In a large prospective cohort study across four ICUs (422 patients enrolled from March 2024 to January 2025), 35.8% of patients acquired carbapenem-resistant Gram-negative bacteria (CR-GNB) during their stay.

Using sophisticated interval-censored Cox models and restricted cubic splines, researchers found that the breadth of antibiotic spectrum—measured as the Antibiotic Spectrum Index per antibiotic day (ASI)—was the dominant, independent driver of CR-GNB acquisition (adjusted HR 1.14 per 1-unit increase, 95% CI 1.09–1.19, P<0.001), showing a clear J-shaped dose-response curve. Surprisingly, neither cumulative dose (Defined Daily Doses) nor total duration (Length of Therapy) retained significant independent associations with CR-GNB risk after adjustment for confounders and the other exposure metrics. Relative importance analysis confirmed that ASI per antibiotic day far outweighed both dose and duration as a risk factor (P<0.001 for dominance). These findings challenge the traditional focus of antibiotic stewardship programs on simply shortening therapy or lowering doses, showing instead that choosing narrower-spectrum agents—whenever clinically safe—is the single most powerful lever to reduce the emergence of carbapenem-resistant superbugs in critically ill patients. Prioritizing spectrum optimization over mere de-escalation of days or milligrams emerges as the new cornerstone for CR-GNB prevention in the ICU.

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