BACKGROUND:Ensitrelvir (ESV) is approved in Japan for the treatment of mild to moderate COVID-19 in standard-risk patients; however, real-world evidence regarding outcomes among hospitalized high-risk patients remains limited. We evaluated whether oral ESV could serve as a feasible alternative to intravenous remdesivir (RDV). METHODS:We conducted a retrospective multicenter cohort study of hospitalized patients with mild to moderate COVID-19 and at least one risk factor for disease progression treated with ESV or RDV between June 2023 and March 2024 at two hospitals in Japan. Patients unable to receive oral therapy were excluded. Propensity score matching adjusted for baseline differences. The primary outcome was a composite of disease progression or all-cause mortality within 28 days. RESULTS:Among 207 patients, 44 received ESV and 163 received RDV. In the overall cohort, the composite outcome occurred in 4 vs. 10 patients (P = 0.49). After matching, 40 patients were included in each group; all patients in the matched cohort had mild disease without oxygen requirement. In the matched cohort, the composite outcome occurred in 4 patients in each group (P > 0.99). Individual components showed no significant differences (mortality: 4 vs. 3; progression: 2 vs. 2). CONCLUSIONS:In this multicenter cohort of hospitalized high-risk patients with mild to moderate COVID-19 able to receive oral therapy, no significant differences were observed between ESV and RDV in the matched cohort of patients with mild disease. ESV may represent a feasible oral alternative in selected high-risk patients able to receive oral therapy.

Interferon-gamma release assays (IGRAs) are widely used for early diagnosis against TB. However, data on their diagnostic utility and clinical significance in elderly patients with active TB remian limited. We retrospectively analyzed patients over 65 years of age who underwent IGRA testing using either T-SPOT.TB (Oxford Immunotec, UK) or QuantiFERON (QFT) (Qiagen, Germany) between 2015–2024. Active pulmonary TB (ATB) was defined as TB confirmed by isolation from respiratory specimens within 90 days of IGRA testing. Latent TB infection (LTBI) was defined as IGRA-positive individuals without microbiological confirmation of TB. For individuals tested multiple times, only the most recent result was included. Values exceeding the detection threshold were recorded as maximum or minimum values. A total of 12,872 T-SPOT.Tb and 7,580 QFT tests were performed during the study period, of which 3,990 and 2,620 tests, respectively, met inclusion criteria. For T-SPOT.TB, 138 (3.5%) were diagnosed with ATB, with a positive rate of 83.3%. The median quantitative scores were 50 (IQR: 16 - 50) for ESAT-6 and 21 (IQR: 9 - 50) for CFP-10. LTBI was identified in 605 patients (15.7%), with median quantitative scores 16 (IQR: 8 - 41) for ESAT-6 and 11 (IQR: 3 - 32) for CFP-10. For QFT, 87 (3.3%) were diagnosed with ATB, with a positive rate of 67.8%. The median quantitative scores were 1.64 (IQR: 0.62 – 4.0) for TB1 and 2.08 (IQR: 0.65 – 4.86) for TB2. The number of LTBI was 198 (7.8 %) with median quantitative scores of 0.85 (IQR: 0.46 – 2.16) for TB1 and 0.94 (IQR: 0.52 – 2.14) for TB2, respectively. The best cut-off values were 3.1 (sensitivity: 23.0%; specificity: 87.4%), 3.6 (sensitivity: 28.7%; specificity: 85.4%) for TB1 and Tb2, 50 (sensitivity: 78.7%; specificity: 42.0%), 33 (sensitivity: 75.5%; specificity: 42.0%) for ESAT-6 and CFP-10, respectively. Quantitative IGRA values were higher in patients with active TB than in those with latent infection. Notably, T.SPOT-TB might be possible to differentiate ATB and LTBI in elderly populations. These findings support the potential clinical utility of TB-SPOT.TB for TB diagnosis in aging populations in Japan. Yoshikazu Mutoh, graduate student, MSD, Co LTD: Honoraria Yusuke Minato, Ph.D., Shionogi & Co., Ltd.: Grant/Research Support Yohei Doi, MD, PhD, GSK: Advisor/Consultant|Meiji Seika Pharma: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Honoraria

BACKGROUND AND HYPOTHESIS:Despite established cardiorenal benefits, concerns about urinary tract infection (UTI) risk may limit SGLT2 inhibitor use, especially in high-risk patients. We hypothesized that urine leukocyte esterase (LE) and nitrite-findings compatible with pyuria or bacteriuria-predict subsequent UTI risk and modify the association between canagliflozin and UTIs. METHODS:We conducted a post hoc analysis of individual-participant data from two randomized, double-blind, placebo-controlled trials of canagliflozin in type 2 diabetes. The primary outcome was time to first UTI; the secondary outcome was total UTI events, analyzed with Cox and Andersen-Gill models. RESULTS:Among 8 614 participants, abnormal LE and nitrite were observed in 10.7% and 3.5%, respectively. After adjustment, the risk of first UTI increased with greater LE positivity (HRs: 1.72, 1.89, 2.77 for 1+, 2+, 3 + vs normal). Abnormal nitrite was also associated with higher risk (HR: 2.28 [1+], 1.66 [2+]). Similar findings were observed for total UTI events. Overall, canagliflozin did not increase risk of first (HR 1.06; 95% CI, 0.93-1.21) or total UTI events (HR 1.01; 0.86-1.18). LE and nitrite results did not significantly modify the effect of canagliflozin on the primary outcome. For LE, the hazard ratio (HR) for first UTI was 1.17 (95% CI, 1.00-1.38) in the normal group and 0.94 (0.73-1.21) in the abnormal group (Pinteraction = 0.10). For nitrite, the HRs were 1.08 (0.94-1.24) and 0.92 (0.59-1.43), respectively (Pinteraction = 0.45). For the secondary outcome, canagliflozin also did not increase the risk of total UTI events in either the abnormal LE or nitrite group (HR 0.76 [0.58-0.99] and 1.18 [0.79-1.76], respectively). CONCLUSIONS:Although abnormal LE and nitrite were associated with increased UTI risk, canagliflozin did not further increase this risk in these subgroups. These findings do not support routine withholding of SGLT2 inhibitors in patients with dipstick findings suggestive of pyuria or bacteriuria.

ABSTRACT 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.

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.

Abstract The genus Aeromonas comprises Gram‐negative facultative anaerobes widely distributed in aquatic environments and increasingly recognized as opportunistic human pathogens. Of the 36 described species, Aeromonas hydrophila , Aeromonas caviae , Aeromonas veronii , and Aeromonas dhakensis are the most clinically relevant, accounting for the majority of human infections. Advances in molecular taxonomy, including multilocus sequencing and whole‐genome analysis, have refined the complex classification of Aeromonas . Nevertheless, species misidentification remains common in routine clinical laboratories due to the limited accuracy of conventional biochemical methods and the imperfect performance of MALDI‐TOF MS. Epidemiologically, Aeromonas species inhabit fresh and brackish water and soil, and are also detected in food products and animal hosts. Human infection typically arises through environmental exposure or ingestion of contaminated food or water. Clinically, aeromonads cause a wide spectrum of diseases, ranging from skin and soft tissue infections to gastroenteritis, hepatobiliary disease, and bacteremia. Disease severity varies considerably, with necrotizing fasciitis and septicemia associated with high mortality, particularly in elderly or immunocompromised hosts. Aeromonas exhibits intrinsic resistance to multiple antimicrobials, notably β‐lactams and colistin, mediated by chromosomally encoded β‐lactamase genes (e.g., bla CphA , bla AmpC , and bla OXA ) and mcr ‐like genes, whose distribution is species‐specific. In addition, some strains acquire extended‐spectrum β‐lactamases or carbapenemases, further complicating therapy. Because susceptibility patterns vary by species and geography, careful microbiological evaluation and susceptibility testing are essential to guide treatment. This chapter reviews current knowledge on taxonomy, epidemiology, clinical manifestations, diagnostics, and antimicrobial resistance, underscoring the significance of Aeromonas as an emerging human pathogen.

ABSTRACT 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.

Phenotypic identification of hypervirulent Klebsiella pneumoniae in routine laboratories remains challenging. We evaluated tellurite resistance and selected carbohydrate fermentation tests as phenotypic tools for screening hypervirulent strains and improving lineage identification. A total of 193 K. pneumoniae species complex strains with available whole-genome sequencing data were analyzed, including K. pneumoniae (n = 152), K. variicola (n = 29), and K. quasipneumoniae (n = 12). Hypervirulent strains were defined as those carrying ≥4 of 5 virulence-associated genes (iucA, iroB, peg-344, rmpA, and rmpA2). A total of 68 strains (35.2%) were classified as hypervirulent, and 74 (38.3%) carried ter genes. Hypervirulent strains were strongly associated with ter gene carriage, and the tellurite-resistant phenotype on MacConkey agar containing 4 μg/mL potassium tellurite closely matched ter gene carriage. Among tellurite-resistant strains, adonitol non-fermentation was useful for excluding non-hypervirulent K. variicola. Using combined tellurite resistance and adonitol fermentation, the assay identified hypervirulent strains with a sensitivity of 86.8%, specificity of 89.6%, and accuracy of 88.6%, all higher than the string test. All 27 ST23 strains showed dulcitol fermentation and l-sorbose non-fermentation. Adonitol fermentation improved screening performance, whereas dulcitol and l-sorbose fermentation patterns supported presumptive identification of prototypical hypervirulent lineages. These findings support the potential utility of this culture-based approach for phenotypic screening of hypervirulent K. pneumoniae in clinical microbiology laboratories. IMPORTANCE:Hypervirulent Klebsiella pneumoniae is associated with severe invasive infections, but practical methods for early recognition in routine clinical laboratories remain limited. Leveraging the strong association between hypervirulence genotype and ter gene carriage, we developed a simple culture-based screening approach for the early presumptive identification of hypervirulent K. pneumoniae. This approach, based on combined tellurite resistance and adonitol fermentation, shows higher sensitivity and specificity than the string test for identifying hypervirulent strains. Additionally, dulcitol and l-sorbose fermentation patterns support presumptive identification of prototypical hypervirulent lineages, including ST23. These phenotypic assays may expedite the identification of hypervirulent K. pneumoniae and selected hypervirulent lineages in clinical microbiology laboratories.

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.

Abstract Mycobacterium abscessus exhibits intrinsic resistance to many antimicrobial agents, including rifampicin, a frontline anti-tuberculosis drug, severely limiting treatment options. Here, we used transposon insertion sequencing (Tn-Seq) to perform a genomewide screen to identify genes required for intrinsic rifampicin resistance in M. abscessus . We uncovered candidate genes that confer intrinsic resistance to the rifamycin-class antibiotics, rifampicin and rifabutin. The genes we identified included previously reported genes such as arr , helR, and MAB_2807 . By comparing our results with the rifampicin intrinsic resistance gene in Mycobacterium tuberculosis , we found that the mechanisms underlying rifampicin intrinsic resistance were distinct between the two species. The contribution of seven representative candidate genes to rifampicin resistance was confirmed by characterizing targeted gene deletion or transposon insertion mutants. Among these determinants, MAB_2807 was identified as a major efflux-based contributor to rifamycin resistance, and its disruption increased intracellular rifampicin accumulation. In addition to known resistance determinants, Tn-Seq revealed contributions from many genes involved in cell envelope processes to rifamycin resistance. Guided by this genetic signature, we evaluated the combined effects of cell wall-targeting antimicrobial agents with rifamycins. We found that rifamycins displayed selective synergistic interactions with specific β-lactam antibiotics. Interestingly, we found that rifamycin exposure altered cell envelope ultrastructure and increased the accumulation of the peptidoglycan precursor UDP-N-acetylglucosamine, suggesting that rifampicin perturbs envelope-associated metabolic homeostasis. These findings highlight rifamycin-induced vulnerable cellular processes that may inform rational combination strategies. Importance Rifamycins are cornerstone antibiotics for the treatment of mycobacterial infections, yet they are ineffective against Mycobacterium abscessus . Although several key resistance mechanisms have been described, the full genetic basis of intrinsic rifamycin resistance remains to be elucidated. Here, we used transposon insertion sequencing to systematically identify genes that contribute to intrinsic rifamycin resistance in M. abscessus . Because recent studies have shown that chemical modification of rifamycins can overcome specific intrinsic resistance mechanisms, a comprehensive understanding of these determinants could facilitate the development of next-generation rifamycins with improved activity against M. abscessus . In addition, we unexpectedly found that rifamycin exposure alters cell envelope structure, the intracellular levels of a key metabolic intermediate in peptidoglycan biosynthesis, and susceptibility to certain β-lactams in M. abscessus . These findings may help guide the rational development of combination therapeutic strategies with next-generation rifamycins.

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.

Carbapenem-resistant Gram-negative bacilli (CR-GNB) infections are associated with high mortality and increased healthcare costs. While certain resistant pathogens, such as extended-spectrum β-lactamase-producing organisms, are increasingly identified in the community, reports of community-associated CR-GNB infections remain limited, particularly in high-income countries like Japan.Table 1.Demographic characteristics of patients with community-associated, healthcare-associated, and hospital-onset CR-GNB infections.CR-GNB, carbapenem-resistant Gram-negative bacilli; CA, community-associated; HA, healthcare-associated; HO, hospital-onset; IQR, interquartile range; IV, intravenous. a P values for comparisons among the three groups (CA, HA, HO) were calculated using the Kruskal–Wallis test for continuous variables and the chi-squared test for categorical variables. b Pairwise comparisons were performed using the Mann–Whitney U test for continuous variables and Fisher’s exact test for categorical variables. For multiple comparisons, a Bonferroni-corrected threshold of P <0.025 was considered statistically significant. Asterisks indicate statistical significance at the corrected threshold.Table 2.Causative pathogens and sites of infection among patients with community-associated, healthcare-associated, and hospital-onset CR-GNB infections.CR-GNB, carbapenem-resistant Gram-negative bacilli; CA, community-associated; HA, healthcare-associated; HO, hospital-onset. a P values for comparisons among the three groups (CA, HA, HO) were calculated using the Kruskal–Wallis test for continuous variables and the chi-squared test for categorical variables. b Pairwise comparisons were performed using the Mann–Whitney U test for continuous variables and Fisher’s exact test for categorical variables. For multiple comparisons, a Bonferroni-corrected threshold of P <0.025 was considered statistically significant. Asterisks indicate statistical significance at the corrected threshold. From April 2019 to March 2022, we prospectively enrolled patients with CR-GNB infections through the Multidrug-Resistant Organisms Clinical Research Network (MDR-net), comprising 13 tertiary care centers in Japan. We compared patient demographics, clinical characteristics, and outcomes across community-associated (CA), healthcare-associated (HA), and hospital-onset (HO) infections.Table 3.Clinical outcome of patients with community-associated, healthcare-associated, and hospital-onset CR-GNB infections.CR-GNB, carbapenem-resistant Gram-negative bacilli; CA, community-associated; HA, healthcare-associated; HO, hospital-onset. a P values for comparisons among the three groups (CA, HA, HO) were calculated using the Kruskal–Wallis test for continuous variables and the chi-squared test for categorical variables. b Pairwise comparisons were performed using the Mann–Whitney U test for continuous variables and Fisher’s exact test for categorical variables. For multiple comparisons, a Bonferroni-corrected threshold of P <0.025 was considered statistically significant. Asterisks indicate statistical significance at the corrected threshold. 95% confidence intervals for death-related outcomes by onset: Death discharge – CA: 11.6% (95% CI: 1.9–21.4), HA: 17.0% (7.3–26.6), HO: 35.8% (30.6–41.0); 30-day mortality – CA: 9.3% (0.5–18.1), HA: 10.2% (2.4–17.9), HO: 23.8% (19.1–28.4).Figure 1.Kaplan–Meier survival curves showing patient days from the first positive culture to death for patients with community-associated, healthcare-associated, and hospital-onset CR-GNB infections.CR-GNB, carbapenem-resistant Gram-negative bacilli Among 426 patients with CR-GNB infections (CA, n=43; HA, n=59; HO, n=324), most were elderly, with comparable Charlson Comorbidity Index scores across groups (median [IQR], 2 [1–4]; P = 0.17). Pseudomonas aeruginosa was the most frequently isolated pathogen in all groups. Aeromonas species were significantly more prevalent in CA and HA compared to HO (CA: 23.3%, HA: 18.6%, HO: 2.2%; P < 0.001 overall), whereas Stenotrophomonas maltophilia was predominantly isolated in HO (HO: 17.3%, HA: 5.1%, CA: 0%; P = 0.001 overall). Clinical outcomes differed significantly by infection type. Compared to CA, HO infections were associated with longer hospital stay (68 vs. 17 days, P < 0.001), lower discharge to home (33.6% vs. 86.1%, P < 0.001), and higher in-hospital mortality (35.8% vs. 11.6%, P = 0.001). Thirty-day mortality also differed, with Kaplan–Meier analysis showing the lowest survival in HO (log-rank P = 0.013). In contrast, HA outcomes were comparable to CA, with no significant differences in length of stay (23 vs. 17 days, P = 0.25), discharge to home (69.5% vs. 86.1%, P = 0.061), or in-hospital mortality (17.0% vs. 11.6%, P = 0.58). These findings suggest that poor outcomes in CR-GNB infections were mainly driven by HO cases. The clinical features and outcomes of CR-GNB infections differ markedly by onset, with HO infections associated with poorer outcomes compared to CA and HA infections. Yasufumi Matsumara, MD, PhD, Beckman Coulter: Research support for a collaborative project|Precision System Science: Research support for a collaborative project Takashi Matono, MD, PhD, FACP, Gilead Sciences: Honoraria|GSK: Honoraria|Meiji Seika Pharma: Honoraria|MSD: Honoraria|Pfizer: Honoraria Naoya Itoh, MD, DTM&H, PhD, Asahi Kasei Pharma Corporation: Honoraria|AstraZeneca K.K: Honoraria|BD Co, Ltd: Honoraria|bioMérieux Japan Ltd: Honoraria|Gilead Sciences Inc: Honoraria|GlaxoSmithKline: Honoraria|Meiji Seika Pharma Co, Ltd: Honoraria|MSD K.K: Honoraria|Pfizer;: Honoraria|shimadzu co ltd: Grant/Research Support|Shionogi Co, Ltd: Honoraria Tetsuya Suzuki, M.D., Ph.D., Meiji Seika Pharma: Honoraria David van Duin, MD, PhD, British Society for Antimicrobial Chemotherapy: Editor stipend|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Roche: Advisor/Consultant|Shionogi: Advisor/Consultant Yohei Doi, MD, PhD, GSK: Advisor/Consultant|Meiji Seika Pharma: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Honoraria Sho Saito, Dr, Shionogi & Co., Ltd.: Grant/Research Support|SUNSTAR: Grant/Research Support

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.

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.

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: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.

Antimicrobial resistance (AMR) continues to pose a significant challenge in modern medicine. Klebsiella pneumoniae (KP) is a major cause of nosocomial infections and is frequently resistant to multiple antibiotics. Current methods in the detection of KP include the use of automated systems like Vitek 2, which rely on general biochemical characteristics of the KP complex, making it difficult to differentiate KP from closely related species like K. variicola and K. quasipneumoniae. These organisms are genetically distinct from KP and may differ in virulence characteristics and clinical features. In this study, we investigated if AMR and virulence genes found in KP are also present in Klebsiella spp. isolates misidentified as KP. We analyzed presumptive KP isolates from blood cultures collected from patients at the Philippine General Hospital between October 2023 and August 2024. Species identification was confirmed using polymerase chain reaction (PCR) and whole genome sequencing (WGS). The species, sequence type (ST), AMR, and virulence genes were identified using the Kleborate software Among 60 unique blood isolates initially identified as KP, seven (12%) were reclassified as non-KP Klebsiella spp. These included K. quasipneumoniae (5 isolates), K. variicola (1 isolate), and K. africana (1 isolate). Notably, β-lactamase genes blaNDM-7 and blaCTX-M-123 were identified in two K. quasipneumoniae isolates.None of the isolates exhibited hypermucoid phenotypes or carried hypervirulence-associated genes (iuc, iro, rmp, rmpA2). Despite the absence of these virulence genes, all-cause in-hospital mortality was seen in 4 of 7 patients (57%). While hypervirulence-associated genes were absent in non-KP Klebsiella spp., infections caused by these organisms were associated with a high mortality rate. Accurate species identification of the KP complex is essential for understanding epidemiology and guiding appropriate treatment. Sohei Harada, MD, PhD, Denka: Honoraria|Eiken Chemical Co., Ltd.: Honoraria|MSD: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Honoraria|Ushio, Inc.: Honoraria Yohei Doi, MD, PhD, GSK: Advisor/Consultant|Meiji Seika Pharma: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Honoraria

Carbapenem-resistant Raoultella planticola (CRRP) is an emerging nosocomial pathogen with limited therapeutic options. Here, we describe the comparative characterization of two novel virulent bacteriophages, Macy and Sally, both isolated from the same soil microenvironment. Macy exhibits exceptional lytic potency, with a burst size of 8,375 PFU per infected cell, narrow host specificity, and pronounced biofilm-disrupting activity likely mediated by a putative depolymerase. In contrast, Sally displays a broader host range, infecting both R. planticola and R. ornithinolytica (including a clinical CRRP isolate), while maintaining moderate lytic activity, notable acid tolerance, and substantial biofilm reduction. SNP analysis revealed that resistant isolates carried mutations in genes linked to surface polysaccharide biosynthesis and LysR-family transcriptional regulation, conferring resistance at a measurable cost to bacterial growth fitness. Genomic and phylogenomic analyses further revealed distinct evolutionary trajectories: Macy is a large (147.8 kb) member of Straboviridae Straboviridae with a mosaic genome related to Raoultella phages, whereas Sally is a compact (48.5 kb) Casjensviridae phage that is siphovirus more closely aligned with Klebsiella and Enterobacter phages. Pangenomic comparisons highlighted Macy’s strain-specific gene expansions versus Sally’s cross-genus homology, emphasizing divergent adaptation strategies. Together, these findings illustrate the complementary therapeutic potential of Macy and Sally and establish a genomic and phenotypic foundation for developing effective phage cocktails against multidrug-resistant Raoultella infections.

Treatment options for Carbapenem-resistant (CR) Gram-negative infections due to metallo-beta-lactamase (MBL) enzymes are limited. The clinical impact of MBLs vs. other mechanisms of carbapenem resistance in Enterobacterales and non-fermenting bacteria remains unclear.Table 1.Demographics, isolate characteristics, and outcomes of patients with carbapenem-resistant Gram-negative infections, stratified by MBL statusFigure 1.30-day desirability of outcome ranking (DOOR) outcomes of patients with carbapenem-resistant Gram-negative infections, stratified by MBL statusCRPA – carbapenem-resistant Pseudomonas aeruginosa, CRAb – carbapenem-resistant Acinetobacter baumannii, CRE – carbapenem-resistant Enterobacterales, DOOR – desirability of outcome ranking. MBL – metallo-beta-lactamase. DOOR events assessed at 30 days include: unsuccessful discharge, lack of clinical response, and C. difficile infection and/or renal failure. Not all rows total to 100 due to rounding. P-value calculated using Wilcoxon test. We conducted a matched cohort study of patients enrolled in one of three MDRO Network studies, POP (CR Pseudomonas aeruginosa [CRPA]), SNAP (CR Acinetobacter baumannii [CRAb]), or CRACKLE-2 (CR-Enterobacterales [CRE]) with isolates that met infection criteria. Patients with MBL-producing isolates (blaVIM, blaIMP, or blaNDM present) were matched 1:2 to patients with non-MBL CR isolates (a different carbapenemase or CR without a carbapenemase) based on study, region, and anatomical source. We compared baseline characteristics, 30- and 90-day mortality, and 30-day desirability of outcome ranking (DOOR) scores.30-day Desirability of Outcome Ranking (DOOR) Probability by MBL StatusLegend: CI – confidence interval, CRPA – carbapenem-resistant Pseudomonas aeruginosa, CRAb – carbapenem-resistant Acinetobacter baumannii, CRE – carbapenem-resistant Enterobacterales, DOOR – desirability of outcome ranking. MBL – metallo-beta-lactamase. The DOOR probability was calculated as the probability of a more desirable result in the presence of MBL as compared to non-MBL isolate. Confidence intervals were calculated using the method in Halperin et al (Biometric 1989; 45:500-521), and CI’s that do not include 50% are considered statistically significant. Estimates less than 50% signify a less favorable outcome for the MBL group, while estimates greater than 50% signify more favorable outcomes for the MBL group. In total, 170 MBL isolates were matched to 340 non-MBL isolates from 10 countries (Table 1). The cohort included 42% CRPA (216/510), 5% CRAb (24/510), and 53% CRE (270/510). Demographics were balanced between groups; median age at culture was 61 (Q1, 44, Q3 73) years. Common infection sources were respiratory (151/510, 30%), urine (141/510, 28%), and blood (105/510, 21%). Of the MBL isolates, 92/170 harbored blaNDM (54%), 62/170 harbored blaVIM (36%), and 20/170 harbored blaIMP (12%); four isolates co-harbored two distinct MBL enzymes. All-cause 30-day mortality was 19% (33/170) for MBL vs 18% (61/340) for non-MBL (p=0.69); MBL presence was not associated with 30- or 90-day mortality. DOOR outcomes at 30-days (Figure 1) did not differ by MBL status in the full cohort or the CRE subgroup, but did differ in the CRPA/CRAb subgroup (p=0.037). Among CRPA/CRAb infections, MBL presence was associated with less desirable outcomes (DOOR probability 42.1%; 95% Halperin confidence interval: 35.0%-49.5%, Figure 2). MBL presence was not associated with increased 30- or 90-day mortality compared to matched non-MBL isolates. However, in non-fermenter infections (CRPA/CRAb), MBL presence was linked to less desirable outcomes, an association not seen in CRE. These findings may inform prioritization of anti-MBL agents in future drug development. Angelique E. Boutzoukas, MD, MPH, Elion Therapeutics: Advisor/Consultant|Innoviva Speciality Therapeutics: DSMB Participant Souha S. Kanj, MD, Menarini: Honoraria|pfizer: Honoraria Vance G. Fowler, MD, MHS, Affinergy, Janssen, Contrafect: Advisor/Consultant|AstraZeneca; EDE; Basilea: Grant/Research Support|Debiopharm, GSK; Affinium, Basilea,: Advisor/Consultant|Destiny, Amphliphi, Armata, Akagera: Advisor/Consultant|Merck; Contrafect; Karius; Janssen: Grant/Research Support|UpToDate: Royalties|Valanbio: Stock options Yohei Doi, MD, PHD, GSK: Advisor/Consultant|Meiji Seika Pharma: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Honoraria Michael Satlin, MD, MS, AbbVie: DSMB Participant|bioMerieux: Grant/Research Support|Merck: Grant/Research Support|SNIPRBiome: Grant/Research Support Robert A. Bonomo, MD, Merck: Grant/Research Support|Shinogi: Grant/Research Support|VenatoRx: Grant/Research Support David van Duin, MD, PhD, British Society for Antimicrobial Chemotherapy: Editor stipend|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Roche: Advisor/Consultant|Shionogi: Advisor/Consultant