ANTIMICROBIAL STEWARDSHIP A practical guide to implementation in hospitals

Transcription

1 02-19 / /GB/B / This document is not egay binding. biomérieux reserves the right to modify specifications without notice / BIOMÉRIEUX and the BIOMÉRIEUX ogo are used, pending and/or registered trademarks beonging to biomérieux or one of its subsidiaries or one of its companies. Any other name or trademark is the property of its respective owner / biomérieux S.A. RCS Lyon / Printed in France / théra / RCS Lyon B biomérieux In vitro diagnostics serving pubic heath A major payer in in vitro diagnostics for more than 50 years, biomérieux has aways been driven by a pioneering spirit and unreenting commitment to improve pubic heath wordwide. Our diagnostic soutions bring high medica vaue to heathcare professionas, providing them with the most reevant and reiabe information, as quicky as possibe, to support treatment decisions and better patient care. biomérieux s mission entais a commitment to support medica education, by promoting access to diagnostic knowedge for as many peope as possibe. Focusing on the medica vaue of diagnostics, our coection of educationa bookets aims to raise awareness of the essentia roe that diagnostic test resuts pay in heathcare decisions. Other educationa bookets are avaiabe. Consut your oca biomérieux representative. The information in this booket is for educationa purposes ony and is not intended to be exhaustive. It is not intended to be a substitute for professiona medica advice. Aways consut a medica director, physician, or other quaified heath provider regarding processes and/or protocos for diagnosis and treatment of a medica condition. biomérieux assumes no responsibiity or iabiity for any diagnosis estabished or treatment prescribed by the physician. biomérieux S.A Marcy Étoie France Te.: + 33 (0) Fax: +33 (0) ANTIMICROBIAL STEWARDSHIP A practica guide to impementation in hospitas E D ITIO N

2 INTRODUCTION CONTENTS The objective of this booket is to provide practica recommendations for heathcare workers in hospitas to improve the quaity of antibiotic prescribing and thereby improve patient cinica outcomes. Most of the recommendations within this booket have been adapted from the IDSA Guideines [Deit et a., 2007; Tamar F et a., 2016], the Austraian Hospita Stewardship Guidance [Duguid et a., 2011], Nationa Stewardship Guidance from Scotand [Nathwani et a., 2006], the UK [Start smart then Focus DOH, 2011; NICE Guideine [NG15], 2015] as we as from ow and midde income countries [Van Dijck et a., 2018; Cox et a., 2017]. A key component of stewardship is the avaiabiity of cinica practice guideines to support empiric and targeted prescribing. Athough a high voume of such guidance is now being produced, for exampe the Nationa Treatment Guideines for Antimicrobia Use in Infectious Diseases in India, there is consistent evidence that guideines on empirica antibiotic use did not routiney consider oca resistance patterns in their recommendations. Decision-makers shoud anayze and report the extent of oca resistance patterns to aow better decision-making [Eias et a., 2017]. For this reason we have not referred to any specific cinica practice treatment guideines. We hope that this booket wi inform, encourage and support heath professionas wishing to pursue the impementation of hospita Antimicrobia Stewardship initiatives, as we as combating antimicrobia resistance. Furthermore, we wish to highight the importance of conducting hospita stewardship programs in tandem with stewardship in the community and other settings. The importance of stewardship in the anima setting is aso recognized as in the One Heath approach to AMR and stewardship recommended by WHO, FAO & OIE. Prof. Diip Nathwani MB; DTM&H, FRCP, OBE Consutant Physician and Honorary Professor of Infection Director Academic Heath Sciences Partnership in Tayside, Ninewes Hospita and Medica Schoo Dundee, Scotand 1 2 WHY IMPLEMENT ANTIMICROBIAL STEWARDSHIP IN HOSPITALS? 1 Antimicrobia use Combating antimicrobia resistance Defining Antimicrobia Stewardship Goas of antimicrobia stewardship and evidence for success Impementation of Antimicrobia Stewardship Programs HOW TO IMPLEMENT AN ANTIMICROBIAL STEWARDSHIP PROGRAM? 1 Assess the motivations Ensure accountabiity and eadership Set up structure and organization Define priorities and how to measure progress and success Identify effective interventions for your setting Identify key measurements for improvement Educate and Train Communicate...40 ADDITIONAL RESOURCES...44 REFERENCES...46 This booket wi primariy consider appropriate use of antimicrobia stewardship in hospitas and the structures and processes to support this.

3 WHY IMPLEMENT ANTIMICROBIAL STEWARDSHIP IN HOSPITALS? 1 WHY IMPLEMENT ANTIMICROBIAL STEWARDSHIP IN HOSPITALS? Figure 2: Percentage change in antibiotic consumption per capita * by country Adapted from Van Boeke TP et a Lancet Infect Dis. 2014;14: Antimicrobia use Misuse and over-use of antibiotics The ast 50 years have witnessed the goden age of antibiotic discovery and their widespread use in hospita and community settings. Regarded as very effective, safe and reativey inexpensive, antibiotics have saved miions of ives. However, this has ed to their overuse and misuse in the human, anima and other sectors (Figure 1). Gobay, between 2000 and 2010 there has been a massive rise in overa antimicrobia consumption (Figure 2), argey as a consequence of uncontroed prescription or over-the-counter saes. At goba eve, 70% of antibiotics are used for animas [O Nei report, 2016]. In the US, this is 85% (Figure 1). In hospitas, up to 50% of antimicrobia use is inappropriate [Deit et a., 2007] >80 No data Figure 3: Overview of antimicrobia/antibiotic quaity indicators for adut inpatients by region, 2015 Goba Point Prevaence Survey Adapted from Versporten A et a. Lancet Goba Heath. 2018; 6: Northern Europe (n=2783) Southern Europe (n=5534) Western Europe (n=8458) More recent goba data on the quaity of antimicrobia prescribing in hospitas, undertaken using a goba point prevaence survey method [Goba PPShttp:// reveas significant variation in practice against commony used metrics of the quaity of prescriptions (Figure 3). Such rea word data is beginning to provide much needed inteigence of what the probem is, the scae of the probem and ways of measuring the effectiveness of our interventions. Figure 1: Current use of antibiotics in the United States Adapted from 6% 9% 15% 70% Most antibiotics are given to animas and most of them are heathy. Anima non-therapeutic Anima therapeutic Human therapeutic Others (pesticides, etc) Africa (n=899) East and south Asia (n=5363) West and centra Asia (n=1612) Latin America (n=1518) North America (n=2139) Targeted treatment Reason in notes Stop / Review date documented Prescriptions with avaiabe guideines (%) 2 3

4 WHY IMPLEMENT ANTIMICROBIAL STEWARDSHIP IN HOSPITALS? The 30% Rue n ~ 30% of a hospitaized inpatients at any given time receive antibiotics n ~ over 30% of antibiotics are prescribed inappropriatey in the community n ~ up to 30% of a surgica prophyaxis is inappropriate n ~ 30% of hospita pharmacy costs are due to antimicrobia use n ~ 10-30% of pharmacy costs can be saved by antimicrobia stewardship programs (Hoffman et a., 2007; Wise et a., 1999; John et a., 1997) The rising threat of antimicrobia resistance Antimicrobia resistance has been identified as a major threat by the Word Heath Organization [WHO, 2012] due to the ack of new antibiotics in the deveopment pipeine and infections caused by muti-drug resistant pathogens becoming untreatabe [Goossens et a., 2011; Caret et a., 2011]. In 2015, the WHO set out the goba action pan for AMR [WHO, 2015] and a subsequent broader stewardship framework. 2 Combating Antimicrobia Resistance To combat AMR, a three-piar approach is recommended: 1. Optimize the use of antimicrobias, 2. Prevent the transmission of drug-resistant organisms, 3. Improve environmenta decontamination. To achieve this approach, an integrated stewardship approach has been advocated, encompassing antimicrobia stewardship, diagnostic stewardship and infection contro (Figure 5). Figure 5: An integrated stewardship mode: antimicrobia, infection prevention and diagnostic (AID). Adapted from Dik JH et a. Future Microbio. 2015; 11: DSP Diagnostic Stewardship Program Patient with possibe infectious probems Loca resistance patterns There are numerous drivers for AMR (Figure 4). Human antimicrobia misuse and overuse is a key driver factor, as are suboptima dosing, ack of avaiabiity and/or under-use of rapid diagnostics or point of care tests and insufficient infection prevention and contro. Performing microbioogica diagnostics Loca formuarium Figure 4: Mechanisms and drivers of antimicrobia resistance. Adapted from Homes AH et a. The Lancet 2016;387: Bacteria identification and susceptibiity Vira identification - Starting empiric antimicrobia therapy Antimicrobia order from cinica pharmacy + Reative contribution of factor as a driver for antimicrobia resistance High Human antimicrobia misuse or overuse Moderate Anima antimicrobia misuse or overuse Environmenta contamination Heath-care transmission Suboptima rapid diagnostics Suboptima vaccination Suboptima dosing, incuding from substandard and fasified drugs Low Trave Mass drug administration for human heath 0 Low Moderate High Evidence that factor is contributing to antimicrobia resistance Diagnostics-based infection prevention ISP Infection Prevention Stewardship Program Case-audit to optimize therapy Persona antimicrobia treatment pan Successfu management of infectious probem Automatic emai aert/automatic stop order ASP Antimicrobia Stewardship Program 4 5

5 WHY IMPLEMENT ANTIMICROBIAL STEWARDSHIP IN HOSPITALS? 3 Defining antimicrobia stewardship Antimicrobia stewardship (AMS) is a key strategy to overcome resistance. It invoves the carefu and responsibe management of antimicrobia use. Two definitions hep to understand the objectives of AMS Adapted from Nathwani D et a Hosp Epidemio Infect Contro * a systems eve Antimicrobia stewardship is an organisationa or heathcare system-wide approach to promoting and monitoring judicious use of antimicrobias to preserve their future effectiveness * an individua/team eve Antimicrobia stewardship: is an inter-professiona effort, across the continuum of care, invoves timey and optima seection, dose and duration of an antimicrobia, for the best cinica outcome for the treatment or prevention of infection, with minima toxicity to the patient, and minima impact on resistance and other ecoogica adverse events such as C. difficie. 4 Goas of antimicrobia stewardship and evidence for success The four main goas of antimicrobia stewardship are iustrated in Figure 6 with exampes of evidence that stewardship programs can hep achieve these goas. The importance of additiona baancing measures or measurement of unintended consequences is aso emphasized [Toma et a., 2017]. Figure 6: The goas of antimicrobia stewardship programs for patient and pubic heath. Adapted from D. Nathwani, persona communication IMPROVE PATIENT OUTCOMES OPTIMIZE PATIENT SAFETY Goa 1: Improve patient outcomes Improve infection cure rates Reduce surgica infection rates Reduce mortaity and morbidity REDUCE RESISTANCE CONTROL HEALTHCARE COSTS The prevention of surgica site infections (SSIs) remains one of the most accessibe and doabe areas of antimicrobia stewardship programs (ASPs) usuay in combination with infection prevention measures. The effect of ASPs on reducing surgica site infections can be dramatic and of high impact, making SSIs a very visibe quick win that can encourage buy-in into stewardship programs (Figure 7). AMS can aso simpy be put as achieving: The right antibiotic for the right patient, at the right time, with the right dose, the right route and cause the east harm to the patient and future patients. www/cdc.gov/getsmart/heathcare/inpatient-stewardship Figure 7: Impact of ASP on surgica site infection rates Adapted from Frenette C et a. Am J Inf Contro. 2016;44: Number of Infections # OF INFECTIONS # OF PROCEDURES INFECTION RATE % % % % % % % % % Infection Rate % 6 7

6 WHY IMPLEMENT ANTIMICROBIAL STEWARDSHIP IN HOSPITALS? Goa 2: Optimize patient safety (Minimize unintended consequences of antimicrobias) Studies have shown that ASPs can effectivey reduce antibiotic utiization, cost of care and even antimicrobia resistance rates, without increasing mortaity. However, ASPs shoud avoid the perception that the goa of the program is primariy to reduce antibiotic purchases and costs, instead of focusing on improving the quaity of care. To address the patient safety concern, data showing no adverse impact on morbidity or mortaity is important for reassurance and engagement (Figure 8). Figure 8: Types of ASP interventions that may impact morbidity and mortaity Adapted from Liew YX et a. Int. J. Antimicrob. Agents 2012;40:55-60 n Reduce duration of hospita stay, without increasing mortaity or infectionreated readmissions (Figure 8). This Singapore-based study showed that in patients whose physicians accepted suggested ASP interventions, there was: shorter average ength of stay (mean 19.4 days vs days), significanty shorter hospita stay between ASP intervention and discharge (mean 10.2 days vs 16.6 days), significant reduction in 14-day re-infection rates between accepted (0%) and rejected (10%) groups, no difference in a-cause mortaity (P = 0.191). n Reduce C.difficie coonization or infection by controing the use of high-risk antibiotics (Figure 9). Intervention De-escaation based on cuture resuts Mortaity rates Figure 9: Exampe of a robust stewardship program with strict impementation of infection contro measures eading to sustained reduction in C. difficie infection (CDI) cases during an epidemic. Adapted from Vaiquette L et a. Cin. Infect. Dis.2007;45:S Discontinue antibiotic Narrowing of empirica coverage Intravenousto-ora switch Tota Incidence of CDAD/1000 patients-days Impementation of infection contro measures Abx optimization intervention CDI Targeted antibiotics jan Apr Apr 2004 Four-week period 1 Apr Apr Patient-days of antibiotic use/1000 patient-days Intervention accepted Intervention rejected Patients who died (%) A more recent exampe in Scotand showed a reduction in C. difficie infection (CDI) appicabe at a nationa eve foowing restriction of high risk antibiotics that incuded cephaosporins, co-amoxicav, quinoones and cindamycin [Lawes et a, 2017]. This iustrates the potentia for massive impact of stewardship programs at nation-wide eves. 8 9

7 WHY IMPLEMENT ANTIMICROBIAL STEWARDSHIP IN HOSPITALS? Goa 3: Reduce resistance Restricting reevant agents can reduce coonization or infection with Gram-positive or Gram-negative resistant bacteria (Figure 10). Numerous other exampes of the effect of ASPs on muti-drug resistant Gram-negative bacteria are given in this meta-anaysis [Baur et a., 2917] Figure 10: Effect of ASPs on the incidence of MDR GNB Adapted from Baur D et a. Lancet Infect Dis. 2017;17: / Systematic review and meta-anaysis (Refer to source artice for fu references of reviewed artices) MDR Pa Apisarnthanarak et a. Am J Infect Contro 2014 XDR Ab Apisarnthanarak et a. Am J Infect Contro 2014 Carbapenem-resistant Pa Cook et a. Int J Antimicrob Agents 2015 Carbapenem-resistant Pa Yeo et a. Eur J Cin Microbio Infect Dis 2012 Meropenem-resistant Pa Arda et a. J Infect 2007 Imipenem-resistant Kp Marra et a. Am J Infect Contro 2009 Imipenem-resistant Pa Meyer et a. Infection 2010 Carbapenem-resistant Ab Yeo et a. Eur J Cin Microbio Infect Dis 2012 Overa I 2 =76 2%, p= ,5 1,0 1,5 2,0 Antibiotic stewardship program effective ABBREVIATIONS GNB: Gram-negative bacteria - MDR: Mutidrug-resistant - XDR: Extremey drug-resistant Ab: Acinetobacter baumannii - Kp: Kebsiea pneumoniae - Pa: Pseudomonas aeruginosa Antibiotic stewardship program not effective Goa 4: Contro heathcare costs (without adversey impacting quaity of care) Antibiotic resistant infections are associated with high costs (Figure 11). Figure 11: The costs of antibiotic resistant infections (ARI) Adapted from Roberts RR et a. Cin Infect Dis. 2009;49: Medica costs attributabe to ARI Excess LOS * Attributabe mortaity 6.5% Excess LOS * LOS: ength of stay Figures 12a and 12b are exampes of how stewardship programs in hospitas can deiver significant costs savings through improved antimicrobia prescribing practices. Figure 12a: Changes in antibiotic prescribing rates Adapted from Bao L et a. PLoS ONE 2015;10:e Antibiotic Prescribing Rates (%) Figure 12b: Changes in outpatients costs Adapted from Bao L et a. PLoS ONE 2015;10:e Outpatients costs ($) Preparation Preparation 2011 $18,588 - $29,069/patient (188 patients studied) days $10,7 - $ 15 biion/year Intervention Intervention 2012 INPATIENTS Assessment 2013 Assessment OUTPATIENTS 2014 ME: medication AN: antibiotics VR: very-restricted antibiotics Time Time 10 11

8 WHY IMPLEMENT ANTIMICROBIAL STEWARDSHIP IN HOSPITALS? 5 Impementation of Antimicrobia Stewardship Programs A goba survey has outined the avaiabiity of stewardship programs across the continents (Figure 13). Figure 13: Summary of AMS standards and programs Adapted from Howard P et a. J Antimicrobia Chemother. 2015; 70: Africa Asia Europe North America Oceania South and Centra America (%) Country AMS standards Country AMS standards in preparation Regiona AMS standards Hospita AMS standards AMS program in pace AMS program in panning This remains a unique goba survey, athough more recent continenta data is emerging showing that in Africa, for exampe, nurses are a key part of hospita stewardship programs (Figure 14) [Buabua et a. 2018]. Figure 14: AMS tasks undertaken by nurses Adapted from Buabua ANH et a. J Antimicrobia Chemother 2018;73: Ensure that adequate doses of antimicrobias are given according to patient characteristics Remind the treating prescriber to review the need for antimicrobias on day 3 and 7 Ensure adequate and prompt timing of antimicrobia administration in criticay i patients ( hang time ) Remind the treating prescriber to review the antimicrobia daiy once the specimen resut is known Ensure that the correct dose of antimicrobias is administered at the right time Ensure the suitabe impementation of protocos for antimicrobia treatments Teach about appropriate use of antimicrobias Teach about infection prevention and contro (%) A recent systematic review of antimicrobia stewardship programs in Asia iustrates emerging experience of their impact on a range of outcomes [Lee et a. 2018]. This meta-anaysis, which reviewed 77 studies, showed that among those studies: n 91% reported reduced antibiotic usage, n 100% reported cost savings, n duration of antibiotic therapy was reduced in 6 of 7 studies, n rates of a-cause mortaity and HAI were not significanty different between the intervention and contro groups, n mortaity rates were significanty improved by ASPs using drug monitoring, n HAI rates were aso improved by ASPs that incuded infection contro or hand hygiene programs

9 2 HOW TO IMPLEMENT AN ANTIMICROBIAL? Antimicrobia stewardship (AMS) strategies can use different methods or techniques to support the adoption, impementation, and sustainabiity of a cinica program or practice. The strategies incude top down/bottom up, push/pu, and carrot/stick tactics, and typicay invove package approaches. They aso incude methods for provider training and decision support; intervention-specific too kits, checkists, and agorithms; forma practice protocos and guideines; earning coaboratives, business strategies and organizationa interventions (such as pan-do-study-act cyces) and economic, fisca, and reguatory methods. Athough strategies depend on oca needs and issues, and avaiabe expertise and other resources, there are a number of core eements that make up the basis of a good stewardship program. In 2014, the CDC reeased The Core Eements of Hospita Antibiotic Stewardship Programs [ pdfs/core-eements.pdf] that identifies key structura and functiona aspects of effective programs. In 2018, these core eements were adapted for a goba audience and suppemented by a check ist descri bing essentia and minimum standards for AMS programs in hospitas wordwide (Figure 15). Figure 15: Core eements and checkist items for goba hospita AMS programs Adapted from Pucini C et a., Cin Microbio Infect. 2019;25:20-25 CORE ELEMENT 1 Senior hospita management eadership towards antimicrobia stewardship This section reates to governance of the programme by hospita executives, and specifies how senior hospita management supports the antimicrobia stewardship programme CORE ELEMENT 2 Accountabiity and responsibiities CORE ELEMENT 3 Avaiabe expertise on infection management CORE ELEMENT 4 Education and practica training CORE ELEMENT 5 Other actions aiming at responsibe antimicrobia use CORE ELEMENT 6 Monitoring and surveiance (on a continuous basis) Does your hospita monitor the quaity of antimicrobia use at the unit and/or hospita wide eve? This can be done for exampe by undertaking point prevaence surveys or audits, assessing appropriateness of infection management and antimicrobia prescription (e.g. indication, choice and duration of antibiotic therapy in pneumonia or surgica prophyaxis according to poicy/guidance) CORE ELEMENT 7 Reporting and feedback (on a continuous basis) A these reports shoud aso be shared with the hospita management eadership Once these core eements have been identified, an 8-step process of impementation described overeaf is one pragmatic way of impementing the stewardship program. A program devised for hospitas within the Netherands is aso worthy of review [ 11/SWABguideine ABShospitas.pdf]

10 EIGHT KEY STEPS for impementing an Antimicrobia Stewardship Program (ASP) Assess the motivations Ensure accountabiity and eadership Set up structure and organization Define priorities and how to measure progress and success Identify effective interventions for your setting Identify key measurements for improvement Educate and Train 8 Communicate 1 Assess the motivations Anayze your situation and what probems you want to address. There are many internationa guideines avaiabe, but you wi need to adapt them to your oca situation. Define where you are and where you want to go, with quantitative figures. One of the ways of obtaining these data is to measure the quantity and quaity of antibiotic use, for exampe, using a Point Prevaence Survey, such as the Goba-PPS (see Section 6.1.1). What can be impemented wi depend on oca needs/issues, geography, avaiabe skis/expertise and other resources. For exampe, easier or ess costy approaches can incude: simpe cinica agorithms, prescribing guidance for treatment, surgica prophyaxis, IV to ora conversion, provision of microbioogica support, restricting avaiabiity of certain antibiotics (formuary restriction), automatic therapeutic substitution, IV antimicrobia batching, promoting education. [Goff et a., 2012] 2 Ensure accountabiity and eadership To ensure a successfu Antimicrobia Stewardship Program: the program shoud be supported by the senior hospita management, who are accountabe for the outcomes, a team of peope and resources shoud be aocated by the head of the organization to impement and evauate the program, the ASP team members must possess power, expertise, credibiity and eadership. These individuas need to convince managers and heathcare staff of the added vaue of the program. A key component of a stewardship program is eadership and cuture. This can be set out as a driver diagram (see Tabe 1 on page 18 for more detais)

11 Tabe 1: Driver Diagram - Overarching Driver: Leadership and Cuture Adapted from: SECONDARY DRIVER Promote a cuture of optima antibiotic use within the faciity KEY CHANGE CONCEPTS Engage administrative and cinica eadership to champion stewardship effort SPECIFIC CHANGE IDEAS 1. Identify cinica providers as champions to be thought eaders about antibiotic stewardship. 2. Work with administrators to ensure that they understand the rationae and goas for stewardship programs and interventions and provide support (financia and non-financia). 3. Engage a physician champion and core team to enhance the focus of antimicrobia stewardship into the current process of care. 4. Bring discipines together to improve communication and coaboration about improving antibiotic use, incuding: - Infection preventionists; - Hospitaists; - Intensivists; - Emergency department physicians; - Microbioogists; - Pharmacists; - Nurses; and - Infectious disease experts. 5. Consider having the mutidiscipinary group perform a gap anaysis of antimicrobia use at the faciity to identify priority areas for improvement. 3 Set up structure and organization The key components of the structure and governance of the ASP are: Dedicated resources, incuding dedicated personne time for stewardship activities, education, and measuring/monitoring antimicrobia use. A mutidiscipinary AS team with core membership of: an infectious diseases physician (or ead doctor or physician champion), a cinica microbioogist, a cinica pharmacist with expertise in infection. Other members coud be speciaist nurses, for exampe infection prevention or stewardship nurses, quaity improvement /risk management/patient safety managers and cinicians with an interest in infection. Governance within the hospita s quaity improvement and patient safety governance structure Cear ines of accountabiity between the chief executive, cinica governance, drug and therapeutics committee, and infection prevention and contro committees, and the AST. Figure 16 iustrates such an organization structure. This structure woud need to be adapted to oca context and avaiabe resources. Figure 16: Mode of Antimicrobia Prescribing Pathway and Organization in Acute Hospitas in Scotand Adapted from Nathwani D. J Antimicrob. Chemother. 2006; 57: Medica Director Chief Executive Infection Contro Manager Drugs and Therapeutics Committee Antimicrobia Stewardship Team Risk Management or Patient Safety Committee Cinica Governance Committee Speciaty-based Antimicrobia Pharmacist with responsibiity for antimicrobia prescribing Dissemination/feedback Infection prevention and contro Committee Ward Based cinica pharmacists Prescribing support/feedback Microbioogist/ Infectious Diseases Physician/cinician PRESCRIBER 18 19

12 4 Define priorities and how to measure progress and success Figure 17: Exampe of a Driver Diagram for Antimicrobia Stewardship Adapted from TIMELY AND APPROPRIATE ANTIBIOTIC UTILIZATION IN THE ACUTE CARE SETTING Decreased incidence of antibiotic-reated adverse drug events (ADEs) Decreased prevaence of antibiotic resistant heathcare-associated pathogens Decreased incidence of heathcare-associated C. difficie infection Decreased pharmacy cost for antibiotics The objectives of the ASP and how they are going to be achieved and measured need to be agreed by a the key stakehoders and communicated ceary. One way of doing this is to produce a Driver Diagram (see Figure 17 as an exampe). A Driver Diagram is a ogic chart with three or more eves, incuding: a goa or vision, the high-eve factors needed to achieve this goa (caed primary drivers ), specific projects and activities that woud act upon these factors. For more compex goas, each primary driver coud have its own set of secondary drivers (or ower eve drivers). Driver diagrams can hep an ASP team to: expore the factors that need to be addressed to achieve a specific overa goa, show how the factors are connected, act as a communication too for expaining a change strategy, provide the basis for a measurement framework. GOAL PRIMARY DRIVERS Timey and appropriate initiation of antibiotics Appropriate administration and de-escaation Data monitoring, transparency and stewardship infrastructure Avaiabiity of expertise at the point of care SECONDARY DRIVERS Prompty identify patients who require antibiotics Obtain cutures prior to starting antibiotics Do not give antibiotics with overapping activity or combinations not supported by evidence or guideines Determine and verify antibiotic aergies and taior therapy accordingy Consider oca antibiotic susceptibiity patterns in seecting therapy Start treatment prompty Specify expected duration of therapy based on evidence and nationa and hospita guideines Make antibiotics patient is receiving and start dates visibe at point of care Give antibiotics at the right dose and interva Stop or de-escaate therapy prompty based on the cuture and sensitivity resuts Reconcie and adjust antibiotics at a transitions and changes in patient s condition Monitor for toxicity reiaby and adjust agent and dose prompty Monitor, feedback, and make visibe data regarding antibiotic utiization, antibiotic resistance, ADEs, C. difficie, cost, and adherence to the organization s recommended cuturing and prescribing practices Deveop and make avaiabe expertise in antibiotic use Ensure expertise is avaiabe at the point of care 5 Identify effective interventions for your setting A range of stewardship interventions has been reviewed in the IDSA guideines [Baram et a.2016]. When estabishing a new stewardship program, it is best to start with the core strategies and focus on achieving and maintaining them before adding some of the suppementa strategies (Tabe 2). Tabe 2: Antimicrobia Stewardship Tookit: Quaity of Evidence to support interventions Adapted from Deit TH et a. Cinica Infectious Diseases 2007; 44:159-77; Baram TF et a. Cinica Infectious Diseases 2016; 62:51-77 CORE STRATEGIES Formuary restrictions and preauthorization * *Strategies with strongest evidence and support by IDSA Two core ASP strategies have evoved (Figure 18): SUPPLEMENTAL STRATEGIES Streamining / timey de-escaation of therapy * Prospective audit with intervention and feedback * Dose optimisation * Mutidiscipinary stewardship team * Parentera to ora conversion * FRONT END STRATEGIES BACK-END STRATEGIES Guideines and cinica pathways * Antimicrobia order forms Education Computerized decision support, surveiance Laboratory surveiance and feedback Combination therapies Antimicrobia cycing Antimicrobias made avaiabe through an approva process (formuary restrictions and preauthorization) Antimicrobias reviewed after antimicrobia therapy has been initiated (prospective audit with intervention and feedback) 20 21

13 Figure 18: Front- and Back-end Antimicrobia Stewardship Strategies Adapted from Chung GW et a. Viruence 2013;4: FRONT-END STRATEGY PREAUTHORIZATION AND RESTRICTION Antibiotic prescription (by primary team) First few doses permitted for seected antibiotics Institution restriction criteria for seected antibiotics Antibiotic prescription (by primary team) Antimicrobia stewardship team or infectious diseases physician Approva BACK-END STRATEGY PROSPECTIVE AUDIT AND FEEDBACK Day1: review dose and possibiity of IV-to-ora switch Day 4: review appropriateness considering microbioogica cuture resuts Day 7: review duration of therapy Intervention to optimize antibiotic treatment Continues uness intervened by ASP Figure 19: Advantages and Disadvantages of Pre-Authorization and Prospective Audit and Feedback Adapted from Deit TH et a. Cin Infect Dis. 2007;44:159 77; Baram TF et a. Cin Infect Dis. 2016;62:51-77 PRE-AUTHORIZATION Prevents unnecessary/ inappropriate initiation of antibiotics Ensures optima empirica therapy Prompts review of cinica parameters, patient history and prior cutures before initiating antimicrobia therapy PROSPECTIVE AUDIT AND FEEDBACK EXAMPLES OF ADVANTAGES Increases visibiity of ASP and heps to form professiona reationships Maintains autonomy of prescribers Frequency can be taiored based on resources avaiabe to the ASP EXAMPLES OF DISADVANTAGES Has itte effect post empirica therapy Compiance vountary Loss of prescriber autonomy May deay initiation of therapy Labour intensive Success is dependent on how feedback is communicated to prescribers Figure 20: Antimicrobia Stewardship Treatment Agorithm Adapted from Start Smart Then Focus Guidance for Antimicrobia Stewardship in hospitas (PHE, UK) ANTIMICROBIAL STEWARDSHIP Right drug, right dose, right time, right duration every patient PATIENT Some of the advantages and disadvantages of these two strategies are given in Figure 19. Athough more abour-intensive, back-end strategies are: more widey practiced, more easiy accepted by cinicians as they refect the daiy decision-making process, provide a higher opportunity for educationa opportunities, utimatey provide a more sustained impact of improving the overa quaity of antimicrobia prescribing. [Chung et a., 2013]. In the UK, this approach has been innovativey adapted to create a simpe pragmatic approach that is aigned with the cinica teams daiy decision-making process (Figure 20). Start Smart Then focus Do not start antibiotics in the absence of cinica evidence of bacteria infection Take history of reevant aergies Initiate prompt effective antibiotic treatment within one hour of diagnosis (or as soon as possibe) in patients with ife threatening infections Compy with oca prescribing guidance Document cinica indication and dose on drug chart and cinica notes Incude review/stop date or duration Ensure reevant microbioogica specimens taken Cinica review & decision * at 48-72h 1. STOP Cinica review check microbioogy, make and document decision * 2. IV/ORAL SWITCH 3. CHANGE: to narrow spectrum agent DOCUMENT DECISION * Antimicrobia Prescribing Decision ** Outpatient Parentera Therapy 4. CONTINUE AND REVIEW after 4 hours 5. OPAT ** 22 23

14 5.1 Front-end strategies Antimicrobia Prescribing Poicy Hospita ASPs shoud incude an Antimicrobia Prescribing Poicy that is reguary reviewed and updated. The important messages that need to be incorporated into the poicy (MINDME) from Austraian Stewardship Guideines [Duguid et a., 2010] are iustrated in Tabe 3. Tabe 3: The Goden Rues of Antimicrobia Prescribing MINDME Adapted from Antibiotic Expert Group. Therapeutic guideines: antibiotic. Version 14. Mebourne: Therapeutic Guideines Limited; 2010 M I N D M E microbioogy guides therapy wherever possibe indications shoud be evidence based narrowest spectrum required dosage appropriate to the site and type of infection minimise duration of therapy ensure monotherapy in most cases Cinica guideines or care pathways Cinica guideines or care pathways shoud take into account oca microbioogy and antimicrobia susceptibiity patterns, as we as oca resources and priorities, cinician preference/views and potentia risk or unintended consequences. For guideines to be reevant to daiy practice, it is important they are updated on a reguar basis and that oder or outdated recommendations are removed. The pubication of nationa guideines for South Africa and India for the antimicrobia treatment of infectious disease are recent exampes of good practice. Furthermore, India has just pubished specific guideines for Antimicrobia Stewardship Programs [ICMR, 2018]. 5.2 Back-end strategies Antimicrobia review methods Antimicrobia review methods are empoyed post-prescription and outined in Tabe 4. The most appropriate interventions for your institution shoud be chosen, according to oca resources. Tabe 4: Antimicrobia Review Methods Adapted from Johannsson B et a. Inf. Contro Hosp. Epidemio. 2011;32: TYPE OF INTERVENTION COMMONLY USED Review of indication for antibiotic and compiance with poicy/guideine/formuary; note any recording of exception Review of appropriateness of antibiotic choice, dose, route and panned duration; review of drug aergy, review of agents that may provide dupicative therapy (potentia overapping spectra) Review of directed therapy based on cuture and susceptibiity test resuts Potentia for conversion from IV to ora route Review requirement for therapeutic drug monitoring Review any antibiotic reated adverse events LESS COMMONLY USED AND DEPENDENT ON LOCAL RESOURCES Unsoicited review of specific resistant pathogens (e.g MRSA) or site of infection (e.g bood stream infections) Specific review of high cost/high use/nove agents Review of optima dose (PK/PD) in reation to dose and frequency; rena adjustment, need for extended infusion, review of any potentia drug interactions Review of directed therapy based on microscopy or PCR or other rapid tests ** Review of empiric or directed therapy based on biomarkers ** **The ack of diagnosis and deay in microbioogy remains a significant hurde to good stewardship and source of high cost Formuary restrictions / approva systems This invoves determining the ist of restricted antimicrobia agents (broad spectrum and ater generation antimicrobias) and criteria for their use combined with an approva system which is subject to reguar audit and feedback to the prescribers. It is essentia that a aspects of prescribing are supported by expert advice 24 hours a day where possibe

15 Audit and direct feedback to prescribers The audit and feedback process can be managed by either the medica infection speciaist or speciaist pharmacist. However, depending on the intervention, speciaist nurses or cinica pharmacists can aso be trained to support this process. During cinica review, a range of point-of-care stewardship interventions are usefu to provide direct and timey feedback to the prescriber at the time of prescription or aboratory diagnosis, and provide an opportunity to educate cinica staff on appropriate prescribing. POINT-OF-CARE INTERVENTIONS CAN INCLUDE: * appropriate use of guidance, * indication for antibiotic, * choice of agent, * route [IV vs. ora] of administration of treatment, * timeiness of treatment, * ikeihood of on-going infection or not, * use of diagnostic tests for investigation, * interpretation of microbioogy with a view to de-escaation * duration of therapy. The types of interventions seected, how they are deivered and by whom, wi be determined by oca resources, need and avaiabe expertise. Feedback on antimicrobia prescribing shoud be provided reguary to prescribers in the critica care setting, and areas of high and/or poor quaity antimicrobia use. One way of evauating prescribing within a unit or hospita is through reguar point prevaence surveys (PPS) [Ansari et a., 2009, Seaton et a., 2007]. These data can be used in an audit process to provide structured feedback to prescribing teams and to define areas for improvement. Such point prevaence surveys can be used to estabish baseine prescribing information and identify priorities for quaity improvement. See section for more detais on Point Prevaence Surveys. 5.3 Roe of Diagnostics in Stewardship Diagnostic stewardship refers to the appropriate use of aboratory testing to guide patient management, incuding treatment, in order to optimize cinica outcomes and imit the spread of antimicrobia resistance. This requires a seamess partnership between cinica aboratories, pharmacists, and infectious diseases cinicians, so that appropriate tests are ordered and diagnostic information is transated into appropriate management in rea time. Figure 21: Exampe of diagnostic and antimicrobia stewardship in the impementation of rapid moecuar disease diagnostics. Adapted from Messacar et a. J. Cin. Microbio. 2017;55: Cinica evauation DIAGNOSTIC STEWARDSHIP n Right test n Right patient n Right time Rapid diagnostic test ordered PATIENT Heath Care Provider Rapid diagnostic test performed MICROBIOLOGY LABORATORY Laboratories pay a key roe in antimicrobia stewardship (Figure 21). However, they are often not used optimay or, in many parts of the word, they do not exist or have poor capacity and capabiity to dea with the probem. An exampe of an antimicrobia stewardship program for the microbioogy aboratory and how it coud be achieved is described in Figure 22. Figure 22: Exampes of essentia, achievabe, and aspirationa antimicrobia stewardship activities for the microbioogy aboratory Adapted from Morency-Potvin et a. Cin Microbio Rev 30: ESSENTIAL n Coaborate in educating oca heathcare workers on microbioogy issues that impact treatment and AMR n Optimize communication of critica resuts and aert systems n Provide annua Cumuative Antimicrobia Susceptibiity Report ACHIEVABLE n Provide comments, in coaboration with ASP team, to guide therapy on microbioogy reports n Use rapid diagnostics, mutipex PCR and AST * for targeted critica specimen types and respiratory pathogens n Coaborate in audit and feedback of antimicrobia therapies when ab tests are critica (eg: C.difficie, boodstream infections) Diagnosis & treatment ANTIMICROBIAL STEWARDSHIP n Right interpretation n Right antimicrobia n Right time ASPIRATIONAL Rapid diagnostic resut reported n Participate in nationa/ regiona surveiance systems n Promote appropriate use of point-of-care microbioogica tests * AST: Antimicrobia Susceptibiity Testing 26 27

16 The O Nei report on AMR highights the critica importance of the aboratory in reducing antimicrobia resistance and supporting prudent prescribing, as we as the roe of new diagnostics and point-of-care tests [O Nei et a. 2015]. The roe that rapid diagnostic tests can pay in optimizing the prescription of the most appropriate antibiotic therapy is iustrated in Figure 23. Figure 23: How rapid diagnostic tests hep optimize treatment Adapted from O Nei et a. The Review On Antimicrobia Resistance 2015 DOCTOR SICK PATIENT Integration of diagnostics with other AS interventions, to provide fast accurate identification and susceptibiity testing, wi achieve better cinica outcomes and timey streamining/de-escaating of empiric broad-spectrum antibiotics in seriousy i patients. Many studies have assessed agorithms based on procacitonin (PCT) as a rapid-reacting biomarker of bacteria infection for antibiotic stewardship. Recent systematic reviews showed benefits of PCT among patients with respiratory tract infection and sepsis by significanty reducing antibiotic exposure as we as a trend towards reduced costs and reduced ength of ICU stay [Schuetz et a., 2011, Agarwa et a., 2011, Heyand et a., 2011, Mann et a., 2011, Matthaiou et a., 2012]. Near-patient rapid tests, e.g. infuenza, Strep A, can be usefu to identify patients with bacteria versus vira infections. Moecuar diagnostics or screening tests providing a faster resut pay an important roe in pathogen detection in criticay i patients which wi improve antibiotic stewardship and cinica outcomes [Afshari et a., 2012]. Empirica diagnosis Traditiona diagnostic test Rapid diagnostic test Figure 25: Roe of diagnostics in supporting ASPs and appropriate antibiotic therapy Treatment may fai: second empirica prescription Optima treatment reached quicky Adapted from biomerieux Communication Initia antibiotic therapy Targeted therapy Personaized therapy Monitoring therapy Optima treatment may never be achieved Optima treatment deayed The case study in Figure 24 iustrates the rea word impact of a rapid respiratory pane (RP) on antibiotic and resource use. Empiric Consoidated AST data t Oriented Rapid tests (IA / moecuar) Biomarkers t ID & AST t MICs TDM t t t Biomarkers Figure 24: Effect of rapid diagnostics on duration of antimicrobia therapy (ABX) and hospita ength of stay (LOS) Adapted from Fie et a. Open Forum Infect Dis. 2017;4(Supp 1): S628 S629 RP resut for virus Mean Duration ABX after test resut LOS after test resut Virus + (n=30) 1.6 days 3.6 days Virus - (n=51) 4 days 4.9 days Virus +; PCT<0.25 (n=17) 1.2 days 2.9 days Virus +; PCT<0.25; AST* (n=10) 0.6 days 2.7 days * Antimicrobia Stewardship Team recommendation. There was no difference in 30-day readmission rates. Of the patients with pneumonia; 11 had + RP for virus (7-HMV), 4 had co-infection with + bacteria with mean PCT of 0.62 and mean duration of ABX 6 days after test resut; of the 7 with no bacteria co-infection the mean PCT was 0.12 with mean duration of ABX 0.28 days after the test resut. RP: Respiratory Pane Risk factors of MDRO s From broad spectrum empiric therapy to targeted/ personaized therapy ABBREVIATIONS AST: Antimicrobia Susceptibiity Testing - IA: Immuno Assay - ID: Identification - MDRO: Muti Drug Resistant Organism - MIC: Minimum Inhibitory Concentration - TDM: Therapeutic Drug Monitoring Diagnostic tests are key components of Antimicrobia Stewardship Programs, enabing the adjustment of treatment from broad spectrum antibiotic therapy to targeted and personaized treatments (Figure 25)

17 6 Identify key measurements for improvement If you cannot measure it, you cannot improve it Lord Kevin Measurement of prescribing performance is essentia to evauate the impact of stewardship interventions on cinica practice and demonstrate benefits for patients. Estabishing what to measure, the frequency of measurement and how the data wi be communicated and acted upon are aso key. In addition to the audit and feedback described in section 5.2.2, three other types of measurement are commony used within stewardship programs: surveiance of antimicrobia use and resistance, data coection for quaity improvement, anaysis of hospita datasets to evauate positive and negative consequences of interventions. 6.1 Surveiance of antimicrobia use and resistance Monitoring trends in antimicrobia use and resistance within a hospita over severa years and aso identifying sma changes in a singe ward over a one-month period are essentia to: adapt empiric treatment according to oca resistance trends, demonstrate changes in practice over time, identify wards with high antimicrobia usage or use of non-poicy antimicrobias and define targeted interventions required. Measure improvement after impemented interventions Surveiance of antimicrobia use and resistance is important: at hospita, oca, regiona, nationa eves (i.e.: Strama [ Waes [Heginbothom M and Howe R, 2012], Austraia [ INFECTIONCONTROL]), at goba eve (i.e.: ECDC: consoidation of resistance data at the European eve [EARSS.net] with consoidation of antibiotic use [ESAC.net]), CDC Nationa Antimicrobia Resistance Monitoring System [cdc.gov/narms] or Goba PPS [ Prescription surveiance through Point Prevaence Surveys Reguar point prevaence surveys (PPS) can be used to evauate prescribing within a unit or hospita [Ansari et a., 2009, Seaton et a., 2007]. A new e-earning modue is aso now avaiabe to provide training for those undertaking these surveys [ These data can be used in an audit process to provide structured feedback to prescribing teams and to define areas for improvement. At a nationa eve, as iustrated in an exampe for Scotand (Tabe 5), such point prevaence surveys can be used to estabish baseine prescribing information and identify priorities for quaity improvement. This information has ed to the deveopment of nationa prescribing indicators [Macom et a., 2012]. Tabe 5: Overview of prescribing from baseine PPS (May 2009) and foow up PPS (September 2011) in acute hospitas in Scotand Adapted from Macom W et a. Antimicrob. Resist. Infect. Contro 2012;2:3 Measure Number of patients surveyed Number of patients (%) prescribed antimicrobias Number of patients (%) prescribed singe antimicrobia Number of prescriptions (%) for parentera antimicrobias Number of prescriptions (%) with indication recorded in notes Number of prescriptions (%) compiant with oca poicy Number of surgica prophyaxis prescriptions (%) with duration singe dose Number of surgica prophyaxis prescriptions (%) with duration = 1 day Number of surgica prophyaxis prescriptions (%) with duration >1 day Baseine PPS (May 2009) 7,573 2,289 (30.2%) 1,432 (62.6%) 1,731 (51.8%) 2,538 (75.9%) 1939 (81.0%) 146 (49.3%) 57 (19.3%) 93 (31.4%) Foow up PPS (Sept 2011) 11,604 3,728 (32.3%) 2,268 (60.8%) 2,147 (47.8%) 3,811 (86.8%) 2,245 (82.8%) 287 (59.5%) 81 (16.8%) 114 (23.7%) 30 31

18 The vaue of these metrics has recenty been iustrated at a goba eve. The GLOBAL PPS mentioned previousy (see Figure 3) can provide not ony metrics in reation to the prescribing quaity process, but the abiity to compare variations in practice between casses of agents. For exampe, in Figure 26, the quaity of antibacteria and antifunga prescribing is compared, the atter being an important and rapidy emerging area for stewardship. Figure 26: Goba-PPS: Difference in quaity of prescribing between antibacterias and antifungas Adapted from Yusuf E et a. J Antimicrob Chemother. 2017;72: Reason for prescribing mentioned in patient notes Prescription according to oca guideines Stop/review dates in note Antibiotics Ora administration Antifungas How is antimicrobia use data coected and anayzed? Antimicrobia use at individua patient eve, using an eectronic prescribing system through the Hospita Information System. Data from hospita pharmacy computer systems, showing antimicrobias deivered to each ward and used as a proxy measure for antimicrobias administered to patients. The measure used is Defined Daiy Dose (DDD) which represents the average daiy maintenance dose of an antimicrobia for its main indication in aduts (Figure 27). For instance, the DDD of ora amoxiciin is 1000 mg, so a patient receiving 500 mg every 8 hours for 5 days consumes 7.5 DDDs. Usage data may then be divided by a measure of hospita activity such as number of admissions or in-patient bed days to provide more meaningfu trend anaysis. In-patient bed days is more commony used as this data can usuay be obtained earier than admissions data. Other denominators are aso used and their strengths and imitations have been described [Monnet D et a., 2007; Berrington A, et a., 2010] Hospita eve data may be transferred to a nationa database for further anaysis (%) Figure 27: Tota antibiotic consumption by key antibiotic groups, expressed as DDD per 1000 inhabitants per day, Engand, Adapted from Pubic Heath Engand. Engish Surveiance Programme for Antimicrobia Utiisation and Resistance (ESPAUR) Report 2017 DDD per 1000 inhabitants per day Other β-actam antibacterias Quinoone antibacterias Anti-Costridium difficie agents Other antibacterias Genera Practice Dentist Hospita Inpatient Hospita Outpatient Other Community ABC Cac is a simpe computer too to measure antibiotic consumption in hospitas. It transforms aggregated data provided by hospita pharmacies into meaningfu antibiotic utiisation rates. [ Pareto charts are another usefu too to provide an overview of antimicrobia usage at ward eve and identify wards that have high tota usage or high use of restricted antimicrobias How is antimicrobia resistance data coected and anayzed? Resistance data is obtained from the Microbioogy aboratory through computer systems. Hospita eve data may then be transferred to nationa databases. This is iustrated by an exampe from Engand (Figure 28). Figure 28: Number of boodstream isoates of E. coi reported to the mandatory surveiance scheme and the proportions non-susceptibe to indicated antibiotics. Adapted from Pubic Heath Engand. Engish Surveiance Programme for Antimicrobia Utiisation and Resistance (ESPAUR) Report 2017 % Non-susceptibe Year Co-amoxicav 3rd-generation cephaosporins Gentamicin Ciprofoxacin Piperaciin/tazobactam Carbapenems 45,000 40,000 35,000 30,000 25,000 20,000 15,000 10,000 5,000 0 Counts of E. coi* * based on vountary SGSS CDR ab reports 2016 No. reports 32 33

19 6.2 Data coection for quaity improvement Antimicrobia stewardship is part of many patient safety programs. To measure the performance of these programs, data is primariy used for 3 purposes [Soberg et a., 1997]: accountabiity (e.g. targets), improvement, research. A range of such measures for antimicrobia stewardship programs have been proposed. They can be summarized as four types (Tabe 6): structura, process, outcomes and baancing (are the changes causing new probems?) [ Dumartin et a., 2011]. Tabe 6: AMS program measures for quaity improvement Adapted from Dumartin C et a. J Antimicrob Chemother. 2011;66:1631-7; Morris AM et a. Inf Contro Hosp Epidemio. 2012;33: STRUCTURAL INDICATORS Avaiabiity of muti-discipinary antimicrobia stewardship team Avaiabiity of guideines for empiric treatment and surgica prophyaxis Provision of education in the ast 2 years PROCESS MEASURES Amount of antibiotic in DDD/100 bed days - Promoted antibiotics - Restricted antibiotics Compiance with acute empiric guidance (documented notes and poicy compiance) % appropriate de-escaation; % appropriate switch from IV to ora Compiance with surgica prophyaxis (<60 min from incision, <24 hours and compiance with oca poicy Compiance with care bundes a or nothing (3-day antibiotic review bunde, ventiator-associated pneumonia, community-acquired pneumonia, sepsis) OUTCOME MEASURES C. difficie infection rates Surgica Site Infection (SSI) rates Surveiance of resistance Mortaity: Standardized Mortaity Rates (SMRs) BALANCING MEASURES Mortaity SSI rates Readmission within 30 days of discharge Admission to ICU Rate of compications Treatment-reated toxicity (e.g. aminogycoside-reated toxicity) A focus on outcomes data must be the key to convincing eadership, budget hoders and decision makers of the vaue of stewardship programs. Such measures are outined in Tabe 7. Tabe 7: Exampes of different outcome measures and some genera remarks Adapted from Dik J et a. Expert Review of Anti-infective Therapy, :6, OUTCOME MEASURES CLINICAL Mortaity Length of Stay Compications Costridium difficie Readmission rates Toxicity (systemic) MICROBIOLOGICAL Resistance eves ANTIMICROBIAL CONSUMPTION Tota use IV/PO ratio Broad/narrow ratio FINANCIAL Tabe 8: Exampes of checkist items Adapted from van Daaen F et a., BMC Infect Dis. 2018;18:16 Bood cutures Cuture from suspected site of infection Guideine adherence Adapt dose to rena function REMARKS Important, but ess suitabe for mid infections (e.g. uncompicated UTI) Genera or ward-specific (e.g. ICU stay); easy to obtain, but highy sensitive to biases Eg: IV catheter-reated probems and phebitis Indirect measure for antimicrobia use Due to reapse. Aso consider effect of neighboring institutions Most frequenty in rena function and iver Difficut to measure due to generay ong time frame (months to years) Often measured in DDDs Of interest with an active IV-to-PO switch program Potentiay reevant with regard to resistance deveopment Preferaby done as cost-effectiveness study UTI: urinary tract infection; ICU: intensive care unit; PO: per os; LOS: Length of stay; DDDs: defined daiy doses; IV: intravenous. Checkists are increasingy used to measure quaity of care. A study of the use of an antibiotic checkist impemented in nine Dutch hospitas showed that use of the checkist resuted in more appropriate antibiotic use (Tabe 8). Documentation of indication Adapt therapy when cutures become avaiabe IV-ora switch 34 35

20 Exampes of measures for improvement A common quaity improvement methodoogy is the Pan- Do- Study- Act mode. What are we trying to accompish? How wi we know that a change is an improvement? What changes can we make that wi resut in improvement? Exampe of measures used for accountabiity Compiance with poicy is a process measure (Figure 30). Figure 30: Antibiotic choice compiant with poicy Adapted from Empirica Prescribing Indicator Report Apri 2011 June Scottish Antimicrobia Prescribing Group August 2012 (%) Nationa data: compiance with poicy (antibiotic choice) and overa median throughout data coection period Medica and Surgica admissions 90 Act Pan Do Apr-2011 May-2011 Jun-2011 Ju-2011 Aug-2011 Sep-2011 Oct-2011 Medica admissions Surgica admissions Nov-2011 Dec-2011 Jan-2012 Feb-2012 Medica median Surgica median Mar-2012 Apr-2012 May-2012 Target Jun-2012 Month Study Quaity improvement programs often use annotated run charts to dispay data and show the effects of changes. Figure 29 shows an exampe of a run chart used to measure improvement of administration of surgica antibiotic prophyaxis on time. Figure 29: Percent on-time administration of prophyactic antibiotics Adapted from Scottish Patient Safety Program (%) 100 goa = Changes to guidance means some times are not achievabe. Consutants have discussed this with Microbioogy and Antibiotic Pharmacy. Agreement reached. Data coection form as part of theatre checkist Not recording on sheet Working with antibiotic pharmacy Review in ine with SIGN guideines new theatres ALL 19 theatres reporting and 17 at 100% this month Month 6.3 Anaysis of hospita datasets Linkage of hospita datasets such as hospita admissions, aboratory data and patient outcomes aows measurement of the impact of stewardship interventions on patient morbidity and mortaity. This provides information about effects of antimicrobia interventions on cinica outcome. Figure 31 shows how restriction of cephaosporins and fuoroquinoones has resuted in reduced Costridium difficie rates by inking antimicrobia usage data and microbioogy data [Tapaert et a., 2011, Vernaz et a., 2009, Mamoon et a., 2012]. Figure 31: New cases of CDI and the number of OBDs before and after the introduction of revised antibiotic guideines. Adapted from Tapaert MJ et a. J Antimicrobia Chemother. 2011; 66: Cases/predicted vaues Introduction of revised antibiotic guideines Move to Riverside Buiding Apr-2005 May-2005 Jun-2005 Ju-2015 Aug-2005 Sep-2005 Oct-2005 Nov-2005 Dec-2005 Jan-2006 Feb-2006 Mar-2006 Apr-2006 May-2006 Jun-2006 Ju-2016 Aug-2006 Sep-2006 Oct-2006 Nov-2006 Dec-2006 Jan-2007 Feb-2007 Mar-2007 OBD (Occupied Bed Days) CDI Predicted vaues (negative binomia regression) 25,000 15,000 14,000 13,000 12,000 11,000 10,000 9,000 8,000 OBDs 36 37

21 7 Educate and Train Education is a key component of any Antimicrobia Stewardship Program. It shoud incude heathcare professionas from a care settings, as we as patients and the pubic. By increasing peope s knowedge and understanding of how antimicrobias shoud be used to treat common infections and why inappropriate use may ead to resistance and oss of effective treatments, we can protect this vauabe resource for future generations. 7.1 Who shoud receive education? Prescribers and other heathcare staff with modues adapted to their background incuding: undergraduate curricuum, internship, professiona training for new staff, continuing professiona deveopment for a prescribers, postgraduate education. The content of education shoud be adapted to each profession and incude: basic knowedge of infection management, basic microbioogy, importance of prudent prescribing in tacking antimicrobia resistance, best practices for prescribing to support safe and effective prescribing, administration and monitoring of antimicrobia therapy. The training is usuay deivered by the antimicrobia management team and shoud incude competency assessment. In 2014, the first nationa antimicrobia prescribing and stewardship competences were deveoped in the UK, and their impementation was an important contribution to the deivery of the UK 5 year Antimicrobia Resistance Strategy [Ashiru-Oredope et a., 2014]. The Stewardship Competency Framework for a heathcare professionas has aso been deveoped by WHO [ WHO-HIS- HWF-AMR /en/] and advocates the principes shown in Tabe 9 [Ashiru-Oredope et a., 2014]. Tabe 9: The Stewardship Competency Framework Adapted from Ashiru-Oredope D et a. J Antimicrob Chemother 2014; 69: This consists of five dimensions, each of which incudes statements that describe the activity and outcomes that prescribers shoud be abe to demonstrate: Infection prevention and contro Antimicrobia resistance and antimicrobias The prescribing of antimicrobias Antimicrobia stewardship Monitoring and earning Educating patients and the genera pubic about hygiene and antibiotic use is aso important, and may indirecty support hospita education efforts. Nationa and regiona pubic heath campaigns, incuding education aimed at parents and chidren, have had a variabe eve of success [Huttner et a., 2010]. Some exampes of pubic awareness campaigns: How to design an education program? Programs shoud take into account oca recommendations for antimicrobia stewardship, if avaiabe. If not, they coud be inspired by internationa poicies (see section on Additiona Resources, page 48) but adapted as required. Tabe 10 shows educationa measures to improve antibiotic use in hospitas. Tabe 10: Main antimicrobia stewardship strategies recommended to improve antibiotic use at the hospita eve Adapted from Pucini C and Gyssens IC. Viruence 2013;4: PASSIVE EDUCATIONAL MEASURES Deveoping/updating oca antibiotic guideines, cinica pathways or agorithms Face to face educationa sessions, workshops, oca conferences ACTIVE INTERVENTIONS Cinica rounds discussing cinica cases, morbidity & mortaity meetings, significant event anaysis/reviews Prospective audit with intervention and feedback Reassessment of antibiotic prescriptions, with streamining and de-escaation Academic detaiing, educationa outreach visits E-earning resources used as individua or group activities can compiment traditiona earning methods, as a bended earning approach (see page 49). An evauation process shoud be incuded in the education program to measure attendance, understanding and assimiation, using reguar training assessment toos such as attendance forms, competion certificates, questionnaires, tests etc

22 8 Communicate Communication is a key component of the success of an ASP. Another key communication too that improves the effectiveness of conveying key messages is data visuaization. Using infographic or other visua aids can be a compeing means of communicating data (Figure 33). DDD per 100 admissions Figure 33: Exampes of infographics on Antibiotic Use R Cear, simpe communication shoud show the vision and the benefits of the program, with core cinica messages. Communicating to prescribers what the program recommends them to do is one of the essentia impementation steps to successfu stewardship. This requires a simpe messaging approach that has identified key processes where stewardship interventions are required to be considered and actioned, such as the Start Smart-Then Focus approach deveoped in the UK. Figure 32 identifies the process for deivering effective surgica prophyaxis. Figure 32: Start Smart Then Focus approach Cean surgery invoving pacement of a prosthesis or impant Cean contaminated surgery Contaminated surgery TOTAL ANTIBIOTIC USE R % increase in DDD per 100 admissions since % R increase in DDD per 100 admissions since 2012 SINGLE DOSE SURGICAL PROPHYLAXIS* Surgica prophyasis ONE DOSE within 60 minutes before knife to skin * A repeat dose dose of prophyaxis may be required for proonged procedures or where there is significant bood oss. A treatment course of antibiotics may aso need to be given (in addition to appropriate prophyaxis) in cases of dirty surgery or infected wounds. The appropriate use and choice of antibiotics shoud be discussed with infection speciaists for each case. VERY BROAD SPECTRUM ANTIBIOTICS DDD per 100 admissions Carbapenems 6.5% increase in 2015 D O C U M E N T Piperaciin-tazobactam 7.9% decrease in 2015 Finay, it is important to keep messages for cinica practice simpe. For exampe, the 10 point principes approach beow is easier to assimiate into practice and is reevant to the whoe team ooking after a patient with infection on antibiotics (Tabe 11). Tabe 11: Ten key points for the appropriate use of antibiotics in hospitaized patients. Adapted from Levy et a. Int J Antimicrob Agents. 2016; 48: Get microbioogica sampes before antibiotic administration and carefuy interpret resuts: if no cinica signs of infection, coonization rarey requires antimicrobia treatment. 2 Ony treat significant bacteria infections. 3 When indicated, start empirica antibiotic treatment, according to site of infection, risk factors for MDR bacteria, and oca microbioogy/susceptibiity patterns. 4 Prescribe drugs at optima dose, administration mode and ength of time. 5 Use antibiotic combinations ony when current evidence suggests some benefit. 6 Avoid antibiotics with a higher ikeihood of promoting drug resistance or hospita-acquired infections. 7 Remove a infected devices. 8 Aways try to de-escaate antibiotic treatment according to cinica situation and microbioogica resuts; switch to ora route as soon as possibe. 9 Stop antibiotics as soon as a significant bacteria infection is unikey. 10 Set up oca teams with an infectious diseases speciaist, cinica microbioogist, hospita pharmacist, infection contro practitioner or hospita epidemioogist; compy with antibiotic poicies/guideines. Another approach is to identify and communicate to prescribers specific situations where antibiotics shoud be withhed (Tabe 12) and guidance in reation to the duration of antibiotic use, which is often an area of misuse (Tabe 13). The importance of communicating, sharing and earning from data is aso important. Face-to-face meetings with prescribers, where there is an opportunity for refection about their prescribing practices, or attending muti-discipinary teams, web-ex conferences, etc. are a important in promoting earning about prudent prescribing

23 Tabe 12: Specific Situations where Antibiotics shoud be withhed Adapted from Wodaver CG et a., Infect. Dis. Cin. Pract. 2012;20:12-17 RESPIRATORY TRACT INFECTIONS Vira pharyngitis Vira rhinosinusitis Vira bronchitis Noninfectious cardiopumonary disorders misdiagnosed as pneumonia ACUTE OTITIS MEDIA (AOM) (for seected cases, refer to artice) Skin and Soft Tissue Infections (SSTI) - Subcutaneous abscesses (for seected cases, refer to artice) - Lower extremity stasis dermatitis ASYMPTOMATIC BACTERIURIA AND PYURIA, INCLUDING CATHETERIZED PATIENTS MICROBIAL COLONIZATION AND CULTURE CONTAMINATION LOW-GRADE FEVER Recenty, as shown in Tabe 13, the move towards shorter duration of therapy, an important antimicrobia stewardship goa, is gaining pace [Speberg, 2016]. Safey and effectivey reducing duration of treatment is aso emerging, as is the whoe concept of competing courses of therapy [Leweyn, 2017]. The use of diagnostic tests, incuding biomarkers, wi further support the move towards a more precise approach to duration of antimicrobia therapy. Tabe 13: Infections for Which Short-Course Therapy Has Been Shown to Be Equivaent in Efficacy to Longer Therapy Adapted from Speberg B. JAMA Intern Med 2016; 176: TREATMENT DURATION IN DAYS SHORT LONG Community-acquired pneumonia Nosocomia pneumonia Pyeonephritis Intraabdomina infection 4 10 Acute exacerbation of chronic bronchitis and COPD* 5 7 Acute bacteria sinusitis 5 10 Ceuitis Chronic osteomyeitis * COPD: chronic obstructive pumonary disease THE KEYS TO SUCCESS A number of interventions are key to the success of a hospita-based Antimicrobia Stewardship Program. * * * * * * * Estabish cear aims/vision that is shared by a the stakehoders and that conveys a sense of urgency. Stewardship shoud be a patient safety priority. Seek management support, accountabiity and secure funding. Assembe a strong coaition incuding a muti-professiona antimicrobia stewardship team with a strong infuentia cinica eader. Estabish effective communication structures within your hospita. Start with core evidence-based stewardship interventions depending on oca needs, geography and resources and pan measurement to demonstrate their impact. Ensure a heathcare staff are aware of the importance of stewardship. Empower them to act and support with education using a range of effective strategies. Ensure eary or short term wins and then consoidate success/gains whie progressing with more change or innovation

24 ADDITIONAL RESOURCES KEY EVIDENCE-BASED PUBLICATIONS ON ANTIMICROBIAL STEWARDSHIP Baur D, et a. Effect of antibiotic stewardship on the incidence of infection and coonisation with antibiotic-resistant bacteria and Costridium difficie infection: a systematic review and meta-anaysis. Lancet Infectious Diseases 2017; 17: Davey P, et a. Interventions to improve antibiotic prescribing practices for hospita inpatients. Cochrane Database of Systematic Reviews 2017;(2): CD Davey P, et a. Interventions to improve antibiotic prescribing practices for hospita inpatients. Cochrane Database of Systematic Reviews 2013;(4): CD Deit TH, et a. Infectious Diseases Society of America and the Society for Heathcare Epidemioogy of America guideines for deveoping an institutiona program to enhance antimicrobia stewardship. Cinica Infectious Diseases 2007;44: Dik J-WH, et a. Financia evauations of antibiotic stewardship programs a systematic review. Frontiers in microbioogy 2015:6:317 Feaze LM, et a. Effect of antibiotic stewardship programmes on Costridium difficie incidence: a systematic review and meta-anaysis. Journa of Antimicrobia Chemotherapy 2014;69: Feaze, LM, Mahotra, A, Perencevich, EN, Kaboi, P, Diekema, DJ, and Schweizer, ML. Effect of antibiotic stewardship programs on Costridium difficie incidence: a systematic review and meta-anaysis. J Antimicrob Chemother. 2014; 69: Karanika S, et a. Systematic review and meta-anaysis of cinica and economic outcomes from the impementation of hospita-based antimicrobia stewardship programs. Antimicrobia Agents and Chemotherapy 2016;60: Schuts EC, et a. Current evidence on hospita antimicrobia stewardship objectives: a systematic review and meta-anaysis. Lancet Infectious Diseases 2016;16: Van Dijck C, et a. Antibiotic stewardship interventions in hospitas in ow-and midde-income countries: a systematic review. Buetin Word Heath Organization 2018; 6(4): USEFUL RESOURCES FOR EDUCATION AND TRAINING IN ANTIMICROBIAL STEWARDSHIP WHO on-ine course - Antimicrobia stewardship: a competency- based approach. Access: CDC on-ine course: Antibiotic Stewardship Access: Ebook- Antimicrobia Stewardship: From Principes to Practice. British Society for Antimicrobia Chemotherapy [BSAC] Access: to-practice-e-book/ Massive Open Onine Course on Antimicrobia Stewardship. Avaiabe in Engish, Mandarin, Spanish, and Russian. BSAC with University of Dundee and FutureLearn Access: New on-ine Stewardship modue for Africa Access: Antimicrobia Stewardship (AMS), Voume 2, 1 st Edition. Access: CIDRAP web-based resource: Antimicrobia stewardship project with emphasis on news, commentary, webinars, podcasts Access: Goba Point Prevaence Survey ed by the University of Antwerp Access: