鈴木 匡弘

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.

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.

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.

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.