Introduction: Early initiation of antimicrobial treatment for acute infection is an important task in the emergency department (ED) with a likely impact on the hospitalwide antibiotic use pattern. We implemented an antibiotic stewardship (ABS) programme focused on nontrauma emergency patients at a large university hospital centre targeting broad-spectrum cephalosporin and fluoroquinolone use. Methods: Guidelines and focused discussion groups emphasised reduced prescription of third-generation cephalosporins and fluoroquinolones and encouraged penicillins. Antibiotic consumption expressed as monthly drug density in WHO-Anatomical Therapeutic Chemical defined and locally recommended daily doses (DDD and RDD) per 100 patient days was analysed before (January 2008 to October 2011) and after starting the intervention (January 2012 to October 2013). We performed a before-and-after uncontrolled interventional study using interrupted time-series (ITS) analysis in one ED to investigate ABS intervention-related effects in a quasiexperimental research setting. Results: The mean monthly total antibiotic use density declined from 111 RDD (138 DDD) per 100 patient days before the intervention to 86 RDD (128 DDD) per 100 patient days after starting the intervention. Among the different antibacterial drug classes, the consumption of third-generation cephalosporins showed the largest reduction and dropped significantly by -68% between preintervention and postintervention periods. Using the RDD dataset, ITS confirmed a highly significant postintervention change in level of third-generation cephalosporins (-15.2, 95% CI (-24.08 to -6.311)) and a corresponding increase in the use of aminopenicillin/betalactamase inhibitor formulations (+6.6, 95% CI (4.169 to 9.069)). The drug use densities for fluoroquinolones and for overall antibiotics declined, however, the postinterventional level changes missed statistical significance - overall (95% CI (-39.99 to 0.466), fluoroquinolones 95% CI (-11.72 to 4.333)). Conclusions: An intensified ABS programme using non-restrictive tools targeting third-generation cephalosporin and fluoroquinolone use in the setting of a large academic hospital emergency medicine department is feasible and effective. The intervention may serve as a model for other emergency medicine departments at hospitals with a similar structure and baseline situation.