were analyzed, comprising 146 Enterobacterales, 106 Pseudomonas aeruginosa, and 40 Stenotrophomonas maltophilia, all collected from hospitals across Japan. Antimicrobial susceptibility testing was performed by broth microdilution (BMD). Disk diffusion testing was also conducted for cefiderocol, and categorical agreement with BMD was assessed. Whole-genome sequencing (WGS) was used for species confirmation and characterization of resistance determinants. RESULTS: Carbapenemase producers accounted for 64.4 % of Enterobacterales (94/146) and 8.5 % of P. aeruginosa (9/106), with metallo-β-lactamase (MBL) producers comprising 92.6 % (87/94) and 77.8 % (7/9), respectively. Based on CLSI breakpoints, 94.5 % (276/292) of isolates were susceptible to cefiderocol, including 91.8 % of Enterobacterales, 99.1 % of P. aeruginosa, and 92.5 % of S. maltophilia. Ceftolozane-tazobactam, ceftazidime-avibactam, and imipenem-relebactam were active against 12.3 %, 44.5 % and 45.9 % of Enterobacterales, and 89.6 %, 86.8 % and 72.6 % of P. aeruginosa, respectively. Categorical agreement between cefiderocol disk diffusion and BMD exceeded 92 % across all groups, although very major errors occurred in Enterobacterales (n = 2) and S. maltophilia (n = 3). Cefiderocol-non-susceptible Enterobacterales isolates frequently harbored carbapenemase and extended-spectrum β-lactamase (ESBL) genes, together with mutations in ftsI (encoding PBP3), ompK35, or siderophore receptor genes (cirA, tonB). DISCUSSION: Cefiderocol showed potent in vitro activity against CRGNB in Japan, including MBL producers. Disk diffusion correlated well with BMD results; however, confirmatory BMD testing should be considered when resistance is clinically suspected.

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.

Extended-spectrum β-lactamase (ESBL)-producing bacteria are increasingly common, especially in community settings of low-resource areas. While intravenous carbapenems are the most effective treatment, rising resistance highlights the importance of limiting their use. Alternative options, including certain penicillins, cephamycins, aminoglycosides, and fluoroquinolones, show promise and are being reconsidered due to availability and cost. Oral therapies like oral carbapenems and trimethoprim-sulfamethoxazole may enable earlier discharge and outpatient care. Newer β-lactams are in development but may be limited by high costs. Overall, combining intravenous and oral noncarbapenem agents with carbapenems used selectively can optimize ESBL infection management.

BACKGROUND: Carbapenem-resistant Gram-negative bacilli (CR-GNB) are a major public health threat, traditionally linked to hospital settings. However, infections are increasingly reported in the community, and the clinical distinctions between community-associated (CA) and healthcare-associated (HA) infections remain unclear. METHODS: We conducted a prospective multicenter study of hospitalized patients with CR-GNB infections across 13 Japanese tertiary hospitals between April 2019 and March 2024. Infections were categorized as CA, HA, or hospital-onset (HO) using standardized criteria. We compared patient demographics, microbiological findings, infection sites, and clinical outcomes based on the setting of onset. RESULTS: Among 425 patients, 43 had CA, 59 HA, and 323 HO infections. Pseudomonas aeruginosa was the predominant pathogen in all groups. Aeromonas species were more frequently associated with CA than HO cases (23.3% of CA vs 2.2% of HO cases), whereas Stenotrophomonas maltophilia was detected almost exclusively among HO cases. Hospital-onset infections were associated with longer median hospital stays compared with CA infections (68 vs 17 days) and a trend toward higher 30-day mortality (23.9% vs 9.5%). In contrast, HA infections demonstrated no significant differences from CA infections in either hospital length of stay (23 vs 17 days) or 30-day mortality rate (10.3% vs 9.5%). CONCLUSIONS: Community-associated CR-GNB infections are an emerging concern in Japan, showing distinct pathogen profiles and infection sites compared to HO cases. Importantly, HA infections resembled CA infections in terms of clinical characteristics and outcomes, suggesting a need to reexamine the clinical relevance of current HA classification criteria for guiding therapy and risk stratification.

Antibiotic resistance is a threat to human health, yet recent work highlights how loss of resistance may drive pathogenesis in some bacteria. In two recent studies, we found that β-lactam antibiotics and nutrient stresses faced during infection selected for genetic inactivation of the Pseudomonas aeruginosa antibiotic efflux pump mexEFoprN. Unexpectedly, efflux pump mutations increased P. aeruginosa virulence during infection; however, neither the prevalence of mexEFoprN inactivating mutations in real human infections, nor the mechanisms driving increased virulence of efflux pump mutants are known. We hypothesized that human infection would select for virulence enhancing mutations. Using genome sequencing of clinical isolates, we show that mexEFoprN efflux pump inactivating mutations are enriched in P. aeruginosa isolates from cystic fibrosis infections relative to isolates from acute respiratory infections. Combining RNA-seq, metabolomics, genetic approaches, and infection models we show that efflux pump mutants have elevated quorum sensing driven expression of elastase and rhamnolipids which increase P. aeruginosa virulence during acute and chronic infections. Restoration of the efflux pump in a representative respiratory isolate and the notorious cystic fibrosis Liverpool epidemic strain reduced their virulence. These findings suggest that mutations inactivating antibiotic resistance mechanisms could lead to greater patient mortality and morbidity.

Carbapenem-resistant Acinetobacter baumannii (CRAb) is a challenging, environmentally hardy organism with a propensity to spread within hospitals and a predilection to infect critically ill, vulnerable patients. With its potential for rapid transmission, limited treatment options, and substantial mortality, CRAb is recognized as a critical, top-priority pathogen. Since its initial discovery in 1985, CRAb has disseminated globally, presenting a significant public health threat. CRAb is now endemic in many regions in Europe, South America, Asia, and Africa and globally contributes to over 50 000 deaths each year. Its ability to adhere to hospital surfaces, withstand desiccation, and form biofilms leads to widespread outbreaks. At-risk populations include those hospitalized and ventilated, and the most frequent presentations are respiratory and bloodstream infections. Carbapenem resistance in CRAb is primarily mediated by plasmid-borne carbapenemase genes, especially bla OXA-23. These genes, carried by several epidemic international clones, including IC1 and IC2, have facilitated the global dissemination of CRAb through horizontal gene transfer in healthcare settings. Mortality rates are >20% and vary substantially by region and by type of infection, with bloodstream infections carrying >40% mortality. Despite its significant impact, the development of treatments for CRAb remains inadequate. The novel agent sulbactam-durlobactam holds promise for improved patient outcomes, but ongoing therapeutic development, infection prevention, and antimicrobial stewardship are critical to combat this formidable pathogen. Here, we review the emergence and dissemination of CRAb, its molecular epidemiology and resistance mechanisms, summarize contemporary global clinical epidemiology and patient outcomes, and briefly describe existing and future therapeutics.

With limited treatments for carbapenem-resistant Klebsiella pneumoniae (CRKp), curtailing transmission is critical. We applied a network analysis using epidemiological admission data and bacterial genetics to characterize CRKp spread among patients in 16 acute care hospitals linked to 217 other healthcare facilities in the United States. Patients with diagnosed CRKp infection were selected from the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE-1), a prospective, observational study conducted from 12/2011 to 6/2016. A network analysis was performed using epidemiological admission data and bacterial genetics to characterize putative CRKp transmission among patients across various healthcare facilities and the community. Overall, 347/526 patients (66%) had a putative transmission link to at least one other patient within the network. Most transmission chains were small (i.e., between 2 patients); however, the largest included 172 patients diagnosed over 1575 days. One-third of patients shared a genetically similar CRKp isolate with another patient but had no observed epidemiological linkages at any healthcare location. Patients with CRKp are part of extensive regional networks involving a large number of non-hospital healthcare settings such as skilled nursing facilities. Thus, controlling spread necessitates integrated surveillance and control initiatives at regional and national levels in addition to institution-specific approaches.

Genomic characteristics and optimal treatment of Corynebacterium jeikeium remain largely unknown. We collected clinical information and performed whole-genome sequencing analysis of the causative strains of six cases of C. jeikeium infection at a single hospital over a 9-year period. Additionally, whole-genome sequencing analysis was performed on 33 C. jeikeium strains from cases of bloodstream infection at eight hospitals. Antimicrobial susceptibility testing was performed, and the results were compared to the resistance genes identified. Publicly available genome data of strains of C. jeikeium complex, consisting of C. jeikeium sensu stricto, Corynebacterium macclintockiae, and Corynebacterium evansiae, worldwide, were combined with the data from this study to determine the distribution of genomic species. In the single-center study, cases of prosthetic osteoarticular infection, postoperative intra-abdominal infection, and catheter-related bloodstream infection were identified, and the causative strains were genomically identified as C. macclintockiae. All but one isolate (32/33, 97.0%) in the eight-center study identified as C. jeikeium by matrix-assisted laser desorption ionization-time of flight mass spectrometry were also genomically identified as C. macclintockiae. Nosocomial transmission was suggested in three strain pairs by core-genome single nucleotide polymorphism analysis. C. macclintockiae strains were generally multidrug-resistant, but all anti-methicillin-resistant Staphylococcus aureus agents, including teicoplanin, had favorable activity, and the strains without the tet(W) gene (22/38, 57.9%) were susceptible to tetracyclines. Genome analysis of 66 C. jeikeium complex strains collected worldwide, consisting mainly of clinical strains, re-identified 51 strains (77.3%) as C. macclintockiae. This study demonstrates that C. macclintockiae is the major genomic species of the C. jeikeium complex causing human infections.IMPORTANCERecent widespread use of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has facilitated the identification of Corynebacterium spp. in microbiology laboratories, thereby raising awareness of the clinical importance of these organisms. Nevertheless, the accumulation of information on genomic characteristics of Corynebacterium jeikeium has been significantly limited compared to other pathogenic organisms thus far. In this study, we analyzed causative strains of infections identified as C. jeikeium by MALDI-TOF MS, collected from multiple institutions throughout Japan, and found that most of these strains were genomically identified as Corynebacterium macclintockiae, a species that has been newly described recently. Collection of clinical information on selected cases showed that C. macclintockiae indeed caused invasive infections that required intravenous or long-term oral antimicrobial therapy. Additional analyses using genomic data of C. jeikeium complex strains registered in public databases suggest that C. macclintockiae is of global clinical importance.

INTRODUCTION: Personalized phage therapy is used in Europe and the United States to treat intractable infections caused by drug-resistant bacteria. This pilot study aimed to acquire feasibility data for clinical trials of individualized phage therapy in Japan. METHODS: An observational study was conducted from August 2023 to September 2024 in adults with drug-resistant bacterial infections and treatment failure or recurrence/relapse following antimicrobial therapy. Phages with activity against the detected bacteria were then identified from the environment and an existing phage library. RESULTS: Thirty patients with drug-resistant bacterial infections were enrolled. Of these, six (20 %) died within 30 days of detection. The most commonly detected bacteria were methicillin-resistant Staphylococcus aureus (MRSA) (n = 10, 33.3 %) and carbapenem-resistant Pseudomonas aeruginosa (CRPA) (n = 5, 16.7 %). The most common nontuberculous mycobacterium (NTM) was Mycobacterium avium (n = 4, 13.3 %), followed by Mycobacterium abscessus (n = 2, 6.7 %). In terms of infection types, respiratory tract infections were the most common (n = 13, 43.3 %), followed by bone and joint infections (n = 6, 20 %) and skin and soft tissue infections (n = 6, 20 %). Phages with a titer of 108 PFU/ml or higher could be prepared for 26 out of 30 strains (86.7 %). Phages against CRPA were more readily identified from the environment than for MRSA and NTM. A phage against CRPA was purified to a lipopolysaccharide concentration of 0.023 EU/108 PFU. CONCLUSION: Personalized phages can be prepared for intractable infections caused by drug-resistant bacteria. These results support the conduct of clinical trials to implement personalized phage therapy in Japan.

The genus Aeromonas is increasingly implicated in human infections. However, accurate species-level identification remains challenging, particularly in clinical microbiology laboratories. This study aimed to develop a multiplex polymerase chain reaction (PCR) assay to identify four Aeromonas species-Aeromonas hydrophila, Aeromonas caviae, Aeromonas veronii, and Aeromonas dhakensis-most frequently associated with human infectious diseases. A total of 788 whole genome sequencing (WGS) data sets from 31 Aeromonas species were analyzed to identify open reading frames (ORFs) specifically present in A. hydrophila, A. caviae, A. veronii, and A. dhakensis. Primer sets were designed based on sequences of ORFs specific to each species to develop a multiplex PCR assay. To validate the efficacy of the assay, 256 clinical Aeromonas isolates were tested, and the results were compared with taxonomic affiliation inferred by WGS data, along with 19 type strains. The multiplex PCR successfully identified all strains of the four target species and produced no amplification in non-target species strains except the band for internal control. The multiplex PCR enables rapid and reliable identification of four Aeromonas spp. commonly involved in human infectious diseases.IMPORTANCEThe multiplex PCR assay facilitates accurate identification of clinically important Aeromonas spp. in clinical microbiology laboratories, providing crucial information to guide appropriate antimicrobial therapy and advance understanding of the epidemiology of Aeromonas spp.

Patients with hematologic diseases have experienced coronavirus disease 2019 (COVID-19) with a prolonged, progressive course. Here, we present clinical, pathological, and virological analyses of three cases of prolonged COVID-19 among patients undergoing treatment for B-cell lymphoma. These patients had all been treated with anti-CD20 antibody and bendamustine. Despite various antiviral treatments, high severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) levels persisted for >4 weeks, and two of them succumbed to COVID-19. The autopsy showed bronchopneumonia, interstitial pneumonia, alveolar hemorrhage, and fibrosis. Overlapping cytomegalovirus, fungal and/or bacterial infections were also confirmed. Sequencing of SARS-CoV-2 showed accumulation of mutations and changes in variant allele frequencies over time. NSP12 mutations V792I and M794I appeared independently in two cases as COVID-19 progressed. In vitro drug susceptibility analysis and an animal experiment using recombinant SARS-CoV-2 demonstrated that each mutation, V792 and M794I, was independently responsible for remdesivir resistance and attenuated pathogenicity. E340A, E340D, and F342INS mutations in the spike protein were found in one case, which may account for the sotrovimab resistance. Analysis of autopsy specimens indicated heterogeneous distribution of these mutations. In summary, we demonstrated temporal and spatial diversity in SARS-CoV-2 that evolved resistance to various antiviral agents in malignant lymphoma patients under immunodeficient conditions caused by certain types of immunochemotherapies. Strategies may be necessary to prevent the acquisition of drug resistance and improve outcomes, such as the selection of appropriate treatment strategies for lymphoma considering patients' immune status and the institution of early intensive antiviral therapy.

BACKGROUND AND OBJECTIVES: Carbapenem-resistant Gram-negative bacilli (CRGNB), especially Enterobacterales, Pseudomonas aeruginosa and Acinetobacter baumannii, are critical pathogens associated with excess morbidity and mortality. To elucidate their molecular epidemiology and clinical outcomes in Japan, patients with CRGNB were enrolled in the MDR organisms clinical research network (MDRnet) consisting of eight tertiary care facilities. METHODS: Between 2019 and 2022, 246 unique patients with carbapenem-resistant Enterobacterales (CRE), carbapenem-resistant P. aeruginosa (CRPA) and carbapenem-resistant A. baumannii (CRAB) isolates were prospectively enrolled. RESULTS: A total of 246 isolates were collected from 246 patients, including 78 (31.7%) CRE, 167 (67.9%) CRPA and 1 (0.4%) CRAB. For CRE, 74.4% of the isolates carried carbapenemase genes with predominance of bla IMP (64.1%). Only 2.4% of CRPA had carbapenemase genes, which was lower than CRE. Among the infected patients, 20.0% and 12.5% died of CRE and CRPA within 30 days, respectively. In patients with CRE, the mortality rate within 30 days for those without carbapenemase-producing Enterobacterales (CPE) was higher compared with those with CPE (22.2% compared with 18.8%). CONCLUSIONS: Our study highlights the unique molecular epidemiology and clinical outcomes of CRGNB in Japan.

Several Ephedra Herb-containing Kampo medicines are common initial treatments for various infections; however, the ephedrine alkaloids in Ephedra Herb can cause side effects by stimulating adrenergic receptors. Accordingly, an ephedrine alkaloids-free Ephedra Herb Extract (EFE) has been developed. This study aimed to evaluate whether EFE can be used effectively and safely in patients with mild coronavirus disease 2019 (COVID-19). We randomized patients with mild COVID-19 to receive EFE equivalent to 6 g of Ephedra Herb per day or a placebo for 14 days. The primary efficacy endpoint was the non-aggravation rate up to Day 15. We allocated 41 and 40 patients to the EFE and placebo groups, respectively. All participants were included in the mITT and safety analysis populations [male ratio, mean age: 31.7%, 42.0 years (EFE); 17.5%, 43.2 years (placebo)]. The non-aggravation rate up to Day 15 for the primary endpoint was 100.0% and 94.6% in the EFE and placebo group, respectively, with no between-group difference. The number of days to the improvement in nausea symptoms was significantly shorter in the EFE group. One patient in the placebo group discontinued the trial due to a side effect. Although EFE demonstrated safety in patients with mild COVID-19, it did not show superior efficacy compared to placebo for symptoms other than nausea.

BACKGROUND: With progressive accumulation of knowledge on SARS-CoV-2 infection clinical management, treatment guidelines recommended several options including remdesivir (RDV), a broad-spectrum antiviral. Given the evolving nature of COVID-19, capturing the totality of scientific evidence from clinical trials and observational studies is critical to inform clinical decision making. We conducted a systematic literature review (SLR) with meta-analysis (MA) to summarize RDV effectiveness among hospitalized adults. METHODS: We systematically searched MEDLINE, Embase and Cochrane Library databases for interventional and observational studies examining RDV efficacy. A rigorous double-reviewer approach was used for source identification, screening, data extraction and risk of bias assessment. A hierarchical random-effects model MA was used, with subgroup analyses for randomized controlled trials (RCT) and real-world (RW) studies. RESULTS: From January 2019 to December 2023 over 18,000 sources were screened and 122 unique studies were identified, reporting on 25,174 participants in RCTs and 1,279,859 in RW studies. Remdesivir significantly increased survival in the overall population [OR: 0.69 (0.55-0.86); p=0.001] across SARS-CoV-2 variants and disease severity levels: no supplemental oxygen [OR: 0.81 (0.75-0.88)], low-flow oxygen [OR: 0.71 (0.64-0.79)], high-flow oxygen [OR: 0.87 (0.83-0.91)] and invasive mechanical ventilation [OR: 0.78 (0.68-0.90)]. Rehospitalization risk was significantly reduced in patients receiving remdesivir [OR: 0.72 (0.64-0.81)]. CONCLUSION: Our comprehensive SLR, capturing the totality of evidence, showed a significant survival benefit among patients hospitalized for SARS-CoV-2 infection receiving RDV across all disease severity levels. To assure that healthcare providers are aware of and deploy evidence-based optimal care, recommendations should rely on both RCT and RW data.

We explored the role of commensal Neisseria in the emergence of third-generation cephalosporin-resistant N. meningitidis. Cefotaxime resistance-conferring penA795 was prevalent among commensal Neisseria isolates in Shanghai, China, and was acquired by a serogroup C quinolone-resistant sequence type 4821 N. meningitidis, Nm507, causing fulminant meningitis in an unvaccinated 2-year-old child.

BACKGROUND: Carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKp) has been increasingly reported worldwide, posing a severe challenge to public health; however, the mechanisms driving its emergence and global dissemination remain unclear. METHODS: We analysed CR-hvKp strains derived from canonical hvKp backgrounds, and acquired a carbapenemase-encoding gene. These strains were identified from 485 CRKp isolates in the CRACKLE-2 China cohort, 259 CRKp isolates from a multi-centre study, and 67,631 K. pneumoniae genomes available in GenBank. Clinical isolates harbouring the IncFIIK34 KPC-2 plasmid were selected for genome sequencing, RNA-Seq, conjugation assays, in vivo, ex vivo, and in vitro phenotypic characterisation. FINDINGS: Analysis of clinical CR-hvKp isolates and the 414 genomes from 24 countries available in GenBank identified an IncFIIK34 KPC-2 plasmid as the prevalent KPC plasmid (detected in 25%, 45/178 of KPC-producing CR-hvKp). Compared with the epidemic IncFIIK2 KPC-2 plasmid, the IncFIIK34 KPC-2 plasmid exhibited a 100- to 1000-fold increase in conjugation frequency (10-4-10-5 vs. 10-7) and an in vitro growth advantage under meropenem challenge-likely due to the overexpression of conjugation-related genes and an increased blaKPC copy number and expression. CR-hvKp isolates and hvKp transconjugants carrying this plasmid often exhibited reduced mucoviscosity, while retaining hypervirulence in both murine models and human neutrophil assays. INTERPRETATION: The IncFIIK34 plasmid may be a key factor driving the global dissemination of CR-hvKp, underscoring the urgent need for enhanced molecular surveillance of this emerging pathogen. FUNDING: National Natural Science Foundation of China and National Institutes of Health.

BACKGROUND: The incidence of syphilis has been rising globally but effective screening strategies are lacking. Preoperative syphilis screening is commonly performed at Japanese hospitals for infection prevention purposes. However, its effectiveness in improving subsequent management is unclear. METHODS: A retrospective cohort study was conducted to assess the effectiveness of universal preoperative syphilis screening testing implemented at a Japanese tertiary care hospital from April 2017 to March 2023. The annual prevalence of positive preoperative treponemal tests was tracked, and subsequent clinical management for patients with a positive test result was investigated. Attributes of patients with a positive result who were more likely to receive further evaluation were also elucidated. RESULTS: In total, 82,439 patients underwent surgery during the study period. Preoperative treponemal testing was performed in 94.8% (78,170/82,439) of the patients. A positive test result was recorded in 544 (0.70%) with an annual positivity rate ranging from 0.61 to 0.83%, whereas the proportion of presumed active syphilis ranged from 0.02 to 0.08%. A total of 85 patients with a positive syphilis screening test, a nontreponemal test with a positive titer, and without history of syphilis were identified. Of those, only 45 patients (52.9%) received further evaluation. CONCLUSION: The positivity of preoperative treponemal testing was low despite the rising incidence of syphilis in Japan, and the prevalence of presumed active syphilis identified during the preoperative period was even smaller. Routine treponemal testing in the preoperative setting had limited utility in effectively identifying patients with active syphilis.