Background: Bacteria-producing extended spectrum β-lactamase (ESBL) enzymes are resistant to commonly used antimicrobials. In 2008, routine monitoring revealed a clonal hospital outbreak of ESBL-producing Klebsiella pneumoniae (ESBL-KP). Methods: At a 510-bed Danish university hospital, a multidisciplinary change project inspired by Kotter's Eight Steps of Change was designed. In addition to revision of antimicrobial guidelines and restriction of selected antimicrobials, the complex, managed, multi-faceted intervention comprised training and education, enhanced isolation precautions, and a series of actions to improve the infection control measures and standardise procedures across the hospital. A prospective interrupted time series design was used to analyse data collected at hospital level from January 2008 through December 2011. Results: Though overall antimicrobial consumption remained unaffected, the intervention led to intended, immediate and sustained reduction in the use of cefuroxime, and an increase in the use of ertapenem, piperacillin/tazobactam and β-lactamase sensitive penicillin. Moreover, a postintervention reduction in the rate of ESBL-KP in diagnostic samples and in the incidence of ESBL-KP infections was observed. The intervention may also have reduced the need for isolation precautions and may have shortened each isolation period. Conclusions: The results indicate that an immediate and sustained change in the antimicrobial consumption and a decreasing rate of ESBL-KP are achievable through the application of a managed, multi-faceted intervention that does not require ongoing antibiotic stewardship.