Along with the emergence of antibiotic resistance, the steady decline in the discovery of new antibiotics creates one of the greatest current threats to human health. Antibiotic Stewardship Programs (ASPs) have been designed to monitor and improve the appropriateness of antibiotic use, which has been shown to be beneficially associated with patient outcomes, adverse events, resistance rates and costs. Current guidelines provide recommendations on three “building blocks” for successful stewardship stewardship prerequisites, stewardship objectives and improvement strategies.This thesis was divided into three main parts:First, we systematically developed a survey based on these three building blocks for ASPs and evaluated the current state of ASP in acute care hospitals in four European countries: the Netherlands, Slovenia, France and Italy.Second, we performed a cluster-randomized multicenter study to assess the difference in effect on length of hospital stay (LOS) and days of antibiotic therapy (DOT) between three recommended methods to measure and feedback information on hospital antibiotic use, when used as the first step of a stewardship intervention. Subsequently, we conducted a cost-benefit analysis alongside the cluster-randomized multicenter study.Third, we applied a modified-RAND Delphi procedure to systematically develop a set of four actionable quality indicators and one quantity metric for appropriate antibiotic use in adult ICUs, In addition, we developed an implementation toolbox, containing possible barriers that lead to poor performance on the selected indicators, and improvement strategies to overcome these specific barriers, with the aim to support stewardship actions aiming at increasing performance on antibiotic use.With this thesis we contributed to optimizing appropriate antibiotic use in hospitalized patients in order to reduce antibiotic resistance rates.