Seven versus 14 days of antimicrobial therapy for severe multidrug-resistant Gram-negative bacterial infections in intensive care unit patients : a randomised, open-label, non-inferiority clinical trial

Background Shorter courses of antimicrobial therapy have been shown to be non-inferior to longer durations for the management of several infections. However, data on critically ill patients with severe infections by multidrug-resistant Gram-negative bacteria (MDR-GNB) are scarce. In the duratiOn of theraPy in severe infecTIons by MultIdrug-reSistant gram-nEgative bacteria (OPTIMISE) trial, we assessed the non-inferiority of 7-day versus 14-day antimicrobial therapy for patients with intensive care unit (ICU)-acquired severe infections by MDR-GNB. Methods This was a randomised multicenter, open-label, parallel controlled, non-inferiority trial. Adult patients with severe infections by MDR-GNB initiated [greater than or equal to] 48 h of ICU admission were eligible if they were hemodynamically stable and without fever > 48 h on the 7th day of appropriate antimicrobial therapy. Patients were 1:1 randomised to discontinue antimicrobial therapy on the 7th (± 1) day or to continue for a total of 14 (± 1) days. The primary outcome was clinical failure, defined as death or relapse of infection within 28 days of randomisation. An upper edge of the two-tailed 95% confidence interval (CI) of the delta between the clinical failure rate in the 7- and the 14-day lower than 10% in both intention-to-treat (ITT) and per protocol (PP) analyses was set as the non-inferiority criteria. Results A total of 106 patients composed the ITT population: 59 and 47 allocated to 7- and 14-day groups, respectively. The PP population included 75 patients: 47 and 28 in the 7- and 14-day groups, respectively. Clinical failure occurred in 42.4% and 44.7% of the ITT population in 7- and 14-day groups, respectively, (risk difference (RD) - 2.3, 95%CI - 21.3 to 16.7), and in 46.8% and 50.0% of the PP population in 7- and 14-day groups, respectively (RD - 3.2, 95%CI - 26.6 to 20.2). Most infections were of the respiratory tract (73/68.9%) and caused by carbapenem-resistant Enterobacterales (42/39.6%). The study was interrupted before reaching planned sample size due to low recruitment rate. Conclusion The OPTIMISE trial could not determine the non-inferiority of 7-day compared to 14-day therapy for severe infections caused by MDR-GNB due to early termination related to the low recruitment rate. Trial registration: NCT05210387 on January 13, 2022. Keywords: Gram-negative bacteria, Antimicrobial therapy, Antimicrobial resistance, Enterobacterales, Klebsiella pneumoniae, Acinetobacter baumannii, P