Outcomes of the PIRASOA programme, an antimicrobial stewardship programme implemented in hospitals of the Public Health System of Andalusia, Spain: an ecologic study of time-trend analysis

Accepted Manuscript Outcomes of the PIRASOA programme, an antimicrobial stewardship programme implemented in hospitals of the public Health system of Andalusia, Spain: an ecological study of time-trend analysis Jesús Rodríguez-Baño, María Antonia Pérez-Moreno, Germán Peñalva, José Garnacho-Montero, Carmen Pinto, Inmaculada Salcedo, Rocío Fernández-Urrusuno, Olaf Neth, María Victoria Gil-Navarro, Alejandro Pérez-Milena, Rafael Sierra, Ángel Estella, Carmen Lupión, Arantxa Irastorza, José Luis Márquez, Álvaro Pascual, María Dolores Rojo-Martín, Ma José Pérez-Lozano, Raquel Valencia-Martín, José Miguel Cisneros, on behalf of the PIRASOA programme group PII: S1198-743X(19)30398-2 DOI: https://doi.org/10.1016/j.cmi.2019.07.009 Reference: CMI 1729 To appear in: Clinical Microbiology and Infection Received Date: 5 April 2019 Revised Date: 28 June 2019 Accepted Date: 4 July 2019 Please cite this article as: Rodríguez-Baño J, Pérez-Moreno MA, Peñalva G, Garnacho-Montero J, Pinto C, Salcedo I, Fernández-Urrusuno R, Neth O, Gil-Navarro MV, Pérez-Milena A, Sierra R, Estella Á, Lupión C, Irastorza A, Márquez JL, Pascual Á, Rojo-Martín MD, Pérez-Lozano MJ, Valencia-Martín R, Cisneros JM, on behalf of the PIRASOA programme group, Outcomes of the PIRASOA programme, an antimicrobial stewardship programme implemented in hospitals of the public Health system of Andalusia, Spain: an ecological study of time-trend analysis, Clinical Microbiology and Infection, https:// doi.org/10.1016/j.cmi.2019.07.009. 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MANUS CRIP T ACCEP TED ACCEPTED MANUSCRIPT 1 TITLE PAGE 1 CATEGORY: ORIGINAL ARTICLE 2 3 TITLE 4 Outcomes of the PIRASOA programme, an antimicrobial stewardship programme 5 implemented in hospitals of the Public Health System of Andalusia, Spain: an ecological 6 study of time-trend analysis 7 8 AUTHORS AND AFFILIATIONS 9 Jesús Rodríguez-Baño 1 , María Antonia Pérez-Moreno 2 , Germán Peñalva 3 , José Garnacho-Montero 4 , 10 Carmen Pinto 5 , Inmaculada Salcedo 6 , Rocío Fernández-Urrusuno 7 , Olaf Neth 8 , María Victoria Gil- 11 Navarro 2 , Alejandro Pérez-Milena 9 , Rafael Sierra 10 , Ángel Estella 11 , Carmen Lupión 1 , Arantxa 12 Irastorza 12 , José Luis Márquez 12 , Álvaro Pascual 1 , María Dolores Rojo-Martín 13 , Mª José Pérez- 13 Lozano 14 , Raquel Valencia-Martín 2 , José Miguel Cisneros 2* , on behalf of the PIRASOA programme 14 group. 15 1 Clinical Unit of Infectious Diseases, Microbiology and Preventive Medicine. University Hospital 16 Virgen Macarena/Department of Medicine/University of Seville. Institute of Biomedicine of Seville 17 (IbiS), Seville, Spain , 2 Clinical Unit of Pharmacy, University Hospital Virgen del Rocio, Seville, Spain, 3 18 Clinical Unit of Infectious Diseases, Microbiology and Preventive Medicine. University Hospital Virgen 19 del Rocio/CSIC/University of Seville. Institute of Biomedicine of Seville (IbiS), Seville, Spain, 4 20 Department of Critical Care, University Hospital Virgen Macarena, University of Seville, Seville, Spain, 21 5 Department of Pharmacy, Guadix-Loja Hospital, Granada, Spain, 6 Department of Preventive 22 Medicine and Public Health, University Hospital Reina Sofia, Cordoba, Spain, 7 Pharmacy Service, 23 Primary Healthcare District Aljarafe-Sevilla Norte, Mairena del Aljarafe, Seville, Spain, 8 Department of 24 MANUS CRIP T ACCEP TED ACCEPTED MANUSCRIPT 2 Paediatric Infectious Diseases, Rheumatology, and Immunodeficiency, Institute of Biomedicine of 25 Seville (IBiS), University Hospital Virgen del Rocio, University of Seville, Seville, Spain, 9 El Valle Health 26 Centre, Jaen, Spain, 10 Intensive Care Unit, University Hospital Puerta del Mar, University of Cadiz, 27 Cadiz, Spain, 11 Intensive Care Unit, Jerez de la Frontera Hospital, Jerez de la Frontera, Cadiz, Spain, 12 28 Department of Comprehensive Health Plans, Supporting Services of the Andalusian Healthcare 29 Service, Seville, Spain, 13 Department of Microbiology, Regional University Hospital of Malaga, Spain, 30 14 Clinical Unit of Prevention, Promotion and Health Surveillance, University Hospital Virgen de Valme, 31 Seville, Spain. 32 33 *Corresponding author: José Miguel Cisneros, Clinical Unit of Infectious Diseases, Microbiology and 34 Preventive Medicine. University Hospital Virgen del Rocío/CSIC/University of Seville. Institute of 35 Biomedicine of Seville (IBiS). Avenida Manuel Siurot s/n, 41013, Seville, Spain. (+34- 24 955- 01-21- 36 85; jmcisner[email protected]). 37 38 KEYWORDS 39 Antimicrobial stewardship programmes; PIRASOA; quality of prescription; antimicrobial consumption; 40 public healthcare system. 41 42 LENGTH OF THE ABSTRACT: 250 WORDS. 43 LENGTH OF THE MANUSCRIPT: 3,058 WORDS. 44 45 MANUS CRIP T ACCEP TED ACCEPTED MANUSCRIPT 3 ABSTRACT 46 Objectives 47 Inappropriate antimicrobial use favours the spread of resistance and multidrug-resistant 48 microorganisms (MDR) are currently of major concern. Antimicrobial stewardship programmes (ASPs) 49 are essential for improving antibiotic use in hospitals. However, their impact on entire healthcare 50 systems has not been thoroughly assessed. Our objective is to provide the results of an institutionally 51 supported ASP involving 31 public hospitals in Andalusia, Spain. 52 Methods 53 We designed an ecological time-series study from 01/01/2014 to 31/12/2017. Quarterly, data on 54 indicators were collected prospectively and feedback reports were provided. PIRASOA is an ongoing 55 clinically-based, quality improvement programme whose key intervention is the educational 56 interview, regular peer-to-peer interventions between advisors and prescribers to reinforce the 57 appropriate use of antibiotics. 72 indicators were monitored to measure prescribing quality 58 (inappropriate treatments), antimicrobial consumption (defined daily doses/1000 occupied bed days 59 [OBD]), incidence density of MDR/1000 OBD, and crude mortality rate associated with bloodstream 60 infections. We used joinpoint regression to analyse the trends. 61 Results 62 The quality of antimicrobial prescribing improved markedly and inappropriate treatment rate was 63 significantly lower with quarterly percentage change (QPC)=-3.0%, P<.001. Total antimicrobial 64 consumption decreased (QPC=-0.9%, P<0.001) and, specifically, carbapenems, amoxicillin/clavulanic 65 acid, quinolones, and antifungal agents consumption, whereas antipseudomonal cephalosporins use 66 increased. While the incidence of MDR showed a sustained decreasing trend (QPC=-1.8%; P=.002), 67 the mortality of patients with bloodstream infections remained stable (QPC=-0.2%, P=.605). 68 Conclusions 69 To date, the PIRASOA programme has succeeded in optimising the use of antimicrobial agents and 70 MANUS CRIP T ACCEP TED ACCEPTED MANUSCRIPT 4 has had a positive ecological result on bacterial resistance at level of an entire healthcare system. 71 72 MANUS CRIP T ACCEP TED ACCEPTED MANUSCRIPT 5 INTRODUCTION 73 Antimicrobial resistance (AMR) is a growing worldwide public health problem recently described by 74 the World Health Organization (WHO) as a global crisis [1]. Healthcare-associated infections and 75 hospital infections caused by multidrug-resistant (MDR) organisms significantly increase morbidity, 76 mortality, and medical costs [2], requiring costly and sometimes toxic alternatives [3]. Inappropriate 77 use of antimicrobials induces resistance mechanisms or selects for resistant microorganisms [4]. 78 Because the development of new antimicrobials has slowed down considerably, the optimal and 79 prudent use of the available antimicrobials and the practise of infection prevention and control have 80 become essential tools for improving this situation [5]. 81 Antimicrobial stewardship programmes (ASPs) have been shown to enhance appropriate use of 82 antimicrobials, reduce antimicrobial use with cost savings [6]. Education is a cornerstone of ASPs 83 [7,8]. Recently, ASPs have shown a beneficial ecological and clinical impact [9,10]. The European 84 Centre for Diseases Prevention and Control (ECDC) has recommended developing national strategies 85 to combat AMR and promote the prudent use of antimicrobials. ASPs are key elements [11] and must 86 be implemented at all levels of care, include prevention/control and vaccination activities and provide 87 standardised open data on antimicrobial consumption and AMR [11,12]. However, most of the 88 evidence on benefits from ASPs is based on local experiences and their impact at the level of 89 healthcare systems has not been thoroughly assessed [10,13]. 90 Spain is among the countries with the highest overall community-level consumption of antibiotics in 91 Europe [14,15] and has high rates of bacterial resistance [5]. However, to date, published data on the 92 consumption of antibiotics in Spanish hospitals are limited [16]. In Andalusia, the most populated 93 autonomous region in Spain with 8.4 million inhabitants, an ASP called the PIRASOA programme — 94 Institutional Programme for the Prevention and Control of Healthcare-Associated Infections and 95 Appropriate Use of Antimicrobials— was designed as a comprehensive programme to be 96 implemented in the Andalusian Public Healthcare System (SSPA) at both primary and hospital 97 MANUS CRIP T ACCEP TED ACCEPTED MANUSCRIPT 6 healthcare levels. This ASP was inspired by the PRIOAM programme [9,10] and the Spanish 98 recommendations for the implementation of ASPs [7]. The programme was approved on February 99 2013 by the Ministry of Health of the Regional Government of Andalusia. 100 The objective of this study was to analyse the effect of the PIRASOA programme on the optimisation 101 of antimicrobial use and its clinical and ecological result in hospitals of a public healthcare system. 102 METHODS 103 Study design, care setting and study period 104 Ecological time-trend analysis to evaluate the performance of the PIRASOA programme in 31 acute 105 care hospitals belonging to the SSPA; three small county hospitals designed only for very short stays 106 were excluded. The participating hospitals included all levels of complexity: tertiary care teaching 107 hospitals (n=8/average number of beds=1080), specialties hospitals (n=7/average number of 108 beds=570) and county hospitals (n=16/average number of beds=190). 109 The study was conducted from January 2014 (when the PIRASOA programme was initiated) to 110 December 2017 and was divided into sixteen quarters. 111 Intervention: the PIRASOA programme 112 The detailed methodology of the PIRASOA programme has been described in a previously published 113 comprehensive protocol, in which the design, structure, organisation and indicators have been 114 explained to facilitate adapting and implementing the programme [17]. This protocol is accessible at: 115 https://www.protocols.io/view/the-pirasoa-programme-design-structure-organisatio- 116 r3bd8in/abstract. Briefly, PIRASOA is an ongoing institutional, comprehensive, education-based 117 programme with an interdisciplinary organisation, which consists of an antimicrobial stewardship 118 programme (ASP) and an infection control programme. The infection control part is the continuation 119 of a previous programme implemented in 2003; here we summarize the ASP part of PIRASOA. The 120 interventions are implemented at each hospital by multidisciplinary antimicrobial stewardship teams 121 (ASTs) including infectious diseases physicians, microbiologists, and pharmacists, plus other specialists 122 MANUS CRIP T ACCEP TED ACCEPTED MANUSCRIPT 7 according to local needs. A generic written ASP was developed by the Scientific Committee, and local 123 ASTs adapted the ASP to the local context. An online platform was developed to serve as the main 124 communication tool between them. 125 The main intervention of the ASP consisted of educational interviews (EIs), one-to-one training 126 activities based on the review of antimicrobial prescriptions between two physicians, an advisor and a 127 prescriber. A multidisciplinary team of advisors was set up at each hospital, including infectious 128 diseases experts from different departments. A number of EIs was scheduled for each department 129 proportionally to their antimicrobial use. On a regular basis, an advisor reviewed a randomly chosen 130 antimicrobial treatment with the prescriber, discussing the main aspects of the diagnosis and 131 treatment of the case, following a purpose-designed checklist. Prescriptions were rated as 132 ‘appropriate’ when all questions on the checklist were assessed positively, taking the hospital clinical 133 guidelines for the management of infectious syndromes as a reference. The approach was strictly 134 pedagogical, aiming to improve prescriber’s knowledge rather than to change any antimicrobial 135 treatment. Patient data remained anonymous. Two tertiary hospitals already had an active ASP 136 before the start of the PIRASOA programme, performing audits of targeted prescriptions that 137 included non-mandatory recommendations; these audits were continued and were used instead of 138 the EIs. Furthermore, hospitals could implement additional interventions in accordance with local 139 problems, such as deferred approval for specific drugs and audits. 140 Additional measures included: publication and dissemination of regularly updated and locally adapted 141 guidelines for the management of infectious syndromes; specific training based on massive online 142 open courses on the appropriate use of antimicrobials; quarterly feedback on the outcomes including 143 comparisons between participating hospitals; annual clinical meetings with local ASTs representatives 144 to analyse the overall results of the programme and to outline improvement strategies; and 145 designation of a central reference laboratory to evaluate the epidemiological relationship between 146 MDR isolates and health-related outbreaks in “real time”. 147 MANUS CRIP T ACCEP TED ACCEPTED MANUSCRIPT 8 This study analysed 72 indicators collected quarterly (see Supplementary Table S1), including data on 148 antimicrobial consumption, rates of resistant pathogens, quality of antimicrobial use, and mortality 149 from bloodstream infections. Data were entered in an online platform by local ASTs members. 150 The main outcome variable was total antimicrobial consumption (ATC codes J01 and J02) and 151 consumption of specific antimicrobial families or drugs: carbapenems, piperacillin/tazobactam, 152 amoxicillin/clavulanic acid, non-antipseudomonal cephalosporins (ceftriaxone+cefotaxime), 153 antipseudomonal cephalosporins ( ceftazidime+cefepime) , fluoroquinolones, vancomycin, and 154 antifungal agents;, calculated as defined daily doses (DDD) per 1000 occupied bed days (OBD), 155 according to the Anatomical Therapeutic Chemical Classification System (ATC/DDD) defined by WHO 156 [18]. 157 Other outcome variables measured included: (a) Prescribing quality, as assessed during the EIs; 158 prescriptions were considered as ‟appropriate” when all items of the checklist were evaluated 159 positively; local guidelines were used as reference.(b) Incidence density of colonisation/infection due 160 to methicillin resistant Staphylococcus aureus (MRSA), extended-spectrum β-lactamases (ESBL)- 161 producing Escherichia coli and Klebsiella pneumoniae, carbapemase-producing Enterobacteriaceae 162 (CPE), MDR Acinetobacter baumannii, MDR Pseudomonas aeruginosa, and vancomycin-resistant 163 Enterococcus spp. (VRE), measured as new patients with positive clinical cultures per 1000 OBD, and 164 Clostridium difficile infections. The results of the surveillance cultures performed to determine the 165 colonisation status were not measured. (c) All-cause crude mortality rate on day +14 after the 166 diagnosis of bloodstream infections caused by E. coli, P. aeruginosa, K. pneumoniae, A. baumannii, S. 167 aureus, Neisseria meningitidis, Streptococcus pneumoniae, and Candida spp. 168 Microbiological definitions 169 Isolates were considered MDR based on the German Society for Hygiene and Microbiology criteria 170 [19]. Detection of ESBL-producers and MRSA followed the European Committee on Antimicrobial 171 Susceptibility Testing (EUCAST) recommendations [20]. 172 MANUS CRIP T ACCEP TED ACCEPTED MANUSCRIPT 15 The antimicrobial stewardship programme was supported by the Ministry of Health of the Regional 323 Government of Andalusia (Spain). One E-learning course was supported by Merck Sharp & Dohme 324 S.A. through an unrestricted grant. JRB, CL, AP, and JMC received research funding from Plan Nacional 325 de I+D+i 2013-2016; and Instituto de Salud Carlos III, Sub-Directorate General for Cooperative 326 Research Centres and Networks, Ministry of Economy, Industry and Competitiveness, Spanish 327 Network for Research in Infectious Diseases (REIPI RD12/0015/0010 and REIPI RD16/0016/0001, 328 RD16/0016/0009) co-financed by the European Development Regional Fund “A way to achieve 329 Europe”, Operative Programme Intelligent Growth 2014-2020. 330 Acknowledgments 331 We would like to thank the invaluable contributions of all the antimicrobial stewardship program 332 professionals: doctors, clinical microbiologists, pharmacists, nurses, and other members of all the 333 healthcare centers who have made the implementation of the program possible. We are grateful to 334 the Progress and Health Foundation, IAVANTE line of the Ministry of Health of the Regional 335 Government of Andalusia (Spain). 336 Authors contributions 337 JMC, MAPM and GP conceived and designed the study. MAPM and JMC performed the scientific 338 literature search. JRB, JGM, CP, RFU, ON, MVGN, APM, RS, AE, CL, AP, MDRM, MJPL, RVM and JMC 339 have contributed to the designed and the start of the programme as members of the Scientific 340 Committee of PIRASOA. MAPM, JMC and GP performed the analysis, and G. P. the statistical analysis. 341 All authors collected the data and performed the interventions together with the rest of the PIRASOA 342 group. Also, all of them interpreted the data, wrote the report, and approved the final version of the 343 manuscript. 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Antimicrobial consumption trends (ATC codes J01+J02 and specific antimicrobials) INDICATOR (DDD/1000 OBD) Consumption Q1: DDD/1000 OBD (range) Consumption Q16: DDD/1000 OBD (range) QPC 95% CI P value Total ATC codes J01 and J02 923 (717 - 1841) 778 (556 - 1003) - 0.9% ( - 1.2%, - 0.6%) P < .001 Carbapenems (imipenem and meropenem) 58.9 (0 - 113.9) 43.6 (14.1 - 91.0) - 1.2% ( - 1.6%, - 0.7%) P < .001 Amoxicillin/clavulanic acid 1 183.1 (50.7 - 423.4) 150.1 (55.5 - 221.6) - 1.3% ( - 1.5%, - 1.1%) P < .001 Piperacillin /tazobactam 50.0 (4.3 - 130.0) 46.2 (14.2 - 85.2) - 0.7% ( - 1.6%, 0.3%) P = .163 Fluoroquinolones 1 194.4 (92.2 - 497.3) 129.4 (79.3 - 263.0) - 1.5% ( - 1.8%, - 1.3%) P < .001 Antipseudomonal cephalosporins 18.7 (2.5 - 49.4) 26.3 (2.1 - 49.1) 3.7% (2.4%, 5.0%) P < .001 No n - antipseudomonal cephalosporins 1 80.8 (48.3 - 286.5) 71.4 (31.8 - 196.8) 0.8% (0.3%, 1.2%) P = .003 Vancomycin 16.4 (0 - 58.0) 14.7 (4.8 - 86.5) - 0.3% ( - 1.1%, 0.5%) P = .420 Antifungal agents 42.7 (4.5 - 79.7) 28.4 (3.2 - 64.7) - 1.3% ( - 1.8%, - 0.8%) P < .001 Azoles Fluconazole Posaconazole 32.3 (4.8 - 60.5) 26.1 (0-49.7) 1.1 (0-4.8) 26.7 (3.2 - 45.7) 12.4 (2.9-39.6) 2.7 (0-9.6) - 1.2% -1.6% 5.8% ( - 1.6%, - 0.7%) (-2.0%, -1.2%) (3.9%, 7.7%) P < .001 P < .001 P < .001 Echinocandins 3.0 (0 - 11.0) 3.4 (0 - 8.3) 0.3% ( - 0.9%, 1.5% ) P = .598 DDD/1000 OBD: DDD/1000 occupied bed days. QPC: quarterly percentage change. 1. Seasonal adjustment analysis MANUS CRIP T ACCEP TED ACCEPTED MANUSCRIPT Figure 1. Trends in the educational interviews performed (n) and in antimicrobial treatment prescribing quality (inappropriate treatment rate, %) QPC: quarterly percentage change 0% 5% 10% 15% 20% 25% 30% 35% 40% 45% 50% 0 500 1000 1500 2000 2500 Educational interviews (n): QPC = 1.4% (95% CI -0.3%, 3.1%; P = .098) Inappropriate treatment rate (%): QPC = -3.0% (95% CI -3.5%, -2.5%; P < .001) Number of educational interviews (n) Inappropriate treatment rate (%) MANUS CRIP T ACCEP TED ACCEPTED MANUSCRIPT Figure 2. Trends in total antimicrobial consumption: J01+J02 ATC codes (DDD/1000 OBD) QPC = -0.9% (95% CI -41.2; -0.6) p < .001 DDD/1000 OBD: DDD/1000 occupied bed days. QPC: quarterly percentage change 923 835 849 835 876 803 794 822 818 770 770 778 815 780 757 778 500 550 600 650 700 750 800 850 900 950 1000 DDD/1000 OBD MANUS CRIP T ACCEP TED ACCEPTED MANUSCRIPT Figure 3. Trends in total antimicrobial consumption per hospital type: J01+J02 ATC codes (DDD/1000 OBD) A) All hospitals (n=31) B) Tertiary care hospitals (n=8) C) Specialties hospitals (n=7) D) County hospitals (n=16) DDD/1000 OBD DDD/1000 OBD DDD/1000 OBD DDD/1000 OBD MANUS CRIP T ACCEP TED ACCEPTED MANUSCRIPT Figure 4. Change in the profile of prescriptions of antimicrobial treatments (DDD/1000 OBD) DDD/1000 OBD: DDD/1000 occupied bed days. * Seasonal adjustment 0 10 20 30 40 50 60 70 1Q2014 2Q2014 3Q2014 4Q2014 1Q2015 2Q2015 3Q2015 4Q2015 1Q2016 2Q2016 3Q2016 4Q2016 1Q2017 2Q2017 3Q2017 4Q2017 DDD71000 OBD Carbapenems 0 5 10 15 20 25 30 35 1Q2014 2Q2014 3Q2014 4Q2014 1Q2015 2Q2015 3Q2015 4Q2015 1Q2016 2Q2016 3Q2016 4Q2016 1Q2017 2Q2017 3Q2017 4Q2017 DDD/1000 OBD Antipseudomonal cephalosporins 0 20 40 60 80 100 120 140 160 180 200 1Q2014 2Q2014 3Q2014 4Q2014 1Q2015 2Q2015 3Q2015 4Q2015 1Q2016 2Q2016 3Q2016 4Q2016 1Q2017 2Q2017 3Q2017 4Q2017 DDD/1000 OBD Amoxicillin/clavulanic acid* 0 20 40 60 80 100 1Q2014 2Q2014 3Q2014 4Q2014 1Q2015 2Q2015 3Q2015 4Q2015 1Q2016 2Q2016 3Q2016 4Q2016 1Q2017 2Q2017 3Q2017 4Q2017 DDD/1000 OBD Non-antipseudomonal cephalosporins* 0 50 100 150 200 250 1Q2014 2Q2014 3Q2014 4Q2014 1Q2015 2Q2015 3Q2015 4Q2015 1Q2016 2Q2016 3Q2016 4Q2016 1Q2017 2Q2017 3Q2017 4Q2017 DDD/1000 OBD Quinolones* 0 5 10 15 20 25 30 35 40 45 50 1Q2014 2Q2014 3Q2014 4Q2014 1Q2015 2Q2015 3Q2015 4Q2015 1Q2016 2Q2016 3Q2016 4Q2016 1Q2017 2Q2017 3Q2017 4Q2017 DDD/1000 OBD Antifungal agents