Background: Gram-negative bacteremia is a major cause of morbidity and mortality in hospitalized patients. Data to guide the duration of antibiotic therapy are limited.

Methods: Randomized, multicenter, open-label, non-inferiority trial. Inpatients with Gram-negative bacteremia, afebrile and hemodynamically stable for at least 48 hours, were randomized to receive 7 (intervention) or 14 days (control) of covering antibiotic therapy. Patients with uncontrolled focus of infection were excluded. The primary outcome at 90 days was a composite of all-cause mortality; relapse, suppurative or distant complications; and re-admission or extended hospitalization (>14 days). The non-inferiority margin was set at 10%.

Results: We included 604 patients (306 intervention, 298 control) between January 2013 and August 2017 in three centers in Israel and Italy. The source of the infection was urinary in 411/604 (68%); causative pathogens were mainly Enterobacteriaceae (543/604, 90%). A 7-day difference in the median duration of covering antibiotics was achieved. The primary outcome occurred in 140/306 (45.8%) patients in the 7 days group versus 144/298 (48.3%) in the 14 days group (risk difference [RD] -2.6%, 95% confidence interval [CI] -10.5% to 5.3%). No significant differences were observed in all other outcomes and adverse events, except for a shorter time to return to baseline functional status in the short therapy arm.

Conclusions: In patients hospitalized with Gram-negative bacteremia achieving clinical stability before day 7, an antibiotic course of 7 days was non-inferior to 14 days. Reducing antibiotic treatment for uncomplicated Gram-negative bacteremia to 7 days is an important antibiotic stewardship intervention. (ClinicalTrials.gov number, NCT01737320).