Long-Term Impact of an Educational Antimicrobial Stewardship Program on Hospital-Acquired Candidemia and Multidrug-Resistant Bloodstream Infections: A Quasi-Experimental Study of Interrupted Time-Series Analysis

Depósito de investigación de la Universidad de Sevilla https://idus.us.es/ Esta es la versión aceptada del artículo publicado en: This is a accepted manuscript of a paper published in: Clinical Infectious Diseases (2017): 15 December DOI: 10.1093/cid/cix692 Copyright: © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, email: [email protected]. DOI: 10.1093/cid/cix692 El acceso a la versión publicada del artículo puede requerir la suscripción de la revista. Access to the published version may require subscription. “This is a pre-copyedited, author-produced version of an article accepted for publication in Clinical Infectious Diseases following peer review. The version of record Molina J, Peñalva G, Gil-Navarro MV, Praena J, Lepe JA, Pérez-Moreno MA, Ferrándiz C, Aldabó T, Aguilar M, Olbrich P, Jiménez-Mejías ME, Gascón ML, Amaya- Villar R, Neth O, Rodríguez-Hernández MJ, Gutiérrez-Pizarraya A, Garnacho-Montero J, Montero C, Cano J, Palomino J, Valencia R, Álvarez R, Cordero E, Herrero M, Cisneros JM; PRIOAM team. Long-Term Impact of an Educational Antimicrobial Stewardship Program on Hospital-Acquired Candidemia and Multidrug-Resistant Bloodstream Infections: A Quasi-Experimental Study of Interrupted Time-Series Analysis. Clin Infect Dis. 2017 Nov 29;65(12):1992-1999. doi: 10.1093/cid/cix692. PMID: 29020166. is available online at: https://academic.oup.com/cid/article/65/12/1992/4069913 doi.org/10.1093/cid/cix692. Clinical Infectious Diseases Long-term impact of an educational antimicrobial stewardship program on hospitalacquired candidemia and multidrug-resistant bloodstream infections: a quasiexperimental study of interrupted time-series analysis --Manuscript Draft-- Manuscript Number: Full Title: Long-term impact of an educational antimicrobial stewardship program on hospitalacquired candidemia and multidrug-resistant bloodstream infections: a quasiexperimental study of interrupted time-series analysis Short Title: Long-term impact of an educational ASP Article Type: Major Article Corresponding Author: José M. Cisneros, Ph.D University Hospital Virgen del Rocío Sevilla, SPAIN Corresponding Author Secondary Information: Corresponding Author's Institution: University Hospital Virgen del Rocío Corresponding Author's Secondary Institution: First Author: José Molina, MD First Author Secondary Information: Order of Authors: José Molina, MD Germán Peñalva, MSEd María Victoria Gil-Navarro, PhD Julia Praena, MD José Antonio Lepe, PhD María Antonia Pérez-Moreno, PhD Carmen Ferrándiz, PhD Teresa Aldabó, PhD Manuela Aguilar, PhD Peter Olbrich, PhD Manuel Enrique Jiménez-Mejías, PhD María Luisa Gascón, MD Rosario Amaya-Villar, PhD Olaf Neth, PhD María Jesús Rodríguez-Hernández, PhD Antonio Gutiérrez-Pizarraya, PhD José Garnacho-Montero, PhD Cristina Montero, PhD Josefina Cano, PhD Julián Palomino, PhD Raquel Valencia, PhD Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation Rocío Álvarez, PhD Marta Herrero, PhD Elisa Cordero, PhD José M. Cisneros, PhD Order of Authors Secondary Information: Manuscript Region of Origin: SPAIN Abstract: Background. The global crisis of bacterial resistance urges the scientific community to implement intervention programs in healthcare facilities to promote an appropriate use of antibiotics. However, the clinical benefits or the impact on resistance of these interventions has not been definitely proved. Methods. We designed a quasi-experimental intervention study with an interrupted time-series analysis. A multidisciplinary team conducted a multifaceted educational intervention in our tertiary-care hospital throughout a five-year period. The main activity of the program consisted of peer-to-peer educational interviews between counselors and prescribers from all departments to reinforce the principles of the proper use of antibiotics. We assessed antibiotic consumption, incidence density of Candida and multidrug-resistant bacteria bloodstream infections (MDR-BSI) and their crude mortality per 1000 occupied bed days (OBD). Results. A quick and intense reduction in antibiotic consumption occurred 6 months after the implementation of the intervention (change in level -216.8 DDD per 1000 OBD, 95% CI -347.5 to -86.1), and was sustained during the subsequent years (average reduction - 19,9%). Additionally, the increasing trend observed in the pre-intervention period for the incidence density of candidemia and MDR-BSI (+0.018 cases per 1000 OBD per quarter, 95% CI -0.003 to 0.039) reverted towards a decreasing trend of -0.130 per quarter (change in slope of -0.029,95% CI -0.051 to -0.008), and so did their mortality (change in slope -0.015, 95% CI -0.021 to -0.008). Conclusions. This education-based ASP was effective in decreasing the incidence and mortality of hospital acquired candidemia and MDR-BSI through a sustained reduction in antibiotic use. Suggested Reviewers: José María López-Lozano, PhD Hospital Comarcal Vega Baja, Orihuela, Alicantes, Spain [email protected] Epidemiologist specialist. Expert in methodology and time series analysis for ASP. Jerome A Leis [email protected] Author of articles on antimicrobial stewardship. Celine Pulcini, PhD [email protected] Coordinator of antimicrobial stewardship programs in France. More than 140 articles published. Secretary of the ESGAP, the group of the ESMID for antimicrobial policies. Mical Paul, PhD Division of Infectious Diseases, Rambam Health Care Campus, Ha-aliya 8 St, Haifa, Israel, 33705 [email protected] Expert in infectious diseases and specially in antibiotics. Opposed Reviewers: Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation June 9, 2017 Dr. Robert T. Schooley Editor in chief Clinical Infectious Diseases 198 Madison Ave. New York, NY 10016 Dear Dr. Schooley, We are submitting for your consideration the manuscript entitled " Long-term impact of an educational antimicrobial stewardship program on hospital acquired candidemia and multidrug-resistant bloodstream infections: quasi-experimental design of interrupted timeseries analysis”. In this work, we show the successful results achieved by an innovative educational-based antimicrobial stewardship program (ASP) developed over a 5-year period in a tertiary hospital. The project has been able to reduce the global antibiotic pressure at the center as well as the incidence and mortality of severe nosocomial infections produced by multidrug-resistant microorganisms, reversing the previous increasing trend recorded in the pre-project period. Whilst educational interventions have been considered dispensable by many authors, our results point out that well-designed pedagogical programs engaging all departments of a large hospital may be as successful as other projects, sustainable over the time, and better accepted by prescribers than traditional restrictive measures. There is a previous publication from the same study (Global impact of an educational antimicrobial stewardship programme on prescribing practice in a tertiary hospital centre. Cisneros, J.M. et al. Clinical Microbiology and Infection, Volume 20, Issue 1, 82 – 88. DOI: http://dx.doi.org/10.1111/1469-0691.12191), in which we presented the short-term outcomes in the first year of the ASP. We think that the manuscript we are submitting for your consideration could be a demonstration of the potential effect of individualized audit and feedback on antimicrobial prescribing practices in the inpatient setting, particularly with regard to having a sustained effect over many years, which has not been demonstrated with stewardship interventions. Cover Letter Click here to download Cover Letter Cover letter CID LONG TERM ASP J Molina et al SIGNED.pdf Thus, we hope you may find our work useful in the contribution to recent evidence produced in the last years on ASPs, much of which we were glad to find published in your journal. I warrant that all authors have seen and approved the manuscript, contributed significantly to the work, and also that the manuscript has not been previously published nor is not being considered for publication elsewhere. With regard to the article figures, we would like to have them published in black and white. The antibiotic crisis has put into the spotlight that the fight against bacterial resistance is no longer the responsibility of a sole specialty, but of every physician prescribing antibiotics. A multidisciplinary approach to the problem and its solutions are critical. This is why it seems essential to spread knowledge on ASP in a transversal way through the scientific community, and to find efficient communication channels to reach everyone. In our opinion your journal has been committed to this need over recent years with several significant publications in this regard. We would be grateful if our work could be considered as a useful addition to this growing body of evidence. Sincerely, Dr. Jose Miguel Cisneros, PhD. Corresponding author Department of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocio, CSIC, University of Seville Av. Manuel Siurot s/n, 41013, Seville, Spain. Phone: +34-955-01-21-85. E-Mail: [email protected] Alternate author: Dr. Jose Molina. E-Mail: [email protected] 1 Title page Title Long-term impact of an educational antimicrobial stewardship program on hospitalacquired candidemia and multidrug-resistant bloodstream infections: a quasiexperimental study of interrupted time-series analysis. Authors José Molina1, Germán Peñalva1, María V Gil-Navarro2, Julia Praena1, José A Lepe1, María A Pérez-Moreno2, Carmen Ferrándiz3, Teresa Aldabó3, Manuela Aguilar1, Peter Olbrich4, Manuel E Jiménez-Mejías1, María L Gascón3, Rosario Amaya-Villar3, Olaf Neth4, María J Rodríguez-Hernández1, Antonio Gutiérrez-Pizarraya1, José Garnacho- Montero5, Cristina Montero6, Josefina Cano6, Julián Palomino1, Raquel Valencia1, Rocío Álvarez1, Elisa Cordero1, Marta Herrero1, José M Cisneros1, and the PRIOAM team. Authors Affiliations 1Department of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocio, CSIC, University of Seville, Seville, Spain. 2Department of Pharmacy, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocio, CSIC, University of Seville, Seville, Spain. 3Department of Critical Care, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocio, CSIC, University of Seville, Seville, Spain. 4Department of Pediatric Infectious Diseases and Immunodeficiency, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocio, CSIC, University of Seville, Seville, Spain. 5Department of Critical Care, University Hospital Virgen Macarena, University of Seville, Seville, Spain. 6Department of Critical Care and Emergency, Department of Pediatrics, University Hospital Virgen del Rocio, Seville, Spain. Corresponding author: José Miguel Cisneros, Department of Infectious Diseases, Microbiology and Preventive Medicine, University Hospital Virgen del Rocio, Av. Manuel Siurot s/n, 41013, Seville, Spain. (+34-955-01-21-85; [email protected]) Summary/Key points: This stewardship program based on a bundle of noncompulsory measures including structured educational interviews as main innovation has effectively reduced the incidence of multi-resistant bacteria and their mortality through a sustained reduction in antibiotic pressure throughout a 5-year period. Running title: Long-term impact of an educational ASP Full Manuscript in .doc format only [no PDFs] Click here to download Full Manuscript in .doc format only [no PDFs] CID manuscript J Molina et al LONG TERM ASP 2 ABSTRACT Background. The global crisis of bacterial resistance urges the scientific community to implement intervention programs in healthcare facilities to promote an appropriate use of antibiotics. However, the clinical benefits or the impact on resistance of these interventions has not been definitely proved. Methods. We designed a quasi-experimental intervention study with an interrupted time-series analysis. A multidisciplinary team conducted a multifaceted educational intervention in our tertiary-care hospital throughout a five-year period. The main activity of the program consisted of peer-to-peer educational interviews between counselors and prescribers from all departments to reinforce the principles of the proper use of antibiotics. We assessed antibiotic consumption, incidence density of Candida and multidrug-resistant bacteria bloodstream infections (MDR-BSI) and their crude mortality per 1000 occupied bed days (OBD). Results. A quick and intense reduction in antibiotic consumption occurred 6 months after the implementation of the intervention (change in level -216.8 DDD per 1000 OBD, 95% CI -347.5 to -86.1), and was sustained during the subsequent years (average reduction -19,9%). Additionally, the increasing trend observed in the pre-intervention period for the incidence density of candidemia and MDR-BSI (+0.018 cases per 1000 OBD per quarter, 95% CI -0.003 to 0.039) reverted towards a decreasing trend of -0.130 per quarter (change in slope of -0.029,95% CI -0.051 to -0.008), and so did their mortality (change in slope -0.015, 95% CI -0.021 to -0.008). Conclusions. This education-based ASP was effective in decreasing the incidence and mortality of hospital acquired candidemia and MDR-BSI through a sustained reduction in antibiotic use. Keywords. Antimicrobial stewardship programs, antimicrobial resistance, educational interviews, hospital acquired infections, candidemia, multi-drug resistant bloodstream infections 3 BACKGROUND The global increase of bacterial resistance over the last decades has been recognized by Public Health organizations as a priority threat that needs to be addressed urgently by the scientific community [1]. Infections caused by resistant bacteria produce increased morbidity and mortality, as well as higher healthcare costs [2], and the inappropriate use of antimicrobial agents is probably the most important factor responsible for this [3]. In this setting, healthcare centers have been encouraged to implement antimicrobial stewardship programs (ASP) in order to improve antibiotic misuse and fight back against bacterial resistance [4]. Evidence supporting the efficacy of ASPs is still incomplete, and recent metaanalysis showed that up to 80% of reviewed studies lacked a minimum methodological quality required to obtain reliable and reproducible conclusions on the clinical impact of ASPs [5]. While many of these programs have proven to be effective in reducing antibiotic consumption and improving the quality of prescriptions, there is still a lack of evidence supporting clear clinical benefits (i.e., reduction in mortality related to infections) [5,6]. The question about which indicators are best to assess the clinical impact of ASPs also remains unanswered [7]. Data on the real impact of these programs on bacterial resistance are also incomplete. Despite antibiotic pressure being a well-known risk factor for developing Candida spp. and multi-drug resistant bacteria bloodstream infections (MDR-BSI) [8-10], the reverse effect i.e., that reducing the consumption of antibiotics can bring susceptible microorganisms back to a center or geographic area, has not been so well established. Hitherto, different ASPs have achieved reductions in specific mechanisms of resistance by restricting concrete antibiotic classes [11-13], but a global improvement in bacterial ecology of healthcare centers has rarely been reported and only the short-term impact has been described in most studies [5,6]. The Institutional Program for thre Optimization of Antimicrobial treatment (PRIOAM) is an educational ASP started at our hospital in January 2011 that resulted in a reduction in antimicrobial consumption within one year of its implementation [14]. We hypothesized that, if this reduction in antibiotic pressure was maintained throughout time, a significant decrease should also be observed on the incidence of hospital acquired BSI produced by MDR bacteria and Candida spp. as well as their mortality. 4 METHODS Study design. An interrupted time series (ITS) quasi-experimental before-after study, based on an ecological time-trend analysis, compliant with the ORION statement. Setting. The program was performed at the University Hospital Virgen del Rocio (Seville, Spain), a tertiary-care teaching hospital with 1177 beds -including 72 intensive care unit (ICU) beds-, and active solid-organ and hematopoietic stem-cell transplantation programs. No data from pediatric patients (134 beds, settled in a different building) were recorded for this study. Study period. 28 quarters between January 2009 and December 2015. The PRIOAM was initiated in January 2011. Intervention. The methodology has been described previously [14]. In brief, a multidisciplinary team of 10 counselors including infectious diseases experts from different departments of the hospital was set-up. They randomly chose one antibiotic prescription each week and held educational interviews with the prescriber, reviewing the key aspects of antibiotic treatment of the case. The interview followed a structured questionnaire (Supplementary file 1), and the approach was strictly educational as clinical charts were not reviewed, and no changes in antibiotic treatments were required. Patient data remained anonymous. Additional educative measures included: a) update, publication and diffusion of local guidelines for the management of most frequent infectious syndromes [15], which were also used as reference to assess the quality of prescriptions during the educational interviews; b) monthly educational meetings with the counselors team to reinforce the homogeneity of criteria, and to encourage continuous learning regarding the main aspects of antibiotic use; c) quarterly information regarding the profile of antibiotic use in every department, d) yearly information on the incidence of bacterial resistance reported to all departments. The program received institutional support and their objectives were included in the agreement signed annually by each department with the hospital management. In November 2012, a parallel transmission control program started at the ICU due to a long-term endemic of carbapenem-resistant Acinetobacter baumannii. This program included active surveillance of hygienic measures in the unit and weekly screening of asymptomatic carriers of MDR gram-negative bacilli for all patients admitted at the ICU. No other interventions were performed in the center during the study period. 11 approved the final version. As corresponding author and principal investigator, JMC had full access to all the data in the study and takes responsibility for the decision to submit for publication. Funding The program received public funding from the Regional Health Ministry of Andalucía [PI-0361-2010], which did not participate in the development of the program or the analysis of its results. Competing interests All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that (1) Dr. Cisneros has served as a speaker for Novartis, Astellas, Pfizer, Merck Sharp & Dohme, Janssen and AstraZeneca, outside the submitted work. Dr. Valencia and Dr. Gil-Navarro report personal fees from Merck Sharp & Dohme Spain; Dr. Praena has served as a speaker for Abbvie; Dr. Ferrándiz has served as a speaker for Gilead, and Dr. Rodríguez-Hernández has served as a speaker for Astellas, all of them outside the submitted work. The rest of the authors declare no competing interests; (2) None of the authors has relationships with any companies that might have an interest in the submitted work in the previous 3 years; (3) None of the authors’ spouses, partners, or children have any financial relationships that may be relevant to the submitted work; and (4) None of the authors has any non-financial interests that may be relevant to the submitted work. Ethical approval The study was approved by the local ethical committee of the University Hospital Virgen del Rocío (Seville). Acknowledgments We acknowledge the invaluable contribution of all the antimicrobial stewardship program professionals: doctors, clinical microbiologists, pharmacists, nurses and other members of the hospital. We thank the hospital manager and medical director, and the Andalusian Health Service (SAS) of the Regional Ministry of Health of Andalucía (Spain) for supporting the antimicrobial stewardship program. We acknowledge Ian 12 Brayshaw for language editing and Patricia Fernández-delValle (Statiscian at the Unit of Clinical Research and Clinical Trials of the University Hospital Virgen del Rocío, Seville, Spain) for her valuable contribution and comments in the time series data analysis. PRIOAM team José M Cisneros, José Molina, Germán Peñalva, M Victoria Gil-Navarro, Julia Praena, J Antonio Lepe, M Antonia Pérez-Moreno, Carmen Ferrándiz, Teresa Aldabó, Manuela Aguilar, Peter Olbrich, Manuel E Jiménez-Mejías, M Luisa Gascón, Rosario Amaya- Villar, Olaf Neth, M Jesús Rodríguez-Hernández, Antonio Gutiérrez-Pizarraya, José Garnacho-Montero, Cristina Montero, Josefina Cano, Julián Palomino, Raquel Valencia, Rocío Álvarez, Elisa Cordero, Marta Herrero, Emilio García-Cabrera, Francisco Porras, Francisco Jiménez-Parrilla, Ignacio Obando, Maite Ruiz-Pérez, Javier Aznar, Manolo Conde, Carlos Ortiz, Fernando Docobo and Javier Bautista. 13 References 1. World Health Organization. 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BMC Infect Dis 2016 Nov; 16(1): 704. 17 Tables Table 1: ITS analysis of changes in antibiotic use before and during the PRIOAM intervention Table 2: ITS analysis of changes in the incidence density of hospital acquired candidemia and MDR-BSI before and during the PRIOAM intervention Table 3: ITS analysis of changes in the incidence density of mortality of hospital acquired candidemia and MDR-BSI before and during the PRIOAM intervention Table 4: ITS analysis of changes in the incidence density of mortality of overall hospital acquired candidemia and MDR-BSI before and during the PRIOAM intervention Table 5: Potential changes in healthcare during the study period Figures Fig.1 Changes in antibiotic consumption Fig.2 Impact on incidence of hospital acquired candidemia and MDR-BSI Fig.3 Evolution of incidence of non-MDR hospital acquired BSI Fig.4 Changes in incidence of mortality of hospital acquired MDR-BSI Fig.5 Changes in incidence of mortality of overall hospital acquired MDR and non- MDR BSI Supplementary files Supplementary file 1: Institutional PRogramme for the Optimisation of AntiMicrobial treatment (PRIOAM): counseling interview form Supplementary file 2: Satisfaction survey form. Supplementary file 3: Incidence Density of MDR bacteremias per 1000 occupied bed days Supplementary file 4: Joinpoint Regression Analysis outcomes 18 Table 1. ITS analysis of changes in antibiotic use before and during the PRIOAM intervention DDD per 1000 occupied bed days Pre-intervention trend Change per quarter (95% CI) -5.12 (-24.69 to 14.45) Change in trend Change in slope after the intervention (95% CI) 2.7 (-17.8 to 23.2) Change in level after the intervention Level effect (95% CI) Relative effect. Difference from the pre-intervention trend (%) Three months after the start of the intervention -216.8 (-347.5 to -86.1)** -21.5 Six months after the start of the intervention -214.1 (357.8 to -70.4)** -21.3 One year after the start of the intervention -208.7 (-382.8 to -34.6)* -21.0 Two years after the start of the intervention -197.9 (-442.2 to 46.5) -20.3 Three years after the start of the intervention -187.0 (-507.1 to 133.1) -19.6 Four years after the start of the intervention -176.2 (-574.4 to 222.1) -18.9 19 quarters after the start of the intervention -168.0 (-625.7 to 289.6) -18.3 PRIOAM intervention started in quarter one 2011 and continued without interruption * P<.05 ** P<.01 19 Table 2. ITS analysis of changes in the incidence density of hospital acquired candidemia and MDR-BSI before and during the PRIOAM intervention Incidence density per 1000 occupied bed days Pre-intervention trend Change per quarter (95% CI) 0.018 (-0.003 to 0.039) Change in trend Change in slope after the intervention (95% CI) -0.029 (-0.051 to -0.008)* Change in level after the intervention Level effect (95% CI) Relative effect. Difference from the pre-intervention trend (%) Three months after the start of the intervention -0.130 (-0.267 to 0.007) -24.4 Six months after the start of the intervention -0.159 (-0.310 to -0.008)* -29.0 One year after the start of the intervention -0.218 (-0.401 to -0.035)* -37.2 Two years after the start of the intervention -0.336 (-0.594 to -0.077)* -50.9 Three years after the start of the intervention -0.453 (-0.793 to -0.114)* -61.9 Four years after the start of the intervention -0.571 (-0.994 to -0.148)* -71.0 19 quarters after the start of the intervention -0.659 (-1.146 to -0.172)* -76.7 PRIOAM intervention started in quarter one 2011 and continued without interruption * P<.05 ** P<.01 20 Table 3. ITS analysis of changes in the incidence density of mortality of hospital acquired candidemia and MDR-BSI before and during the PRIOAM intervention Incidence density per 1000 occupied bed days Pre-intervention trend Change per quarter (95% CI) 0.011 (0.005 to 0.017) ** Change in trend Change in slope after the intervention (95% CI) -0.015 (-0.021 to -0.008)** Change in level after the intervention Level effect (95% CI) Relative effect. Difference from the pre-intervention trend (%) Three months after the intervention -0.045 (-0.087 to -0.004)* -27.9 Six months after the intervention -0.060 (-0.106 to -0.015)* -34.7 One year after the intervention -0.090 (-0.146 to -0.034)** -46.0 Two years after the intervention -0.150 (-0.228 to -0.072)** -62.4 Three years after the intervention -0.209 (-0.312 to -0.107)** -73.7 Four years after the intervention -0.269 (-0.396 to -0.142)** -82.0 19 quarters after the intervention -0.314 (-0.460 to -0.168)** -86.8 PRIOAM intervention started in quarter one 2011 and continued without interruption * P<.05 ** P<.01 27 Fig.5 Changes in incidence of mortality of overall hospital acquired MDR and non-MDR BSI 0,000 0,050 0,100 0,150 0,200 0,250 0,300 0,350 0,400 0,450 0,500 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Incidence Density of mortality due to nosocomial MDR and non-MDR bloodstream infections/1000 OBD Time (quarters) Before intervention Expected without intervention After intervention Baseline Intervention 28 Supplementary file 1: Institutional PRogramme for the Optimisation of AntiMicrobial treatment (PRIOAM): counseling interview form Targeted antimicrobial treatment 1. Was antimicrobial treatment indicated? Yes No 2. Was the timing of the treatment initiation appropriate? Yes No 3. Was the interpretation of the microbiological results correct? Yes No 4. Was the chosen agent appropriate? Yes No 5. Was the chosen agent the most appropriate? Yes No 6. Was the dosing appropriate? Yes No 7. Was the way of administration appropriate? Yes No 8. If other therapeutic measures were indicated, were they performed correctly? They were not indicated and not performed They were indicated and correctly performed They were indicated, but not correctly performed 1. Is the planned treatment duration appropriate? Yes No Date of interview: Centre Clinical department Episode number Advisor: Prescriber Antimicrobial agent(s) Clinical indication: Perioperative prophylaxis Diagnosis without microbiological confirmation Diagnosis with microbiological confirmation Describe Perioperative prophylaxis 1. Was prophylaxis indicated? Yes No 2. Was the chosen agent appropriate? Yes No 3. Was the administration timing appropriate? Yes No 4. Was the total number of doses appropriate? Yes No Empirical antimicrobial treatment 1. Was empirical treatment initiation indicated? Yes No 2. Was the timing of treatment initiation appropriate? Yes No 3. Were microbiological samples collected? It was not indicated: Not performed It was indicated: Performed Not performed or incorrectly performed 4. Was the chosen agent appropriate? Yes No 5. Was the dosing appropriate? Yes No 6. Was the way of administration appropriate? Yes No 7. If other therapeutic measures were indicated, were they performed correctly? They were not indicated and not performed They were indicated and correctly performed They were indicated, but not correctly performed 8. Is the planned treatment duration appropriate? Yes No 29 Supplementary file 2: Satisfaction survey form Date of the interview:_________ Centre:_________ Clinical department:_________________ Dear colleague: We would appreciate your participation in this questionnaire. Knowing your opinion about the advisory you have just received will help us to improve our stewardship programme. Did you find the advisory useful? Yes No Do you have any additional comment? Thank you for your cooperation, The PRIOAM Operations Team 30 Supplementary file 3: Incidence Density of MDR bacteremias per 1000 occupied bed days Trimester Quarter No. Overall MDR Bacteriemias Candidemias MDR A. baumannii ESBL E. coli MRSA ESBLK. pneumoniae MDR P. aeruginosa 1t2009 1 0.374 0.137 0.100 0.050 0.075 0.000 0.012 2t2009 2 0.417 0.182 0.104 0.052 0.065 0.000 0.013 3t2009 3 0.488 0.129 0.100 0.115 0.086 0.043 0.014 4t2009 4 0.377 0.052 0.208 0.065 0.052 0.000 0.000 1t2010 5 0.289 0.105 0.118 0.039 0.026 0.000 0.000 2t2010 6 0.420 0.105 0.105 0.039 0.131 0.026 0.013 3t2010 7 0.591 0.152 0.243 0.121 0.076 0.000 0.000 4t2010 8 0.447 0.131 0.184 0.066 0.053 0.000 0.013 1t2011 9 0.560 0.182 0.273 0.026 0.039 0.013 0.026 2t2011 10 0.339 0.130 0.156 0.039 0.000 0.013 0.000 3t2011 11 0.446 0.104 0.223 0.059 0.030 0.030 0.000 4t2011 12 0.340 0.173 0.080 0.027 0.040 0.066 0.013 1t2012 13 0.365 0.091 0.104 0.039 0.078 0.000 0.052 2t2012 14 0.342 0.053 0.119 0.040 0.053 0.026 0.053 3t2012 15 0.459 0.107 0.076 0.061 0.031 0.122 0.061 4t2012 16 0.430 0.183 0.026 0.104 0.000 0.065 0.052 1t2013 17 0.254 0.040 0.027 0.067 0.013 0.094 0.013 2t2013 18 0.312 0.117 0.026 0.052 0.026 0.039 0.052 3t2013 19 0.259 0.137 0.000 0.015 0.031 0.061 0.015 4t2013 20 0.186 0.106 0.000 0.013 0.027 0.027 0.013 1t2014 21 0.239 0.093 0.000 0.053 0.040 0.013 0.040 2t2014 22 0.160 0.080 0.000 0.027 0.013 0.027 0.013 3t2014 23 0.272 0.152 0.000 0.061 0.015 0.045 0.000 4t2014 24 0.334 0.107 0.000 0.093 0.053 0.067 0.013 1t2015 25 0.162 0.068 0.000 0.027 0.014 0.027 0.027 2t2015 26 0.280 0.140 0.000 0.056 0.070 0.014 0.000 3t2015 27 0.293 0.147 0.000 0.049 0.033 0.065 0.000 4t2015 28 0.186 0.146 0.000 0.013 0.013 0.000 0.013 31 Supplementary file 4: Joinpoint Regression Analysis outcomes Table s1. Joinpoint Regression Analysis. Trend slopes and changes in trends. Variable Trend 1 Quarter percentage change Change in trend Joinpointa Trend 2 Quarter percentage change Change in trend 2ndJoinpointa Trend 3 Quarter percentage change DDD (J01) per 1000 OBD Quarters 1 to 9 = +0.1% (CI95% -1.6 to 1.8, P=0.92) Quarter 9 (CI95% 7 to 11) Quarters 9 to 13 = -7.8% (CI95% -15.6 to 0.6, P=0.07) Quarter 13 (CI95% 11 to 17) Quarters 13 to 28 = +0.3% (CI95% -0.5 to 1.0, P=0.51) MDR-BSI cases per 1000 OBD Quarters 1 to 8 = +3.2% (CI95% -3.6 to 10.5, P=0.35) Quarter 8 (CI95% 5 to 14) Quarters 8 to 28 = -4.1%** (CI95% -5.6 to - 2.5, P=0.001) - - Mortality by MDR-BSI per 1000 OBD Quarters 1 to 7 = +14.8%* (CI95% 1.1 to 30.2, P=0.03) Quarter 7 (CI95% 5 to 11) Quarters 7 to 28 = -4.6%** (CI95% -6.3 to - 2,9, P=0.001) - - Non-MDR- BSI cases per 1000 OBD Quarters 1 to 28 = +0.5% (CI95% -0.4 to 1.5, P=0.28) - - - - Mortality by overall BSI per 1000 OBD Quarters 1 to 7 = +12.9% (CI95% -1.4 to 29.2, P=0.08) Quarter 7 (CI95% 3 to 13) Quarters 7 to 28 = -2.4%** (CI95% -4.1 to - 0.7, P=0.01) - - (a)Trend change points are significant with a P=.05 (*)Statistically significant P≤.05 (**)Statistically significant P≤.01 32 Joinpoint Regression Analysis Graphics Fig. s1. Antibiotic consumption Joinpoint Regression Analysis Fig. s2. MDR bloodstream infections Joinpoint Regression Analysis 33 Fig. s3. Mortality of MDR bloodstream infectionsJoinpoint Regression Analysis Fig. s4. Non-MDR bloodstream infectionsJoinpoint Regression Analysis 34 Fig. s5. Mortality of MDR and non-MDR bloodstream infectionsJoinpoint Regression Analysis