Difficult-to-treat resistance (DTR), treatment, and outcomes of carbapenem-resistant Enterobacterales infections in the setting of IMP-type carbapenemase predominance in Japan

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%). bla_IMP-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.