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Objective: The aim of this study was to evaluate the safety and efficacy of de-escalation in patients under treatment with carbapenems and its impact on clinical outcomes. Methods: A prospective observational study was conducted for 1 year. Patients administered active carbapenems for at least 24 h were included. Primary outcomes were in-hospital mortality, mortality at 30 days after carbapenem prescription, and infection-related readmission within 30 days. De-escalation was defined as the substitution of carbapenem with narrower spectrum antimicrobial agents or its discontinuation during the first 96 h of treatment. Results: The study included 1161 patients, and de-escalation was performed in 667 (57.5%) of these. In the de-escalation group, 54.9% of cultures were positive. After propensity score matching, 30-day mortality was lower (17.4% vs. 25.7%, p = 0.036), carbapenem treatment was 4 days shorter (4 vs. 8 days, p < 0.001), total antibiotic therapy duration was 2 days longer (12 vs. 10 days, p = 0.003), and length of hospital stay was 5 days shorter (8 vs. 13 days, p = 0.008) in the de-escalated versus non-de-escalated patients. In-hospital mortality and 30-day readmission rates did not differ significantly between these groups. Conclusion: Carbapenem de-escalation is a safe strategy that does not compromise the clinical status of patients. Keywords: Carbapenems, De-escalation, Antimicrobial stewardship programme, Extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae