土井 洋平

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.