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This article belongs to the Section Antibiotics Use and Antimicrobial Stewardship., Carbapenem-resistant Gram-negative bacilli (CR-GNB) are a critical public health threat, and carbapenem use contributes to their spread. Antimicrobial stewardship programs (ASPs) have proven successful in reducing antimicrobial use. However, evidence on the impact of carbapenem resistance remains unclear. We evaluated the impact of a multifaceted ASP on carbapenem use and incidence of CR-GNB in a high-endemic hospital. An interrupted time-series analysis was conducted one year before and two years after starting the ASP to assess carbapenem consumption, CR-GNB incidence, death rates of sentinel events, and other variables potentially related to CR-GNB incidence. An intense reduction in carbapenem consumption occurred after starting the intervention and was sustained two years later (relative effect −83.51%; 95% CI −87.23 to −79.79). The incidence density of CR-GNB decreased by −0.915 cases per 1000 occupied bed days (95% CI −1.743 to −0.087). This effect was especially marked in CR-Klebsiella pneumoniae and CR-Escherichia coli, reversing the pre-intervention upward trend and leading to a relative reduction of −91.15% (95% CI −105.53 to −76.76) and −89.93% (95% CI −107.03 to −72.83), respectively, two years after starting the program. Death rates did not change. This ASP contributed to decreasing CR-GNB incidence through a sustained reduction in antibiotic use without increasing mortality rates., This research was funded by the Plan Nacional de I + D+i 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0008; RD16/0016/0009) co-financed by European Development Regional Fund ‘A way to achieve Europe’ and Operative program intelligent Growth 2014–2020, which did not participate in the development of the program or the analysis of its results.

Background: Evidence on the impact of antimicrobial stewardship programmes (ASPs) on carbapenem resistance is needed. We aimed to study the efficacy and safety of a bundle of educational and restrictive measures to optimise carbapenem use and its impact on carbapenem-resistant Gram-negative bacilli (CR-GNB) in a hospital with a carbapenem-resistant KPC-3 producing Klebsiella pneumoniae endemic. Methods: A quasi-experimental study with an interrupted time-series analysis was designed and conducted in a tertiary-care hospital before and after the implementation of an ASP aimed at hospitalised adult patients with Gram-negative infections treated with carbapenems (meropenem or imipenem). The core activity of the ASP consisted of a prescription validation interview held between the prescribers and an infectious disease specialist from the ASP team to reinforce the appropriate antibiotic indication. A standardised prescription form for carbapenem was also developed. We assessed carbapenem consumption, incidence of CR-GNB, crude death rate of sentinel events per 1000 occupied bed days (OBDs), hand-hygiene compliance, and complexity of the hospital activity. Findings: The study was conducted from January 2013 to February 2016. The intervention started in February 2014. Throughout the intervention period, 1359 educational interviews were conducted between the prescribers and the consultants. An intense reduction in carbapenem consumption occurred after starting the intervention, and was sustained two years later (relative effect -83·51%; 95% CI -87·23 to -79·79). The incidence density of CR-GNB decreased by -0·915 cases per 1000 OBDs (95% CI -1·743 to -0·087). This effect was especially marked in CR K. pneumoniae and CR Escherichia coli, reversing the pre-intervention upward trend and leading to a relative reduction of -91·15% (95% CI -105·53 to -76·76) and -89·93% (95% CI -107·03 to -72·83), respectively, two years after starting the programme. Mortality of sentinel events and hand-hygiene compliance trends did not change. Interpretation: This ASP to optimise carbapenem use based on prescription validation interviews can contribute to decreasing the incidence of CR-GNB, in particular Enterobacteriaceae, without increasing death rates. Funding: Spanish Network for Research in Infectious Diseases, Instituto de Salud Carlos III, European Regional Development Fund, and Sub-Directorate General for Research Assessment and Promotion, Spain. Declaration of Interests: LMM has been a consultant for MSD and Shionogi, has served as speaker for MSD, Astra- Zeneca, Astellas, Becton Dickinson and bioMerieux, and has received research support from Shionogi, Janssen-Cilag and Pfizer. AC has received honoraria for the development of educational presentations for Pfizer JMC has received travel grants and honoraria as a speaker from Novartis, Astellas Pharma, Pfizer, MSD, Janssen Pharmaceuticals, and AstraZeneca, outside the submitted work. GP and JMC report grants from Instituto de Salud Carlos III, Spanish Government, co-financed by the European Development Regional Fund “A way to achieve Europe”, during the conduct of the study. All other authors declare no competing interests. Ethics Approval Statement: The study was approved by the HURS Ethics Committee (approval number 4731), which renounced obtaining written informed consent as all collected data were anonymised.