Implementing an Antibiotic Stewardship Program : louddoc.com

Clinical Infectious DiseasesIDSA FEATURESImplementing an Antibiotic Stewardship Program:Guidelines by the Infectious Diseases Society of Americaand the Society for Healthcare Epidemiology of AmericaTamar F. Barlam,1Sara E. Cosgrove,2Lilian M. Abbo,3Conan MacDougall,4Audrey N. Schuetz,5Edward J. Septimus,6Arjun Srinivasan,7Timothy H. Dellit,8Yngve T. Falck-Ytter,9Neil O. Fishman,10Cindy W. Hamilton,11Timothy C. Jenkins,12Pamela A. Lipsett,13Preeti N. Malani,14Larissa S. May,15Gregory J. Moran,16Melinda M. Neuhauser,17Jason G. Newland,18Christopher A. Ohl,19Matthew H. Samore,20Susan K. Seo,21and Kavita K. Trivedi221Section of Infectious Diseases, Boston University School of Medicine, Boston, Massachusetts;2Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland;3Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida;4Department of Clinical Pharmacy, School of Pharmacy, University of California, San Francisco;5Department of Medicine, Weill Cornell Medical Center/New York–Presbyterian Hospital, New York, New York;6Department of Internal Medicine, Texas A&M Health Science Center College ofMedicine, Houston;7Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia;8Division of Allergy and Infectious Diseases, University of WashingtonSchool of Medicine, Seattle;9Department of Medicine, Case Western Reserve University and Veterans Affairs Medical Center, Cleveland, Ohio;10Department of Medicine, University of PennsylvaniaHealth System, Philadelphia;11Hamilton House, Virginia Beach, Virginia;12Division of Infectious Diseases, Denver Health, Denver, Colorado;13Department of Anesthesiology and Critical CareMedicine, Johns Hopkins University Schools of Medicine and Nursing, Baltimore, Maryland;14Division of Infectious Diseases, University of Michigan Health System, Ann Arbor;15Department ofEmergency Medicine, University of California, Davis;16Department of Emergency Medicine, David Geffen School of Medicine, University of California, Los Angeles Medical Center, Sylmar;17Department of Veterans Affairs, Hines, Illinois;18Department of Pediatrics, Washington University School of Medicine in St. Louis, Missouri;19Section on Infectious Diseases, Wake Forest UniversitySchool of Medicine, Winston-Salem, North Carolina;20Department of Veterans Affairs and University of Utah, Salt Lake City;21Infectious Diseases, Memorial Sloan Kettering Cancer Center, New York,New York; and22Trivedi Consults, LLC, Berkeley, CaliforniaEvidence-based guidelines for implementation and measurement of antibiotic stewardship interventions in inpatient populations in-cluding long-term care were prepared by a multidisciplinary expert panel of the Infectious Diseases Society of America and the Societyfor Healthcare Epidemiology of America. The panel included clinicians and investigators representing internal medicine, emergencymedicine, microbiology, critical care, surgery, epidemiology, pharmacy, and adult and pediatric infectious diseases specialties. Theserecommendations address the best approaches for antibiotic stewardship programs to inﬂuence the optimal use of antibiotics.Keywords. antibiotic stewardship; antibiotic stewardship programs; antibiotics; implementation.EXECUTIVE SUMMARYAntibiotic stewardship has been deﬁned in a consensus state-ment from the Infectious Diseases Society of America (IDSA),the Society for Heal thcare Epidemiology of Ameri ca (SHEA),and the Pediatric Infectious Diseases Society (PIDS) as “coordi-nated i nterventions desig ned to improve and measure the ap-propriate use of [antibiotic] agents by promoting the selectionof the optimal [antibiotic] drug regimen including dosing, du-ration of therapy, and route of administration” [1]. The beneﬁtsof antibiotic stewardship include improved patient outco mes,reduced adverse events including Clostridium difﬁcile infection(CDI), improvement in rates of antibiotic susceptibilities to tar-geted antibiotics , and optimization of resource utilization acrossthe continuu m of care. IDSA and SHEA strongly believe thatantibiotic stewardship programs (ASPs) are best led by infec-tious disease physicians with additional stewardship training.Summarized below are the IDSA/SHEA recommendations forimplementing an ASP . The expert panel followed a process used inthe development of other IDSA guidelines, which included a sy s-tematic weighting of the str ength of recommenda tion and qualityof evidence using the GRADE (Grading of Recommenda tions As-sessment, Development and Evaluation) sy s tem (Figure 1)[2–5].A detailed description of the methods, backgr ound, and evidencesummaries th at support each of the recommendations can befound online in the full text of the guidelines. For the purposesof this guideline, the term antibiotic will be used instead of anti-microbial and should be considered s ynonymous.RECOMMENDATIONS FOR IMPLEMENTING ANANTIBIOTIC STEWARDSHIP PROGRAMInterventionsI. Doe s the Use of Preauthorization and/o r Prospective Audit andFeedback Interventions by ASPs Improve Antibi otic Utilization andPatient Outcomes?Recommen dation1. We recommend preauthorization and/or prospective auditand feedback over no such interventions (strong recommen-dation, moderate-quality evidence).Received 22 February 2016; accepted 23 February 2016.It is important to realize that guidelines cannot always account for individual variation amongpatients. They are not intended to supplant clinician judgment with respect to particular patientsor special clinical situations. IDSA considers adherence to these guidelines to be voluntary, withthe ultimate determination regarding their application to be made by the clinician in the light ofeach patient’s individual circumstances.Correspondence: T. F. Barlam, Boston Medical Center, One Boston Medical Center Place, Bos-ton, MA 02118 (tamar.barlam@bmc.org).Clinical Infectious Diseases®© The Author 2016. Published by Oxford University Press for the Infectious Diseases Societyof A merica. All rights reserved. For permi ssions, e-mail journals.permissions@oup.com .DOI: 10.1093/cid/ciw118Guideline for Implementing an Antibiotic Stewardship Program•CID•e1 Clinical Infectious Diseases Advance Access published April 13, 2016 at IDSA member on May 12, 2016http://cid.oxfordjournals.org/Downloaded from

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Comment: Preauthorization and/or prospective audit andfeedback improve antibiotic use and are a core component ofany stewardship program. Programs should decide whetherto include one strategy or a combination of both strategiesbased on the availability of facility-speciﬁc resources for con-sistent i mplementation, but some implementati on isessential.II. Is Didactic Education a Useful Antibiotic Stewardship Interventionfor Reducing Inappropriate Antibiotic Use?Recommen dation2. We suggest against relying sol ely on didactic educati onalmat erials for stewardship (weak recommendation, low-quality evidence).Comment: Passive educational activities, such as lectu resor informational pamphlets, should be used to complementother stewardship activities. Academic medical centersand teaching hospitals should integrate education onfundamental antibiotic stewardship principles into their pre-clinical and clinical curricula.III. Should ASPs Develop and Implement Facility-Specic ClinicalPractice Guidelines for Common I nfectious Diseases Syndromes toImprove Antibiotic Utilization and Patient Outcomes?Recommen dation3. We suggest ASPs develop facility-speciﬁc clinical practiceguidelines coupled with a dissemination and implementationstrategy (weak recommendation, low-quality evid ence).Comment: Facility-speciﬁc clinical practice guidelines andalgorithms can be an effective way to standardize prescribingpractices based on local epidemiology. ASPs should developthose guidelines, when feasible, for common infectious dis-eases syndromes. In addition, ASPs should be involved inwriting clinical pathways, guidelines, and order sets that ad-dress antibiotic use and are developed within other depart-ments at their facility.Figure 1. Approach and implications to rating the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Developmentand Evaluation (GRADE) methodology (unrestricted use of this figure granted by the US GRADE Network).e2•CID•Barlam et al at IDSA member on May 12, 2016http://cid.oxfordjournals.org/Downloaded from

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IV. Should ASPs Impl ement I nterventions to Improve Antibiotic Use andClinical Outcomes That Target Patients With Specic InfectiousDiseases Syndromes?Recommen dation4. We suggest ASPs implement interventions to improve anti-biotic use and clinical outcomes that target patients with spe-ciﬁc infectious diseases syndromes (weak recommendation,low-quality evidence).Comment: AS P interventions for patients with speciﬁc in-fectious diseases syndromes can be an effective way to im-prove prescribing because the message can be focused,clinical guidelines and algorithms reinforced, and sustain-ability improved. ASPs should regularly evaluate areas forwhich targeted interventions are needed and adapt their ac-tivities accordingly. This approach is most useful if the ASPhas a reliable way to identify patients appropriate for review.V. Shoul d ASPs Implement Interventions Designed to Reduce the Use o fAntibiotics Associated With a Hi gh Risk of CDI?Recommen dation5. We recommend antibiotic stewardship interventions de-signed to reduce the use of antibiotics associated with ahigh risk of CDI compared with no such intervention (strongrecommendation, moderate-quality evidence).Comment: The goal of reducing CDI is a high priority forall ASPs and should be taken into consideration when craft-ing stewardship interventions.VI. Do Strategies to Encourage Prescriber-Led Review ofAppropriateness of Antibiotic Regimens, in the Absence of Direct InputFrom an Antibiotic Stewardship Team, I mprove Ant ibiotic Prescribing?Recommen dation6. We suggest the use of strategies (eg, antibiotic time-outs,stop orders) to encourage prescribers to perform routine re-view of antibiotic regimens to improve antibiotic prescribing(weak recommendation, low-quality evidence).Comment: Published data on prescriber-led antibiotic re-view are limited, but successful programs appear to require amethodology that includes persuasive or enforced prompt-ing. Without such a mechanism, these interventions are like-ly to have minimal impact.VII. Should Computerized Clinical Decision Su pport System s IntegratedInto the Electronic Health Record at the Time of Prescribing beIncorporated as Part of ASPs to Improve Antibiot ic Prescribing?Recommen dation7. We suggest incorporation of computerized clinical decisionsupport at the time of prescribing into ASPs (weak recom-mendation, moderate-quality evidence).Comment: Computerized clinical decision support forprescribers should only be implemented if informationtechnology resources are readily available. However, comput-erized surveillance systems that synthesize data from theelectronic health record and other data sources can stream-line the work of ASPs by ide ntifying opportunities forinterventions.VIII. Should ASPs Impl ement Strategies That Promote Cycling o r Mixingin Antibiotic Selection to Reduce Antibiotic Resistance?Recommen dation8. We suggest against the use of antibiotic cycling as a steward-ship strategy (weak recommendation, low-quality evidence).Comment: Available data do not support the use of anti-biotic cycling as an ASP strategy, and further research is un-likely to change that conclusion. Because c linical data aresparse for antibiotic mixing, we cannot give any recommen-dation about its utility.OptimizationIX. In Hospitalized Patients Requiring Intravenous (IV) Antibiotics, Doesa D edi cated Pharmacokinetic (PK) Monitori ng and Adju stment ProgramLead to Improved Clinical Outcomes and Reduced Costs?Recommen dations9. We recommend that hospitals implement PK monitoringand adjustment programs for aminoglycosides (strong rec-ommendation, moderate-quality evidence).10. We suggest that hospitals implement PK monitoring andadjustment programs for vancomycin (weak recommend a-tion, low-quality evidence).Comment: PK monitoring and adjustment p rograms canreduce costs and decrease adverse effects. The ASP shouldencourage implementation and provide support for train-ing and assessment of competencies. The conduct ofthose programs should be integrated into rout ine pharma-cy activities.X. In Hospitalized Patients, Should ASP s Advocate for AlternativeDosing Strategies Based on PK/Pharmacodynamic Principles toImprove Outc omes and Decrease Costs for Broad-Spectrum ß-Lactamsand Vancomycin?Recommen dation11. In hospitalized patients, we suggest ASPs advocate for theuse of alternative dosing strategies vs standard dosing forbroad-spectrum β-lactams to decrease cost s (weak recom-mendation, low-quality evidence).Comment: Although data for improved outcomes forbroad-spectrum β-lacta m dosing with this appro ach arestill limited, these interventions are associated with antibioticcost savings. ASPs should consider implementation but musttake into account logistical issu es such as nursing andpharmacy education and need for dedicated IV access.Considering the limited evidence, we cannot give anyGuideline for Implementing an Antibiotic Stewardship Program•CID•e3 at IDSA member on May 12, 2016http://cid.oxfordjournals.org/Downloaded from

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recommendation about the utility of alternative dosing strat-egies for vancomycin.XI. Should ASPs Implement Interventions to Increase Use of OralAntibiot ics as a Strate gy to I mprove Outcom es or Decrease Costs ?Recommen dation12. We recommend ASPs implement programs to increaseboth appropriate use of oral antibiotics for initial therapyand the timely transition of patients from IV to oral antibi-otics (strong recommendation, moderate-quality evidence).Comment: Programs to increase the appropriate use oforal antibiotics can reduce costs and length of hospitalstay. I V-to-oral conversion of the same antibiotic is lesscomplicated than other strategies and i s applicable tomany healthca re se tting s. The conduct of those programsshould be integrated into routine pharmacy activities.ASPs should implement strategies to assess patients whocan safely complete therapy with an oral regimen to reducethe need for IV catheters and to avoid outpatient parenteraltherapy.XII. In Patients With a Reported Hi story of ß-Lactam Allergy, ShouldASPs Facilitate Ini tiatives to Implement Allergy Assessments With theGoal of Improved Use of Frst-Line Antibio tics?Recommen dation13. In patients with a history of β-lactam allergy, we suggestthat ASPs promote allergy asse ssments and penicillin(PCN) skin testing when appropriate (weak recommenda-tion, low-quality evidence).Comment: Allergy assessments and PCN skin testingcan enhance use of ﬁrst-line agents, but it is largely unstudiedas a primary ASP intervention; however, AS Ps should pro-mote such assessments with providers. In facilities with ap-propriate resources for skin testing, the ASPs should activelyw ork to develop testing and treatment strategi es withallergists.XIII. Should ASPs Implement Interventions to Reduce Antibiotic Therapyto the Shortest Effective Duration?Recommen dation14. We recommend that ASPs implement guidelines and strat-egies to reduce antibiotic therapy to the shortest effective du-ration (strong recommendation, moderate-quality evidence).Comment: Recommending a duration of therapy based onpatient-speciﬁc factors is an important activity for ASPs.Su itable approaches include developing written guidelineswith speciﬁc suggestions for duration, in cluding durationof therapy recommendations as part of the preauthorizationor prospective audit and feedback process, or specifying du-ration at the time of antibiotic ordering (eg, through an elec-tronic orde r entry system).Microbiology and Laboratory DiagnosticsXIV. Should ASPs Work With the Microbiology Laboratory to DevelopStratiﬁed Antibiograms, Compared With Nonstratiﬁed Antibiograms?Recommen dation15 . We suggest development of stratiﬁed antibiograms oversolely relying on nonstratiﬁed antibiograms to assist ASPsin de veloping guidelines for empiric therapy (weak recom-mendation, low-quality evidence).Comment: Although there is limited evidence at this timethat stratiﬁed antibiograms (eg, by location or age) lead toimproved empiric antibiotic therapy, stratiﬁcation can expo-se important differences in susceptibility, which can helpASPs develop optimized treatment recommendations andguidelines.XV. Should ASPs Work With the Microbiology Laboratory to PerformSelective or Cascade Reporting of Antibiotic Susceptibility TestResults?Recommen dation16. We suggest sele ctive and cascade reporting of antibioticsover reporting of all tested antibiotics (weak recommenda-tion, low-quality evidence).Comment: Although data are limited that demonstrate di-rect impact of those strategies on prescribing, some form ofselective or cascaded reporting is reasonable. After imple-mentation, ASPs should review prescribing to ensure thereare no unintended consequences.XVI. Shoul d ASPs Advocate for Use of Rapid Viral Testing forRespiratory Path ogens to Reduce the Use of I nappropriate Antibiotics?Recommen dation17 . We suggest the use of ra pid viral testing for respiratorypathogens to reduce the use of inappropriate antibiotics(weak recommendation, low-quality evidence).Comment: Althou gh rapid viral testing has the potential toreduce inappropriate use of antibiotics, results have been in-consistent. Few studies have been perfo rmed to assess wheth-er active ASP intervention would improve those results.XVII. Should ASPs Advocate fo r Rapid Dia gnostic Testing on BloodSpecimens to Optimize Antibioti c Therapy and Im prove Cli nicalOutcomes?Recommen dation18. We suggest rapid diagnostic testing in addition to conven-tional culture and routine reporting on blood specimens ifcombined with active ASP support and interpretation(weak recommendation, moderate-quality evidence).Comment: Availability of rapid diagnostic tests is expectedto increase; thus, ASPs must develop processes and interven-tions to assist clinicians in i nterpreting and respondingappropriately to results.e4•CID•Barlam et al at IDSA member on May 12, 2016http://cid.oxfordjournals.org/Downloaded from

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XVIII. In Adults in Int ensive Care Units (ICUs) With Suspected Infection,Should ASPs Advocate Procalcitonin (PCT) Testing as an Intervention toDecrease Antibiotic Use?Recommen dation19. In adults in ICUs with suspected infection, we suggest theuse of serial PCT measurements as an ASP intervention todecrease anti biotic use (weak recommendation, moderate-quality evidence).Comment: Although randomized trials, primarily inEurope, have shown reduction in antibiotic use through im-plementation of PCT algorithms in the ICU, similar data arelacking for other regions including the United States where thepatterns of antibiotic prescribing and approach to stewardshipmay differ. If implemented, each ASP must develop processesand guidelines to assist clinicians in interpreting and respond-ing appropriately to results, and must determine if this inter-vention is the best use of its time and resources.XIX. In Patients With Hematologic Malignancy, Should ASPs Advocatefor Incorporation of Noncu lture-Based Fungal Markers i n Interventionsto Optimize Antifungal Use?Recommen dation20. In patients with hematologic malignanc y at risk of con-tracting invasive fungal disease (IFD), we suggest incorporat-ing nonculture-based fungal markers in ASP interventions tooptimize antifungal use (weak recommendation, low-qualityevidence).Comment: ASPs with an existing intervention to optimizeantifungal use in patients with hematologic malignancy canconsider algorithms incorporating nonculture-based fungalmarkers. Those interventions must be done in close collabo-ration with the primary te ams (eg, hematology-oncology).Antib iotic stewards must dev elop expe rtise in ant ifungaltherapy and fungal diagnostics for the programs to be suc-cessful. The value of those markers for interventions inother populations has not been demonstrated.MeasurementXX. Which Overall Measures Best Reﬂect the Impact of A SPs an d Th eirInterventions?Recommen dation21. We suggest monitoring antibiotic use as measured by daysof therapy (DOTs) in preference to deﬁned daily dose (DDD)(weak recommendation, low-quality evidence).Comment: Every ASP must measure antibiotic use, strati-ﬁed by antibiotic. DOTs are preferred, but DDDs remain analternative for sites that cannot obtain patient-level antibioticuse data. ASPs should consider measurement of appropriateantibiotic use within thei r own institutions by examiningcompliance with local or national guidelines, particularlywhen assessing results of a targeted intervention, and sharethat data with clinicians to help inform their practice. Al-though rates of CDI or antibiotic resistance may not reﬂectASP impact (because those outcomes are affected by patientpopulation, infection control, and other factors), those out-comes m ay also be used for measurement of targetedinterventions.XXI. What is the Best Measure of Expend itures on A ntibio tics to As sessthe Impact of ASPs and Interventions?Recommen dation22. We recommend measuring antibiotic costs based on pre-scriptions or administrations instead of purchasing data(good practice recommendation).XXII. What Measu res Best Reﬂect the Impact of Inter ventions to ImproveAntibiotic Use and Clinical Outcomes in Patients With SpeciﬁcInfectious Diseases Syndromes?Recommen dation23. Measures that consider the goals and size of the syndrome-speciﬁcinterventionshouldbeused( good practicerecommendation).Special PopulationsXXIII. Should ASPs Develop Facility-Speciﬁc Clinical Guidelinesfor Management of Fever and Neutropenia (F&N) in Hematology-Oncology Patients to Reduce Unnecessary Antibiotic Use and ImproveOutcomes?Recommen dation24 . We suggest ASPs develop facility-speciﬁcguidelinesforF&N management i n hematology-oncology patients overno such approach (weak recommendation, low-quali ty evi-dence).Comment: Clinical guidelines with an implementationand dissemination strategy can be successfully used in thecare of cancer patients with F&N and are stronglyencouraged.XXIV. In Immunocompromised Patients Receiving Antifungal Therapy,do Interventions by ASPs Improve Utilization a nd Outcomes?Recommen dation25. We suggest implementation of ASP interventions toimprove the appropriate prescribing of antifungal treatmentin immunoc ompromised patients (weak recommendation,low-quality evidence).Comment: In facilities with large immun oco mpromisedpatient populations, ASP interventions targeting antifungaltherapy can show beneﬁt. Those interventions must bedone in close collaboration with the primary teams (eg he-matology-oncology, solid organ transplant providers). Anti-biotic stewards must develop expertise in antifungal therapyand fungal diagnostics for the programs to be successful.Guideline for Implementing an Antibiotic Stewardship Program•CID•e5 at IDSA member on May 12, 2016http://cid.oxfordjournals.org/Downloaded from

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XXV. In Residents of Nursing Homes and Skilled N ursing Facilities, doAntibiotic Stewardship Strategies Decrease Unnecessary Use ofAntibiotics and Improve Clinical Outcomes?Recommen dation26. In nursing homes and skilled nursing facilities, we suggestimplementation of antibiotic stewardship strategies to de-crease unnecessary use of antibiotics (good practic e recom-mendation).Comment: Implementing ASPs at nursing homes andskilled nursing facilities is important and must involvepoint-of-care providers to be successful. The traditional phy-sician–pharmacist team may not be available on-site, and fa-cilities might need to investigate other approaches to reviewand optimize antibiotic use, such as obtaining infectious dis-eases expertise through telemedicine consultation.XXVI. In Neonatal Intensive Care Units (NICUs) , do Antibi oticStewardship I nte rventions Reduce Inappropriate Antibiotic Us e and/orResistance?Recommen dation27. We suggest implementation of antibiotic stewardshipinter ventions to reduce inappropriate antibiotic use and/orresistance in the NICU (good practice recommendation).XXVII. S hould ASPs Implement Interventions to Reduce AntibioticTherapy in Terminall y Ill Patients?Recommen dation28. In terminally ill patients, we suggest ASPs provide supportto clini cal care provider s in d ecision s related t o antibiotictreatment (good practice recommendation).INTRODUCTIONThe discovery of antibiotics in the early 20th century trans-formed healthcare, dramatically reducing morbidity and mor-tality from infectious diseases and allowing for majoradvancements in medicine. The increase in organisms with re-sistance to antibiotics in our armamentarium, however, com-bined with the slow pace of development of new ant ibioticsthreatens those gains. Approaches to optimize the use of bothexisting antibiotics and newly developed antibiotics are of crit-ical importance to ensure that we continue to reap their beneﬁtsand provide the best care to patients.The need for antibiotic stewardship across the spectrum ofhealthcare has been recognized in the National Action Planfor Combating Antibiotic-Resistant Bacteria issued by theWhite House in March 2015 [6]. This plan calls for establish-ment of ASPs in all acute care hospitals by 2020 and f or theCenters for Medicare and Medicaid Services to issue a Condi-tion of Participation that p articipating hospitals develop pro-grams based on recommendations from the Centers forDisease Control and Prevention’s (CDC) Core Elements ofHospital Antibiotic Stewardship Programs [7]. Expansion ofstewardship activities to ambul atory surgery centers, dialys iscenters, nursing homes and other long-term care facilities,and emergency departments and outpatient settings is alsorecommended.The purpose of this guideline is to comprehensively evaluatethe wide range of in terventions that can be implemente d byASPs in eme rgency department, acute inpatient, and long-term care settings as they determine the best approaches to in-ﬂuence the optimal use of antibiotics within their own institu-tional environments. In addition, this guideline addressesapproaches to measure the success of these interventions.This guideline does not speciﬁcally address the structure of anASP, which has been well outlined in a previous guideline [8]and in the CDC’s Core Elements of Hospital AntibioticStewardship Programs and Core Elements of AntibioticStewardship for Nursing Homes [7, 9]. These documents em-phasize the importance of physician and pharmacist leadershipfor an ASP, the need for infectious diseases expertise, and therole of measurement and feedback as critical components ofASPs. This guideline does not address antibiotic stewardshipin outpatient settings.Although not all of the antibiotic stewardship interventions,optimization measures, diagnost ic approaches, and programmeasurements described in this guideline have been imple-mented or evaluated in all populations or clinical settings, themajority could be considered f or use in pediatrics, oncology,community hospitals, small hospitals, and nurs ing hom e andlong-term care environments, and not limited to acute care fa-ciliti es. Any antibiotic stewardship i ntervention must be cus-tomized based on local needs, prescriber behaviors, barriers,and resources. In contrast to other guidelines, this guidelineprovides comments that supplement the formal recommenda-tions and contain practical input from the expert panel to betterguide ASPs in determining which interventions to implement.METHODSPanel CompositionLed by Co-chairs Tamar Barlam and Sara Cosgrove, a panel of18 multidisci plin ary experts in the management of ASPs wasconvened per the IDSA Handbook on Clinical Practice Guide-line Development [10] in 2012. In addition to members ofIDSA and the SHEA, representatives from diverse geographicareas, pediatric and adult practitioners, and a wide breadth ofspecialties representing major medical societies were includedamong the panel’s membership (American College of Emergen-cy Physicians [ACEP], American Society of Health-SystemPharmacist s [ASHP], American Society for Microbiology[ASM], PIDS, Society for Academic Emergency Medicine[SAEM], Society of Infectious Diseases Pharmacists [SIDP],and the Surgical Infection Society [SIS]). 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methodologist and member of the GRADE Working Group anda medical writer were added to assist the panel.Literature Review and AnalysisPubMed, which includes Medline (1946 to present), wassearched to identify relev ant studies for each of the antibioticstewardship guideline PICO (population/patient, intervention/indicator, comparator/control, outcome) questions. Searchstrategies were developed and built by 2 independent health sci-ences librarians from the Health Sciences Library System, Uni-versity of Pittsburgh. For each PICO question, the librariansdeveloped the search strategies using PubMed’s command lan-guage and appropriate search ﬁelds. Medical Subject Headingsterms and keywords were used for the main search concepts ofeach PICO question. A data supplement that includes searchstrings can be found following publication on the IDSA website[11]. Articles in all languages and all publication years were in-cluded. Initial searches were created and conﬁrmed with inputfrom the guideline committee chairs and group leaders fromFebruary through mid-July 2013. The searches were ﬁnalizedand delivered between late July and September 2013. After theliterature searches were performed, authors continued to reviewthe literature and added relevant articles as needed.Process OverviewTo evaluate evidence, the panel followed a process consistentwith other IDSA guidelines. The process for evaluating theevidence was based on the IDSA Handbook on C linical PracticeGuideline Development [10] a nd in volved a syst em at icweightingofthequalityoftheevidenceandthegradeofre-commendation using the GRADE system (Figure 1)[2–5].Unless otherwise stated, each PICO comparator was u sualpractice.For recommendations in the category of good practice state-ments, we followed published principles by the GRADE work-ing group on how to identify such recommendations and useappropriate wording choices. Accordingly, a formal GRADErating was not pursued for those statements [12].Panel members were divided into 5 subgroups: (1) interven-tions, (2) optimization of antibiotic administration, (3) micro-biology and laboratory diagnostics, (4) measurement andanalysis, and (5) antibiotic stewardship in special populations.Each author was asked to review the literature, evaluate th eevidence, and determine the initial strength of the re-commendations along with an evid ence summary supportingeach recommendation in his/her assigned subgroup. The evi-dence was graded based on the effectiveness of the antibioticstewardship intervention, not the underlying data that providedthe groundwork for the intervention. The panel reviewedall recommendations, along with their strength and the qualityof the evidence. Discrepancies were discussed and resolved,and all panel members are in agreement with the ﬁnalrecommendations.Consensus Development B ase d on EvidenceThe panel met face to face on 3 occasions and conducted nu-merous teleconferences to complete the work of the guideline.The purpose of the meetings and telec onferences was to developand discuss the clinical questions to be addressed, assign topicsfor review and writing of the initial draft, and develop recom-mendations. The whole panel reviewed all sections. The guide-line was reviewed and approved by the IDSA Stand ar ds andPractice Guidelines Committee (SPGC), the IDSA Board of Di-rectors, the SHEA Guidelines Committee, and the SHEA Boardof Directors, and was en dorsed by ACEP, ASHP, ASM, PIDS,SAEM, SIDP, and SIS.Guidelines and Conﬂicts of InterestThe expert p anel complied with the IDSA policy on co nﬂ ic tsof interest, which requires disclosure of any ﬁnancial or otherinterest that may be construed as constituting an actual,potential, or apparent con ﬂict. Panel m embers were prov idedIDSA’sconﬂic t s of in tere st di s c l o s u re stat e m e n t an d wereasked to identify ties to companies developing products thatmay be affected by promulgation of the guideline. Informa-tion was requested regarding employment, consultancies,stock ownership, honoraria, research funding, expert tes-timony, and membership on company advisory committees.Decisions were made on a case-by-case basis as to whetheran individual’s role should be limited as a result of a conﬂict.Pot ential conﬂicts of interests are listed in the Not es section atthe end of the guideline.Revision DatesAt annual intervals, the panel chair, the SPGC liaison advisor,and the chair of the SPGC will determine the need for revisionsto the guideline based on an examination of current literature. Ifnecessary, the entire panel will reconvene to discuss potentialchanges. When appropriate, the panel will recommend revisionof the guideline to the IDSA SPGC and SHEA guidelinescommittees.RECOMMENDATIONS FOR IMPLEMENTING ANANTIBIOTIC STEWARDSHIP PROGRAMInterventionsI. Doe s the Use of Preauthorization and/o r Prospective Audit andFeedback Interventions by ASPs Improve Antibi otic Utilization andPatient Outcomes?Recommen dation1. We recommend preauthorization and/or prospective auditand feedback over no such interventions (strong recommen-dation, moderate-quality evidence).Comment: Preauthorization and/or prospective audit andfeedback improve antibiotic use and are a core componentof any stewardship program. Programs should decide whetherto include o ne strategy or a combination of both strategi esGuideline for Implementing an Antibiotic Stewardship Program•CID•e7 at IDSA member on May 12, 2016http://cid.oxfordjournals.org/Downloaded from

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based on the availability of facility-speciﬁc resources for con-sistent implementation, but some implementation is essential.Evidence SummaryPreauthorization is a strategy to improve antibiotic use by re-quiring clinicians to get approval for certain antibiotics beforethey are prescribed. Prospective audit and feedback (PAF) isan intervention that engages the provider after an antibiotic isprescribed. Each type is associated with unique a dvantagesand disadvantages (Table 1).Preauthorization has been associated with a signiﬁcant re-duction in the use of the restricted agents and of associatedcosts [13 –16]. Outcome studies with preauthorization haveshown decreased antibiotic use and decreased antibiotic resis-tance, particularly among gram-negative pathogens [13–15,17]. Preauthorization studies have demonstrated no adverse ef-fects for patients [13, 14]. White et al [13] reported that initia-tion of a preauthorization requirement for selected antibiotics ata county teaching ho spital was associated with a 32% decreasein total parenteral antibiotic expenditures (P <.01) and in-creased percentages of susceptible gram-negative isolates—allwithout changes in hospital length of stay and survival. For ex-ample, Pseudomonas aeruginosa susceptibility to imipenem in-creased for isolates recovered in the ICU (percentage ofsusceptible isolates before vs after preauthorization: 65% v s83%; P ≤ .01) and other inpatient settings (83% vs 95%;P ≤ .01). Overall 30-day su rviva l rates were unchanged in pa-tients with gram-negative bacteremia (79% vs 75% ; P =.49)[13]. In addition, restrictive policies such as preauthorizationhave been shown to be more effective than persuasive strategiesin reducing CDI, according to a meta-analysis evaluating anti-biotic stewardship and CDI [18].There are several factors to consider when implementing apreauthorization intervention. The skills of the person provid-ing approval are important. Antibiotic approval by an antibioticstewardship team consisting of a clinical pharmacist and an in-fectious diseases attending physician was more e ffe ctive thanoff-hour approval by infectious diseases fellows in recommen-dation appropriateness (87% vs 47%; P < .001), cure rate (64%vs 42%; P = .007), and treatment failu res (15% vs 28%; P = .03)[19]. Inaccuracy in c ommuni cation of the clinical scenario bythe requesting prescriber to the antibiotic stewardship team in-creases the likelihood of inappropriate recommendations [20].Direct chart review optimizes preauthorization. It is also impor-tant to consider the alternative treatments that clinicians maychoose when antibiotics are restricted and monitor changes inusage patterns. Rahal et al [21] implemented a preauthorizationrequirement for cephalosporins. This was associated with a re-duction in the incidence of ceftazidime-resistant Klebsiella, butimipenem use increased and a 69% increase in the incidence ofimipenem-resistant P. aeruginosa was seen. Preauthorization re-quires real-time availability of the person providing approval.Institutions that use preauthorization often allow administra-tion of the restr icte d anti biotic overn ig ht until approval canbe obtain ed the next day. To provide 24-hour availability andto facilitate communication without impeding provider work-ﬂow, Buising et al [14] developed a computerized approval sys-tem based on deﬁned indications for restricted agents,demonstrating reduced antibiotic consumpti on and increasedPseudomonas susceptibility rates over a 2-year period.PAF interventions also have been shown to improve anti-biotic use, reduce antibiotic resistance, and reduce CDI rates[22–27], without a negative impact on patient outc omes [26,28–30]. For instance, PAF conduct ed by a clinical pharmacistand infectious diseases physician at a community hospital ledto a 22% reduction in the use of parenteral broad-spectrum an-tibiotics as well as a reduction in rates of CDI and nosocomialinfections due to antibiotic-resistant Enterobacteriaceae over a7-year pe riod of time [22]. PAF has also been effective in theICU [24, 25]. For example, a PAF interv ention in mul tipleICUs at a large academic institution demonstrated decreasedmeropenem resistance and decreased CDIs (P =.04) withoutadversely affecting mo rtality [25]. PAF has been effective inchildren’s hospitals by signiﬁcantly reducing antibiotic useand dosing errors while limiting the development of antibioticresistanc e [26, 27]. PAF can also be a strategy to improveTabl e 1 . Comparison of Preauthorization and Prospective Audit andFeedback Strategies for Antibiotic StewardshipPreauthorization Prospective Audit and FeedbackAdvantages•Reduces initiation ofunnecessary/ inappropriateantibiotics•Optimizes empiric choices andinfluences downstream use•Prompts review of clinical data/prior cultures at the time ofinitiation of therapy•Decreases antibiotic costs,including those due to high-costagents•Provides mechanism for rapidresponse to antibiotic shortages•Direct control over antibiotic use•Can increase visibility ofantimicrobial stewardship programand build collegial relationships•More clinical data available forrecommendations, enhancinguptake by prescribers•Greater flexibility in timing ofrecommendations•Can be done on less than dailybasis if resources are limited•Provides educational benefit toclinicians•Prescriber autonomy maintained•Can address de-escalation ofantibiotics and duration of therapyDisadvantages•Impacts use of restricted agentsonly•Addresses empiric use to a muchgreater degree than downstreamuse•Loss of prescriber autonomy•May delay therapy•Effectiveness depends on skill ofapprover•Real-time resource intensive•Potential for manipulation ofsystem (eg, presenting request ina biased manner to gain approval)•May simply shift to otherantibiotic agents and select fordifferent antibiotic-resistancepatterns•Compliance voluntary•Typically labor-intensive•Success depends on deliverymethod of feedback to prescribers•Prescribers may be reluctant tochange therapy if patient is doingwell•Identification of interventions mayrequire information technologysupport and/or purchase ofcomputerized surveillancesystems•May take longer to achievereductions in targeted antibioticusee8•CID•Barlam et al at IDSA member on May 12, 2016http://cid.oxfordjournals.org/Downloaded from

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antibiotic use in hematology-oncology patients. In one study,the addition of PAF led to a signiﬁcant decrease in th e use ofrestricted antibiotics during the intervention period from574.4 to 533.8 study-antibio tic days per 1000 patient-days (in-cidence rate ratio, 0.93 ; 95% conﬁdence interval [CI], .88–.97;P = .002), although neutropenic patients and those undergoinghematopoietic stem cell transplant were excluded [31].The effectiveness of PAF may depend on the infrastructure inplace at an institution. A multicenter study of a PAF programadd ed to existing ASPs found overall that 27.3% of antibioticcourses were determined to be unjustiﬁed, and clinicians ac-cepted recommendations to change or stop the antibiotics in66.7% of these. In the 2 sites with established ASPs and dedicat-ed personnel, the addition of PAF led to signiﬁcant reductionsin antibiotic usage; however, among the 3 centers without estab-lished resources, no impact was identiﬁed [31].PAF can be very labor intensive, and identiﬁcation of appro-priate patients for intervention can be challenging and requirecomputerized surveillance systems; however, where daily reviewor preauthorization is not feasible, limited PAF can still havean impact [32]. A pharmacist-driven PAF intervention conduct-ed 3 days a week at a 253-bed community hospital demonstrateda 64% decline in DOTs per 1000 patient-days after imple-mentation, a 37% reduction in total antibiotic expenditures,and a decrease in use of carbapenems, vancomycin, and levo-ﬂoxacin [33].The beneﬁt of preauthorization compared with PAF has hadlimited study. Restrictive measures such as preauthorizationwere compared with persuasive measures such a s PAF in ameta-analysis of 52 interrupted time series in a Cochrane review[34] . Persuasive interventions included PAF, dissemination ofeducational resources, reminders, and educational outreach. Al-though equivalent to persuasive measures at 12 or 24 months,restrictive interventions had statistically greater effect size onprescribing outcomes at 1 month (+32%; 95% CI, 2%–61%;P = .03) and on colonization or infection with C. difﬁcile orantibiotic-resistant bacteria at 6 months (+53%; 95% CI,31%–75%; P = .001). The authors concluded that restrictive in-terventions are preferred when the need is urgent [34]. Anotherstudy [35] at an academic institution demonstrated that when apreauthorization strategy was switched to a PAF strategy, overallantibiotic use increased ( preauthorization vs PAF: –9.75 vs+9.65 DO Ts per 1000 pati ent-days per month; P < .001), asdid hospital length of stay (–1.57 vs +1.94 days per 1000 pa-tient-days; P = .016).Whether one chooses preauthorization, PAF, or a combina-tion of those strategies, implementation should serve a s thefoundation of a comprehensive ASP. Effective implementationrequires the support of hospital administration, allocationof necessary resources for a persistent effort by dedicated,well-trained personnel, and ongoing communication withclinicians.II. Is Didactic Education a Useful Antibiotic Stewardship Interventionfor Reducing Inappropriate Antibio tic Use?Recommen dation2. We suggest against relying solely on didactic educationalmat erials for stewardship (weak recommendation, low-quality evidence).Comment: Passive educational activities, such as lecturesor informational pamphlets, should be used to complementother stewardship activities. Academic medical centers andteaching hospitals should integrate education on fundamen-tal antibiotic stewardship principles into their preclinical andclinical curricula.Evidence SummaryEducation is a common tool for ASPs. Str a tegies include educa-tional meetings with didactic lectures and distribution of educa-tional pa mphlets and materials. No comparative studies areavailable to determine which educational stra tegy is most effective.Dissemination of e ducational materials in the context of afocused stewardship goal can be successful. For example, in a Co-chrane review published in 2013 [34],dissemina tion of education-al materials via printed forms or meetings was associated withimproved antibiotic use in 5 of 6 studies; the median effect sizebased on the type of study ranged from 10.6% to 42.5%. Educa-tion alone, however, can result in nonsustainable improvementsin antibiotic prescribing. Landgren et al [36] performed a cross-over study with an educational marketing campaign that targetedperioperative prophylaxis. Prescribing improved during the inter-vention period but was not sustained over the next 12 months[36]. Educational strategies are likely most effective when com-bined with other stewardship strategies such as PAF [34].Educational strategies should include medical, pharmacy,physician assistant, nu rse practitioner, and nursing studentsand train ees. In a survey of fourth-year medical students at 3schools in the United States [37], 90% of respondents conﬁrmedthat they would like more education on appropriate antibioticuse. In addition, they had low mean knowledge scores on thistopic, suggesting the need for instruction in fundamental anti-biotic stewardship prin ciples. The Acc reditation Council forGraduate Medical Education announced its commitment to an-tibiotic stewardship in 2015 and will provide resources and ma-terials to postgraduate training hospitals [38].III. Should ASPs Develop and Implement Facility-Speciﬁc ClinicalPractice Guidelines for Common I nfectious Diseases Syndromes toImprove Antibiotic Utilization and Patient Outcomes?Recommen dation3. We suggest ASPs develop facility-speciﬁc clinical practiceguidelines coupled with a dissemination and implementationstrategy (weak recommendation, low-quality evid ence).Comme nt: Fa ci lity-speciﬁc clinical practice guidelines and al-gorithms can be an effective way to standardize prescribingGuideline for Implementing an Antibiotic Stewardship Program•CID•e9 at IDSA member on May 12, 2016http://cid.oxfordjournals.org/Downloaded from

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pra cticesbasedon local epidemiology .ASPs should developthoseguidelines, when feasible, for common infectious diseases syn-dromes. In addition, ASPs should be involv ed in writing clinicalpathw ays, guidelines, and order sets that address antibiotic useand are developed within other departments at their facility .Evidence SummaryImplementation of facility-speciﬁc clinical practice guidelines canlead to substantial changes in antibiotic use for infections com-monly treated in hospitals. Most published stu dies of clinicalpractice guidelines have involved pneumonia, including commu-nity-acquired pneumonia (CAP) in adults [39–41] and children[42], and healthcare-associated pneumonia [43–46]. One studyinvolved cellulitis and cutaneous abscesses [47]. Several of thesestudies described a process of interdisciplinary guideline de-velopment along with a multifaceted disse mination and im-plementation strategy to increase awareness and uptake of theguideline [40, 43, 45, 47]. Such strategies included guidelinedissemination in electronic or hard-copy formats, provider edu-cation, engagement of peer champion advocates, audit and feed-back of prescribing practices to providers, checklists, andincorporation of recommendations into electronic order sets.Speciﬁc improvements in antibiotic use associated with im-plementation of facility-speciﬁc guidelines have included statis-tically signiﬁcant increases in likelihood of adequate initialtherapy [40, 46], use of narrower-spectrum antibiotic regimens[41, 42, 47], earlier switch from IV to oral therapy [39], andshorter duration of treatment [39, 41, 45–47]—all without ad-verse effects on other clinical outcomes. For those studies pow-ered to detect differences in clinical outcomes, reductions inmortality [40] , le ngth of hospital stay [39–41, 43, 44], adverseevents [ 39, 48], recurrence or readmission [46], and treatmentcosts [40, 44] have been demonstrated.The sustainability of the effects of guideline implementationhas not been well established. In one study, changes in prescrib-ing and outcomes were sustained 3 years after guideline imple-mentation [43]; however, in another study, removal of measuresto promote guideline adherence after 1 year was associated witha reduction in adherence [49]. Therefore, interventions to main-tain guideline adherence over time may be necessary, andintended outcomes should be monitored.IV. Should ASPs Impl ement I nterventions to Improve Antibiotic Use andClinical Outcomes That Target Patients With Speciﬁc Infectio usDiseases Syndromes?Recommen dation4. We suggest ASPs implement interventions to improve anti-biotic use and clinical outcomes that target patients with spe-ciﬁc infectious diseases syndromes (weak recommendation,low-quality evidence).Comment: AS P interventions for patients with speciﬁc in-fectious diseases sy ndromes can be an effective way toimprove prescribing because the messag e can be focused,clinical guidelines and a lgorithms reinforced, and sustain-ability improved. ASPs should regularly evaluate areas forwhich targeted interventions are needed and adapt their ac-tivities accordingly. This approach is most useful if the ASPhas a reliable way to identify patients appropriate for review.Evidence SummaryIn addition to hospital-wide activities, such as preauthorizationor development of clinical guidelines, a strategy for targeted ef-forts to improve antibiotic use and clinical outcomes for a spe-ciﬁc infectious diseases issue has been shown to be effective.Studi es have involved skin and soft tissue i nfections (SSTIs),asymptomatic bacteriuria (ASB), or CAP.For exampl e, to re duce the use of broad-spectrum therapyand shorten the duration of treatment for adults with uncom-plicated SSTIs, an intervention was developed that included dis-semination of a treatment algorithm, electronic order sets,recruitment of physician champions, and quarterly f eedbackto providers of compliance with the guide line. This study of169 adults demonstrated a 3-day reduction in the length of ther-apy, 30% red uction in broad -spectru m antibiotic prescribing,and 0.3% reduction in clinical failure [47].Interventions to reduce inappropriate treatment of ASB at ge-riatric or long-term care institutions have resulted in signiﬁcantdecreases in antibiotic use [50, 51]. For example, Zabarsky et al[50] developed an intervention that discouraged bo th nursesfrom collecting urine cultures from asymptomatic patientsand primary care providers from treating ASB. After the inter-vention, urine cultures decreased from 2.6 to 0.9 per 1000 pa-tient-days (P < .0001), ASB overall rate of treatment declinedfrom 1.7 to 0.6 per 1000 patient-days (P = .0017), and totaldays of antibiotic therapy were reduced from 167.7 to 117.4per 1000 patient-days (P < .001). The improvements were sus-tained for 30 months of follow-up.ASP interventions for CAP have increased the proportion ofpatients receiving appropriate therapy (54.9% to 93.4% in onehospital and 64.6% to 91.3% in a second hospital) [52]. In a pe-diatric population, a CAP intervention resulted in an increase inthe proportion of patients receiving empiric ampicillin from13% to 63% and a decrease in the proportion of patients receiv-ing empiric ceftriaxone from 72% to 21%, without an increasedrisk of treatment failure. [42]. Other studies have demonstratedoptimization of antibiotic use, such as reduced time to oral an-tibiotic conversion by 1–2days[39, 53], decreased duration oftherapy from a median of 10 to 7 days [54] with 148 days of an-tibiotic therapy avoided in the 6-month study period, and im-proved appropriate narrowing of antibiotic therapy from 19% to67%. There was no difference be tween the baseline and inter-vention periods in the proportions of patients who were read-mitted within 30 days (14.5% vs 7.7%; P =.22) or whodeveloped CDI (4.8% vs 1.5%; P = .28). In a study involving 5e10•CID•Barlam et al at IDSA member on May 12, 2016http://cid.oxfordjournals.org/Downloaded from

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hospitals, implementation of a guideline that included criteriafor oral conversion and hospital discharge reduced length ofstay from 7.3 to 5.7 days (P < .001); 30-day readmission propor-tions did not differ (1.9% vs 2.4%; P = .6) [53].An alternative approach is assessing patients with blood cul-tures growing speciﬁc pathogens. Patients with bacteria or yeastin their blood can usually be identiﬁed through comm unicationwith the microbiology laboratory or through alerts from com-put erized surveillance systems. For example, Antwort h et al[ 55] described the i mpact of a candidemia-care bundle inwhich patients were identiﬁed by electronic medi cal recordsand clinical microbiology reports. Implementation of this bun-dle was associated with improved care related to both drug ther-apy (eg, appropriate antifungal therapy selection rates forbundle vs historic control: 100% vs 86.5%; P < .05) and nondrugtherapy (eg, ophthalmologic examination rates: 97.6% vs 75.7%;P = .01). Similarly, Borde et al [56]observedimprovementsinbo th d rug the rapy (appropriate initial ant i-infective therapy:85% vs 4%; P < .001) and nondrug therapy (follow-up cultures:65% vs 33%; P < .001)—as well as decreased mortality (10% vs44%; P < .001) after implementing an ASP bundle targetingStaphylococcus aureus bacteremia. In a study targeting gram-negative bacteremia, Pogue et al [57] combined active alertingof positive blood cultures with ASP intervention. In the sub-group of patients not on appropriate antibiotic therapy at thetime of the initial positive blood culture, the intervention wasassociated with reduced mortality (odds ratio [OR], 0.24; 95%CI, .08–.76) and length of stay (OR, 0.76; 95% CI, .66–.86). Inall patients, the intervention group had shorter time to appro-priate therapy (8 vs 14 hours; P = .01) and length of stay (7 vs 8days; P < .001).V. Shoul d ASPs Implement Interventions Designed to Reduce the Use o fAntibiotics Associated With a Hi gh Risk of CDI?Recommen dation5. We recommend antibiotic stewardship interventions de-signed to reduce the use of antibiotics associated with ahigh risk of CDI compared with no such intervention (strongrecommendation, moderate-quality evidence).Comment: The goal of reducing CDI is a high priority forall ASPs and should be taken into consideration when craft-ing stewardship interventions.Evidence SummaryASPs have been shown to reduce hospital-onset CDI. The pri-mary ASP interventions were restriction of high-risk antibioticssuch as clindamycin [58–61] and/or broad-spectrum antibiot-ics, especially cephalosporins [59–64]andﬂuoroquinolones[59–63, 65]. Climo et al [58]wereamongtheﬁrst to reportthat restriction of clindamycin was associated with decreasedclindamycin use, decreased CDI (P < .001), increased clindamy-cin susceptibility (P < .001), and overall cost savings attributableto fewer cases of CDI [58]. More recent studies have been con-ducted in a variety of hospital settings. Some have been prompt-ed by outbreaks [59 , 65],whereasotherswereperformedinendemic situations [22, 63].Implementation of ASPs has been associated with statisticallysigniﬁcant sudden or linear-trend decreases in nosocomial CDIrates [22, 58–61, 63–65], which have been sustained for up to 7years [22]. A meta-analysis [18] highlights the effectiveness ofstewardship for CDI prevention and outlines ASP interventionstrategies. Other studies support that antibiotic restriction canfurther reduce CDI rates when added to previous infection con-trol measures [58, 59]. In fact, Valiquette et al [59] reported thatsimply strengthening basic infection control measures did not re-duce the CDI rate. CDI rates, however, declined (P < .007) withantibiotic stewardship interventions to reduce the use of second-and third-generation cephalosporins, clindamycin, macrolides,and ﬂuoroquinolones through dissemination of local treatmentguidelines, PAF, and reduction in duration of therapy.VI. Do Strategies t o Encourage Prescriber-Led Review ofAppropriateness of Antibiotic Regimens, in the Absence of Direct InputFrom an Antibiotic Stewardship Team, Improve Antibiotic Prescribing?Recommen dation6. We suggest the use of strategies (eg, antibiotic time-outs,stop orders) to encourage prescribers to perform routine re-view of antibiotic regimens to improve antibiotic prescribing(weak recommendation, low-quality evidence).Comment: Published data on prescriber-led antibiotic re-view are limited, but successful programs appear to require amethodology that includes persuasive or enforced prompt-ing. Without such a mechanism, these interventions are like-ly to have minimal impact.Evidence SummaryStrategies to prompt prescribers to assess antibiotic therapywithout formal ASP intervention have undergone only limitedevaluation. Lee et al [66] developed a structured electronicchecklist for antibiotic time-out a udit to be performed twiceweekly by a senior resident on the medical care team (referredto as “self-stewardship”). Unit pharmacists reminded residentsto complete the checklist and compliance was 80%. Initially, thetime-outs resulte d in changes in antibiotic therapy in 15% ofcases; however, the magnitude of cha nge diminished over the18-month study period. CDI rates decreased by 19% and annualantibiotic costs decreased by 46% (from $149 743 to $80 319),but overall antibiotic use did not [66]. Checklists to guide pro-cess of care in a medical ICU have been studied [67, 68]. In onestudy [67], physicians received face-to-face promptin g if theyoverlooked the antibiotic review on the checklist. Promptingimproved compliance with the checklist and was associatedwith a reduced duration of antibiotic therapy and a lowerrisk-adjusted mortality than no prompting in patients receivingGuideline for Implementing an Antibiotic Stewardship Program•CID•e11 at IDSA member on May 12, 2016http://cid.oxfordjournals.org/Downloaded from

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empiric antibiotics (OR, 0.41; 95% CI, .18–.92; P = .03) [67].Even with prompting, prescribers may have difﬁculty perform-ing self-stewardship. For example, in a study by Le sprit et al[ 69], clinicians were promp ted to review IV therapy at 72hours. There was no signiﬁcant change in the frequency of an-tibiotic regimen modiﬁcation compared with the control group;however, requests for infectious diseases input increased.Antibiotic stop orders are another approach to requiringphysicians to review their antibiotic use. This has been beststudied for 3-day stop orders for vancomycin [70, 71]. Gugliel-mo et al [70] reported that the stop order was associated withless continuation of vancomycin in the absence of documentedgram-positive infection (33/133 [25%] vs 15/142 [11%];P = .002) and less use of vancomycin in febrile neutropenia(37/133 [28%] vs 22/142 [15%]; P < .013). Hospital-wide vanco-mycin use decreased as well (160 g vs 100–120 g per 1000 pa-tient-days; P not stated) [70]. A safety mechanism should bepaired with stop orders to avoid unintended interruptionsand to prevent alienating prescribers against antibiotic steward-ship interventions.Collectively, these ﬁndings suggest that antibio tic review bythe prescriber can have an important stewardship im pact ifdon e wit h appropriate reminders or p rompting, but availabl edata do not conﬁrm feasibility or sustainability.VII. Should Computerized Clinical Decision Su pport System s IntegratedInto the Electronic Health Record at the Time of Prescribing beIncorporated as Part of ASPs to Improve Antibiot ic Prescribing?Recommen dation7. We suggest incorporation of computerized clinical decisionsupport at the time of prescribing into ASPs (weak recom-mendation, moderate-quality evidence).Comment: Computerized clinical decision support forprescribers should only be implemented if information tech-nology resources are readily available. However, computer-ized surveillance systems that synthesize data from theelectronic health record and other data sources can stream-line the work of ASPs by identifying opportunities forinterventions.Evidence SummaryComputerized decision support systems are designed to im-prove antibiotic use by providing treatment recommendationsto clinicians at the time of prescribing [72–77].Implementation of computerized decision support systemsfor prescribers has been associated with reduced use of broad-spectrum antibiotics [73, 74], improved antibiotic dosing [75],reduced antibiotic resistance [74], more appropriate antib ioticselection [73, 77], fewer prescribing errors [72, 75, 78], reducedadverse events [72, 76], reduced antibiotic costs [72, 73, 75, 76],reduced length of stay [72], and reduced mortality [76]. Com-puterized surveillance systems for ASPs may improve efﬁciencyby facilitating more PAF interventions and reducing the timefor such interventions [79–81]. Use of those systems by ASPshas been associated with reduced use of broad-spectrum antibi-otics [81] and reduced antibiotic costs [79].Among the potential d isadvantages of computer decisionsupport and surveillance systems are the time and ﬁnancial re-sources required for implementation and maintenance, and thepotential for a high proportion of nonactionable alerts that maylead to “alert fatigue” [80, 81].VIII. Should ASPs Impl ement Strategies That Promote Cycling o r Mixingin Antibiotic Selection to Reduce Antibiotic Resistance?Recommen dation8. We suggest against the use of antibiotic cycling as a steward-ship strategy (weak recommendation, low-quality evidence).Comment: Available data do not support the use of anti-biotic cycling as an ASP strategy, and further research is un-likely to change that conclusion. Because c linical data aresparse for antibiotic mixing, we cannot give any recommen-dation about its utility.Evidence SummaryAntibiotic cycling involves withdrawal of an antibiotic or anti-biotic class from general use (within a ward or an institution)for a designated period of time and substitution with antibioticsfrom a different class having a comparable spectrum of activitybut for which bacteria may have different resistan ce me cha-nisms. Antibiotic cycli ng is difﬁcult to achieve, labor intensive,and impractical for most inpatient facilities.Many studies have been performed, but they fail to providecompelling evidence of the beneﬁt of antibiotic cycling, partlybecause of methodologic shortcomings. Common weaknessesinclude single -center setting (usually in ICUs), before-and-after time-series analysis, lack of adherence to prescribing pro-tocols, multiple simultaneous interventions (including infectionpreventio n and guideline implementation), and lack of long-term follow-up. Brown and Nathwani [82] performed a system-atic review of antibiotic cycling in 20 05 and concluded thatavailable study results did not perm it conclusions regardingthe efﬁcacy of cycling.In contrast to cycling that is performed at the level of themedical facility or patient care ward, a strategy known as anti-biotic mixing is performed at the level of the individual patient,in which consecutive patients with the same diagnos is receivean a ntibiot ic from a different class in rotation. Mathematicalmodeling suggests that antibiotic mixing is a more promisingstrategy for limiting emerg ence of resistance than cycling, butfew clinical studies validate these models [83, 84]. Comprehen-sive rev iews published in 2010 [85, 86] concluded t hat morework is needed to demonstrate the usefulness of antibioticmixing.e12•CID•Barlam et al at IDSA member on May 12, 2016http://cid.oxfordjournals.org/Downloaded from

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OptimizationIX. In Hospitalized Patients IV Intravenous Antibiotics, Does aDedicated PK Monitoring and Adjustment Program Lead to ImprovedClinical Outcomes and Reduced Costs?Recommen dations9. We recommend that hospitals implement PK monitoringand adjustment programs for aminoglycosides (strong rec-ommendation, moderate-quality evidence).10. We suggest that hospitals implement PK monitoring andadjustment programs for vancomycin (weak recommend a-tion, low-quality evidence).Comment: PK monitoring and adjustment programs canreduce costs and decrease adverse effects. T he ASP shouldencourage implementation and provide support for trainingand assessment of competencies. The conduct of those pro-grams should be integrated into routine pharmacy activities.Evidence SummaryIn randomized studies, individualized PK monitoring and adjus t-ment of aminoglycoside dosing compared with standard dosing isassociate d with increased likelihoo d of obtaining serum concentr a-tions within therapeutic r ange [87, 88] and reduced institutionalcosts [87, 89]. Reductions in nephrotoxicity, hospital length ofstay, and mortality [87,90–92] have been observe d in some studies.Leehey et al [88] randomized patients receivi ng aminoglycosides todosing directed by one of 3 groups: (1) physicians with PK mon-itoring input from a pharmacist; (2) physician–pharmacist PKmonitoring team; or (3) physicians with no ext ernal input (controlgroup). The PK monitoring groups achieved higher peak and mar-ginally lower trough concentrations; how ev er, there was no statisti-cally signiﬁcant difference in the likelihood of nephrotoxicityamong groups 1, 2 , and 3 (27%, 16%, and 16%, respectively;P = .31). Clinical failure was less common in the PK-monitoredgroups across all patient s (1%, 0%, and 11%, respecti vely;P = .004), but not among patients with micr obiologically pro veninfection. Bartal et al [90] compared the outcomes of usual carevs an intensiv e PK monitoring progr am among patients receivi nginitial high-dose extended-interval gentamicin dosing. Nephrotox-icity was low er in the PK monitoring group (5% vs 21%; P =.03),with similar propo rtions of pa tients experiencing cure of infectionor deat h at 28 days between the groups.On ly one randomized control led study [93] has been per-formed assessing the impact of a PK monitoring and adjustmentprogram for vancomycin; no difference in efﬁcacy in the concen-tration-monitoring arm was demonstrated, but there was a lowerincidence of nephrotoxicity (adjusted OR, 0.04; 95% CI, .006–.30)at a cost per case of nephrotoxicity avoided of $435. Observation-al studies [93–96] of vancomycin dose individualization showedsimilar effects, with costs stable or lower.Broade r interventions directed at antibiotic dosi ng, usuallyinvolving integration of dosing support into computerized phy-sician order-entry systems, have shown improved adherence todosing guidelines as well as fewer adverse effects, but no differ-ence in effectiveness (eg, clinical cure, hospital mortality, orlength of stay) [97– 99]. No studies have examined the relation-ship between PK monitoring and adjustment programs and in-stitutional antibiotic resistance prevalence.X. In Hospitalized Patients, Should ASP s Advocate for AlternativeDosing Strategies Based on PK/Pharmacodynamic Principles toImprove Outc omes and Decrease Costs for Broad-Spectrum ß-Lactamsand Vancomycin?Recommen dation11. In hospitalized patients, we suggest ASPs advocate for theuse of alternative dosing strategies vs standard dosing forbroad-spectrum β-lactams to decrease cost s (weak recom-mendation, low-quality evidence).Comment: Although data for improved outcomes for broad-spectrum β-lactam dosing with this approach are still limited,these interventions are associated with antibiotic cost savings.ASPs should consider implementation but must take into ac-count logistical issues such as nursing and pharmacy educationand need for dedicated IV access. Considering the limited ev-idence, we cannot give any recommendation about the utilityof alternative dosing strategies for vancomycin.Evidence SummaryDosing strategies based on PK/pharmacodynamic (PK/PD)principles for aminoglycosides, such as once-daily dosing,have been shown to be effective in reducing nephrotoxicityand, in some studies, improve clinical outcomes [100, 101].The effectiveness of alternative dosing schemes for β-lactam an-tibiotics and vancomycin based on PK/PD principles is unclear.For β–lactam antibiotics, one meta-analysis showed de-creased mortality (risk ratio, 0.59; 95% CI, .41–.83) amongpatients receiving continuous infusions of carbapenems or pi-peracillin-tazobactam vs standard infusions. Th is meta-analysis included 3 randomized controlled tri als (RCTs) thatcomprised only 25% of the patient outcomes anal yzed [102].In contrast, another meta-analysis t hat included 14 RCT s didnot support improved outcomes usin g prolonged infusions ofbroad-spectrum β-lactam antibiotics (either extended or con-tinuous infus ion) [103]. A Cochrane review [104] and a recentrandomized trial [105] in critically ill patients of continuous in-fusions of β-lactam antibiotics compared with standard inter-mittent dosing also did not demonstrate beneﬁts in outcome.For vancomycin, continuous infusion has not been shown toimprove clinical outcomes in adults but has been associatedwith decreased nephrotoxicity in a meta-analysis [106]. Similar-ly, continuous-infusion vancomycin has been associated withfew adverse effects and no nephrotoxicity in children [107].Alternative dosing strategies for β-lactam antibiotics [108]and vancomycin [ 109 ] were associated with signiﬁcantly lowercosts than intermittent infusions in randomized studies. SavingsGuideline for Implementing an Antibiotic Stewardship Program•CID•e13 at IDSA member on May 12, 2016http://cid.oxfordjournals.org/Downloaded from

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were attributable to lower acquisition costs of β-lactam antibiot-ics but not overall hospit al expenses [10 8], and lower costs ofvancomycin acquisition and monitoring [109].XI. Should ASPs Implement Interventions to Increase Use of OralAntibiot ics as a Strate gy to I mprove Outcom es or Decrease Costs ?Recommen dation12. We recommend ASPs implement programs to increaseboth appropriate use of oral antibiotics for initial therapyand the timely transition of patients from IV to oral antibi-otics (strong recommendation, moderate-quality evidence).Comment: Programs to increase the appropriate use oforal antibiotics can reduce costs and length of hospital stay.IV-to-oral conversion of the same antibiotic is less compli-cated than other strategies and is applicable to many health-care settings. The conduct of those programs should beintegrated into routine pharmacy activities. ASPs should im-plement strategies to assess patients who can safely completetherapy with an oral regimen to reduce the need for IV cath-eters and to avoid outpatient parenteral therapy.Evidence SummaryThe ﬁndings of many studies [110–116] have shown that pro-grams aimed to increase the use of oral antibiotics are associatedwith reduc ed drug costs and length of hospital stay withoutcom promisi ng efﬁ cacy or safety. For example, Omidvari et al[115] reported that patients with CAP randomized to receive anabbreviated course of IV cephalosporin followed by oral cephalo-sporin had a lower total cost of care ($5002 vs $2953; P <.05)andshorter hospital stay (10 vs 7 days; P = .01) than those trea ted withconventional IV cephalosporin therapy. There were no differencesin clinical course, cure rate, survival, or resolution of chest radio-graphs [115]. Laing et al [116] reported that the incidence of linecomplications was lower in patients who were switched to oraltherapy than in those who remained on IV therapy (17/81 vs26/81), but this difference was not signiﬁcant (P = .077).Unlike automatic conversion from IV to oral formulations ofthe same antibiotic, switching from IV antibiotics without anequivalent oral formulation needs more advanced assistance.Mertz et al [114] reported that early switching on medicalwards was ass ociated wi th a shorter duration of IV antibiotictreatment (reduction in median days, 19%; 95% CI, 9%–29%;P = .001), a trend toward a decreased overall duration of antibi-otic treatment, and economic savings—all wi thout signiﬁcantchanges in mortality or rea dmissions; however, only 151 of246 (61.1%) of potential cases were switched. This might havebeen partly attributable to the lack of precise recommendationsfor switching when an oral equivalent was not available (eg, pi-peracillin-tazobactam or me ropenem) as switching occurredless often in such patients. In contrast, Sevinç et al [112] report-ed an increased percentage of eligible patients being convertedfrom IV to oral antibiotics (52/97 [54%] vs 66/80 [83%];difference, 29%; 95% CI, 16%–42%; P < .001) after implementa-tion of guidelines for switching therapy. They directed providersto seek infectious diseases consultation for patients on IV for-mulations without an oral equivalent. ASPs can have an impor-tant role with more complicated IV-to-oral transitions.Another example of the potential beneﬁt of IV-to-oral transi-tion is reduction in the need for outpatient parenteral antibiotictherapy (OPAT). For example, Conant et al [117] reported out-comes in 56 patients who received oral (n = 50) or no additionalantibiotics (n = 6) after mandatory infectious diseases approval ofOPAT. Denial of OPAT was associated with true clinical failure inonly 1 of 56 patients and a per-patient cost savings of $3847.XII. In Patients With a Reported History of ß-Lactam Allergy, ShouldASPs Facilitate Initiatives to I mplement Allergy Assessments With theGoal of Improved Use of First-Line Antibiot ics?Recommen dation13. In patients with a history of β-lactam allergy, we suggestthat ASPs promote allergy assessments and PCN skin testingwhen appropriate (weak recomm endation, low-quality evi-dence).Comment: Allergy assessments and PCN skin testing canenhance use of ﬁrst-line agents, but it is largely unstudied asa primary ASP intervention; however, ASPs should promotesuch assessments with providers. In facilities with appropriateresources for skin testing, the ASPs should actively work to de-velop testing and treatment strategies with allergists.Evidence SummaryPCN is the most common drug “allergy” noted at hospital ad-mission, and is reported in 10%–15% of patients and 15%–24%of those requiring antibiotic therapy [118, 119]. Compared withnonallergic patients, patients labeled as having a PCN allergyare exposed to more alternative antibiotics; have increased prev-alence of C. difﬁcile, methicillin-resistant S. aureus, and vanco-mycin-resistant enterococcal infections; and have longerhospital stays [118 ].Properly performed skin testing using major and minor PCNdeterminant reagents has a negative predictive value of 97%–99%and a positive predictive value of 50%. Studies demonstrate thatPCN and other β-lactam antibiotics can be safely given to patientswith a putative PCN allergy who have had an allergy assessmentand negative PCN skin testing [119, 120]. Rimawi et al [121]re-ported that all but one of 146 patients with a history of PCN al-lergy who had a negative skin te st tolerated β-lactam therapy,resulting in a negative predictive value of >99%. They alsofound that the use of skin testing to guide antibiotic therapy yield-ed an annual savings of $82 000 at a university teaching hospital.Using structured drug allergy assessments has been associat-ed with improved antibiotic stewardship as demonstrated by an-tibiotic selection, reduced alternative antibiotic use, decreasedlength of hospital stay and c osts, and increased guidelinee14•CID•Barlam et al at IDSA member on May 12, 2016http://cid.oxfordjournals.org/Downloaded from

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adherence [119, 120]. For example, Park et al [122] reported thatcollaboration between trained pharmacists and allergists was as-sociated with increased β-lactam prescriptions in patients with ahistory of PCN allergy. ASPs sh ould encourage mechanismsthat ensure allergy assessments are performe d.XIII. Should ASPs Implement Interventions to Reduce Antibiotic Therapyto the Shortest Effective Duration?Recommen dation14. We recommend that ASPs implement guidelines andstrategies to reduce antibiotic therapy to the shortest effectiveduration (strong recommendation, moderate-quality evidence).Comment : R ecommendi ng a dur a ti on of thera py based on pa-tient-speciﬁc factors is an important activity for ASPs. Suitableapproaches include developing written guidelines with speciﬁcsuggestions for dur a tion, including dur a tion of therapy recom-mendation s as part of the preaut horiza t ion or prospect iv e auditand feedback process, or specifying durat ion a t the time of anti-biotic ordering (eg, through an electronic order entry system).Evidence SummaryFindings from 2 pre–post investigations suggest that antibioticstewardship interventions aimed at reducing the duration of an-tibiotic therapy lead to similar clinical outcomes compared withthe preintervention period. Speciﬁcally, education and PAF foradult inpatients with CAP led to a median decrease in antibioticuse from 10 to 7 days (P < .001), with no signi ﬁcant differencesin lengt h of stay or 30-day readmiss ion rates [54]. A s econdstudy [47] found reduced antibiotic utilizat ion and durationof therapy (from 13 to 10 days; P < .001) after implementationof a guideline for inpatients with SSTIs. There are limited stud-ies speciﬁcally evaluating the impact of ASP interventions to re-duce duration of antibiotic therapy on clinical outcomes;howe ver, evid ence from systematic reviews [123–126]andRCTs [127–136] demonstrated that presc ription of shortercourses of antibiotic therapy is associated with outcomes similarto those with longer courses in both adults and children with avariety of infection types (Table 2) and few adverse events.Microbiology and Laboratory DiagnosticsXIV. Should ASPs Work With the Microbiology Laboratory to DevelopStratiﬁed Antibiograms, Compared With Nonstratied Antibiograms?Recommen dation15 . We suggest development of stratiﬁed antibiograms oversolely relying on non stratiﬁed antibiograms to assist ASP sin de veloping guidelines for empiric therapy (weak recom-mendation, low-quality evidence).Comment: Althou gh there is limited evidence at this timethat stratiﬁed anti biograms (eg, by locatio n or age) lead toimproved empiric antibiotic therapy, stratiﬁcation can expo-se important differences in susceptibility, which can helpASPs develop optimized treatment recommendations andguidelines.Evidence SummaryInstitutional antibiograms are helpful to ASPs for the developmentof guidelines for empiric therapy. The Clinical and LaboratoryStandards Institute [137] provides guidelines for antibiogram con-struction and reporting, both for routine cumulative antibiogramsand for enhanced antibiogra ms, which may be str atiﬁed by variousparameters including patient location or population if at least 30isolates are available for each organism. A single institutional, orhospital-wide, antibiogram may mask important susceptibility dif-ference s acro ss units within the institution. For exampl e, certain an-tibiotic-resistant organisms are often signiﬁcantly more commonin ICU than in non-ICU settings. At one medical center, the per-centages of bacterial isolates resistant to antibiotics were signiﬁ-cantly higher in medical and surgi cal ICUs than were t hosepredicted by the hospital-wide antibiogram, whereasthe per centageof isolates susceptible to antibiotics was higher in non-ICU units,compared with the hospital overall [138]. Similarly , antibiogramscan be str a tiﬁed by population age group (eg, pediatrics) [139], byinfection site (eg, blood or respir a tory vs all sources) [140, 141], bypatient comorbidities (eg, cys tic ﬁbr o sis) [142], or by acquisition inthe community vs healthcar e setting [143].One institution [144] constructed a pediatric-speciﬁcantibio-gram for Escherichia coli and compared it with antibiograms gen-erated from combined data from both adult and pediatric isolates.There were signiﬁc ant antibiotic susceptibility differences be-tween E. coli isolates obtained from pediatric patients vs the hos-pital-wide antibiogram data [144]. Provision of pediatric-speciﬁcdata optimized prescribing choice when compared with no anti-biogram and also with the hospital-wide antibiogram. Anotherinstitution [139] also found age-speciﬁc differences with overes-timation of resistance in E. coli and S. aureus for children and un-derestimation for the elderly.XV. Should ASPs Work With the Microbiology Laboratory to PerformSelective or Cascade Reporting of Antibiotic Susceptibility TestResults?Recommen dation16. We suggest sele ctive and cascade reporting of antibioticsover reporting of all tested antibiotics (weak recommenda-tion, low-quality evidence).Comment: Although data are limited that demonstrate di-rect impact of those strategies on prescribing, some form ofselective or cascaded reporting is reasonable. After imple-mentation, ASPs should review prescribing to ensure thereare no unintended consequences.Evidence SummarySelective reporting is the practice of reporting susceptibility re-sults for a limited number of antibiotics instead of all testedGuideline for Implementing an Antibiotic Stewardship Program•CID•e15 at IDSA member on May 12, 2016http://cid.oxfordjournals.org/Downloaded from

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antibiotics. For example, a laboratory that practices selective re-porting would rout inely release linezolid and daptomycin re-sults only when enterococci are nonsusceptible to ampicillinand vancomycin. In a randomized study for urinary tract infec-tions, Coupat et al [145] used a case-vignette format and ran-domly assigned residents to an intervention group, whichreceived antibiotic susceptibility results for 2–4 antibiotics, orto a control group, which received full-length results for all 25antibiotics tested. The increase in appropriateness of antibioticprescription with the use of selecti ve reporting ranged from 7%to 41%, dependin g upon the c linical scenario. Similar resultshave been seen in some prospective surveys [146, 147].Cascade reporting is one type of selective reporting in whichsusceptibility results of secondary antibiotics (either more costlyor broader spectrum) are only reported if an organism is resis-tant to the primary antibiotic within the particular antibioticclass (eg, if the organism is cefazolin susceptible, ceftriaxonewould not be reported). There are no published guidelines forcascade antibiotic reporting. The Clinical and Laboratory Stan-dards Institute [148] provides guidance for testing and report-ing susceptibilities for certain organisms, but does not cover allorganism-antibiotic combinations. ASPs should work with themicrobiology laboratory to assess the impact t hese strategiesmay have on development of the antibiogram (eg, susceptibilitydata for suppressed results may not be available for inclusion).XVI. Shoul d ASPs Advocate for Use of Rapid Viral Testing forRespiratory Path ogens to Reduce the Use of I nappropriate Antibiotics?Recommen dation17 . We suggest the use of ra pid viral testing for respiratorypathogens to reduce the use of inappropriate antibiotics(weak recommendation, low-quality evidence).Comment: Althou gh rapid viral testing has the potential toreduce inappropriate use of antibiotics, results have been in-consistent. Few studies have been perfo rmed to assess wheth-er active ASP intervention would improve those results.Evidence SummaryStudies of the value of ASP interventions based on rapid testingfor respiratory viruses are lacking. However, some data are avail-able on decreased inappropriate antibiotic use with rapid viraltesting. Those studies have been performed primarily in pediatricpopulations such as children presenting to physicians’ ofﬁces[149] or emergency departments [150–152], or childrenrequiring hospitalization [153]. One study focused speciﬁcallyon immunocompromised children [154] and 2 focused on adults[155, 156].Findings from some trials showed that rapid diagnostic testingfor respiratory viruses by rapid antigen, rapid immunoassay, ordirect ﬂuorescent antigen was associated with decreased ancillarytest orders (eg, chest radiograph, urinalysis) [150, 157], decreasedTable 2. Meta-analyses and Examples of Randomized Clinical Studies Comparing Shorter Versus Longer Duration of AntibioticsReference Clinical Condition/PopulationTreatmentDuration, d Clinical OutcomeaMeta-analysesDimopoulos et al, 2008 [123] Adults and children with CAP 3–7vs5–10 Clinical success, relapse, mortality, adverse eventsPugh et al, 2011 [124] Adults with VAP 7–8vs10–15 Antibiotic-free daysb, recurrencebDimopoulos et al, 2013 [125] Adults with VAP 7–8vs10–15 Relapse, mortality, antibiotic-free dayscRandomized clinical trialsChastre et al, 2003 [127] Adults with VAP 8 vs 15 Mortality, recurrent infectionsdEl Moussaoui et al, 2006 [128] Adults with CAP 3 vs 5 Clinical and radiological successGreenberg et al, 2014 [129] Children with CAP 5 vs 10 Treatment failureeHepburn et al, 2004 [130] Adults with cellulitis 5 vs 10 Clinical successSandberg et al, 2012 [131] Adult females with acute pyelonephritis 7 vs 14 Clinical efficacy, adverse eventsTalan et al, 2000 [132] Women with acute uncomplicated pyelonephritis 7 vs 14 Bacteriologic and clin ical curefRunyon et al, 1991 [133] Adults with spontaneous bacterial peritonitis 5 vs 10 Mortality, bacteriologic cure, recurrenceSaini et al, 2011 [134] Neonatal septicemia 2–4 vs 7 (withsterile culture)Treatment failureSawyer et al, 2015 [135] Adults with intra-abdominal infection 4 vs ≤10 Composite of surgical site infection, recurrentintra-abdominal infection, or deathBernard et al, 2015 [136] Adults with vertebral osteomyelitis 42 vs 84 Cure at 1 y by independent committee andsecondary outcomesAbbreviations: CAP, community-acquired pneumonia; VAP, ventilator-associated pneumonia.aThere were no statistically significant between-group differences in outcomes unless otherwise noted.bShorter course was associated with more antibiotic-free days (mean difference, 4.02; 95% confidence interval [CI], 2.26–5.78) and fewer VAP recurrences due to multidrug-resistant organisms(odds ratio [OR], 0.44; 95% CI, .21–.95), without adverse effects on other outcomes. For VAP due to nonfermenting gram-negative bacilli, however, shorter course was associated with morerecurrences (OR, 2.18; 95% CI, 1.14–4.16).cShorter course was associated with more antibiotic-free days (mean difference, 3.40 days; 95% CI, 1.43–5.37).dShorter course was associated with more antibiotic-free days (13.1 v 8.7 days; P < .001) and no increase in recurrent infection except in the subset with nonfermenting gram-negative bacilli.eThe 5-day, but not the 3-day, course was not inferior to the 10-day course.fShorter course was associated with higher bacteriologic (99% vs 89%; 95% CI, .04–.16; P = .004) and clinical cure rates (96% vs 83%; 95% CI, .06–.22; P = .002).e16•CID•Barlam et al at IDSA member on May 12, 2016http://cid.oxfordjournals.org/Downloaded from

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antibiotic use [149, 150, 153, 156, 157], and increased antiviral use[149,150, 157]. For example, Bonner et al [150] reported that phy-sician awareness of positive inﬂuenza results by a rapid immuno-assay reduced the number of laboratory tests ordered (P = .01),the number of radiographs ordered (P < .001), and the associatedcharges (P < .001). The authors also noted decreased antibioticuse (P < .001), increased antiviral use (P = .02), and sho rtenedtime to discharge (P <.001). Therewasno impacton the aboveoutcomes for patients with negative rapid test results.Kadmon et al [154] recently reported that polymerase chainreaction (PCR) test results prompted initiation of speciﬁc anti-viral therapy and avoidance of unnecessary antibiotics in 17 of50 episodes (34%). Other studies [152, 155], however, havefailed to detect statistically signiﬁcant beneﬁts in antibioticuse, hosp ital stays, or hospital admissions when reportingPCR or direct ﬂuorescent antigen results. The lack of an appre-ciable beneﬁt was attributable in part to the time to reporting ofPCR results, which ranged from 12 to 24 hours in one study[152] to a mean of 30 ho urs in another study [155].XVII. Shoul d ASPs Advocate for Rapid Dia gnostic Testing on BloodSpecimens to Optimize Antibiotic Therapy and Improve ClinicalOutcomes?Recommen dation18. We suggest rapid diagnostic testing in addit ion to con-ventional culture and routine reporting on blood specimensif combined with active ASP support and interpretation(weak recommendation, moderate-quality evidence).Comment: Availability of rapid diagnostic tests is expectedto increase; thus, ASPs must develop processes and interven-tions to assist clinicians in interpreting and responding ap-propriately to results.Evidence SummaryThe use of rapid molecular assays and mass spectrometry t oidentify bacterial species and susceptibility in blood cultureshas been associated with statistically signiﬁcant improvementsin time to initiation of appropriate antibiotic therapy [158–162], rates of recurrent infection [159], mortality [159, 163],length of stay [159, 161], and hospital costs [160, 161]. For ex-ample, Forrest et al [163] described the use of peptide nucleicacid ﬂuorescence in situ hybridization (PNA-FISH) for entero-cocci. Compared with pre–PNA-FI SH, rapid testing coupledwith antibiotic stewardship team support was associated withmore rapid identiﬁcation of Enterococcus faecalis (1.1 vs 4.1days) and Enterococcus faecium (1.1 vs 3.4 days), faster time toeffective therapy (1.3 vs 3.1 days), and decreased 30-day mortalityfor E. faecium (26% vs 45%) (all P < .05) [163 ]. Matrix-assistedlaser desorption/ionization time-of-ﬂight (MALDI-TOF) massspectrometrycanrapidlyidentifybacteria,includingrarespecies not ordinarily associated with clinical infection or path-ogens that are difﬁcult to grow or to identify to the species level[164]. In the study by Huang et al [159], the stewardship teamreceived immediat e notiﬁcation of blood culture Gram stain,MALDI-TOF identiﬁcation, and susceptibility results, andthen gave recommendations. MALDI-TOF was associated withmore ra pid identiﬁcation of organisms (55.9 vs 84.0 hours;P < .001). Identiﬁcation of organisms w ith MALDI-TOF incom bination with real-time ASP review and intervention wasassociated with faster time to initiation of both effective (20.4vs 30.1 hours; P = .021) and optimal antibiotic therapy (47.3vs 90.3 hours; P < .001). A recent RCT [162] compared standardblood culture processing (that included MALDI-TOF for or-ganism identiﬁcation) with rapid multiplex PCR (rmPCR)with templated comments, and rmPCR with templated com-ments and real-time ASP audit and feedback (rmPCR/AS).Both interventions were associated with g reater use of nar-row-spectrum β-lactams (rmPCR 71 hours and rmPCR/AS 85hours vs control 42 hours; P = .04) and faster time to appropri-ate escalation (rmPCR 6 hours and rmPCR/AS 5 hours vs con-trol 24 hours; P = .04). The intervention with ASP involvementwas also associated with more rapid appropriate de-escalation(21 hours vs con trol 34 hours and rmPCR 38 hours;P < .0001). These interventions were not, however, assoc iatedwith improved mortality, length of stay, or cost, possibly be-cause of the use of other rapid tests and ASP support at theinstitution.These studies underscore the importance of combining use ofrapid testing with 2 strategies to maximize the beneﬁts and like-lihood of a favorable impact on outcomes. First, ASP support[159–163] or rapid notiﬁcation of results [158 , 162] was a con-sistent feature of the studies that found statistical ly signiﬁcantassociations between rapid testing and outcomes. In contrast,studies lacking these features often did not ﬁnd evidence of as-sociations between rapid testing and i mproved antibiotic use[ 165], time to initiation of appropriate antibiotic therapy[166], or length of stay beneﬁt[165]—despite shortening thetime to pathogen identiﬁcation. Second, rapid testing shouldbe performed continuously (ie, 24/7) or at least in frequentbatches [167, 168]. The optimal implementation of rapid testingrequires increased laboratory resources and additional costs.XVIII. In Adults in ICUS With Suspected Inf ection, Should ASPsAdvocate PCT Testing as an Intervention to Decrease A ntibiotic Use?Recommen dation19. In adults in ICUs with suspected infection, we sugges t the useof serial PCT measurements as an ASP intervention to de-crease antibiotic use (weak recommendation, moderate-qual-ity evidence).Comment: Although randomized trials, primarily inEurope, have shown reduction in antibiotic use through im-plementation of PCT algorithms in the ICU, similar data arelacking for other regions including the United States wherethe patterns of antibiotic prescribing and approach toGuideline for Implementing an Antibiotic Stewardship Program•CID•e17 at IDSA member on May 12, 2016http://cid.oxfordjournals.org/Downloaded from

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stewardship may differ. If implemented, each ASP must devel-op processes and guidelines to assist clinicians in interpretingand responding appropriately to results, and must determine ifthis intervention is the best use of its time and resources.Evidence SummaryPCT has been assessed for its role in (1) shortening the durationof antibiotic therapy for bacterial infection based on serial mea-surements of PCT levels, and (2) avoidance of initiation of an-tibiotic therapy when the PCT level is low. Evidence fromseveral prospective RCTs supports the use of PCT in decisionsconcerning discontinuation of antibiotic therapy in critically illpati ents in ICUs [169–172]. In general, trials assessing PCT-guided discontinuation of antibiotic therapy report signiﬁcantlymore antibiotic-free days (2–4 days) in the PCT arm, without anegative effect on mortality. A meta-analysis focusing exclusive-ly on critically ill ICU patients with severe sepsis or septic shock(including 7 studies and 1075 patients) showed no signiﬁcantdifference in 28-day mortality or hospital mortality and a medianreduction of approximately 2 days in the length of antibiotictherapy with PCT guidance [173]. In a European multicenterstudy, Bouadma et al [ 172] examined de-escalation of therapyin 621 septic pati ents and demonstrated 2.7 more antibiotic-free days in the PCT group (P < .001), although days of antibioticexposure per 1000 inpatient-days were high for each group (653PCT vs 812 control) [172]. Available evidence does not supportthe use of PCT to avoid initiation of antibiotics in the criticallyill ICU population when the PCT result is negative [174, 175].XIX. In Patients With Hematologic Malignancy, Should ASPs Advocatefor Incorporation of Noncu lture-Based Fungal Markers i n Interventionsto Optimize Antifungal Use?Recommen dation20. In patients with hematologic malignanc y at risk of con-tracting IFD, we suggest incorporating nonculture- basedfungal markers in ASP interventions to optimize antifungaluse (weak recommendation, low-quality evidence).Comment: ASPs with an existing intervention to optimizeantifungal use in patients with hematologic malignancy canconsider algorithms incorporating nonculture-based fungalmarkers. Those interventions must be done in close collabo-ration with the primary te ams (eg, hematology-oncology).Antib iotic stewards must dev elop expe rtise in ant ifungaltherapy and fungal diagnostics for the programs to be suc-cessful. The value of those markers for interventions inother populations has not been demonstrated.Evidence SummarySome studies have demonstrated that the use of nonculture-based fun gal markers can safely reduce antifungal t reatmentsfor patients with hematologic malignancy at high risk forIFD. Although not speciﬁcally studied as part of an ASP inter-vention, incorporation into existing ASPs for antifungalstewardship in that population may be useful. A variety of fun-gal tests such as galactomannan (GM), (1,3)-β-D-g lucan(BDG), or single- or multipathogen fungal PCR have been stud-ied. For example, Cordonnier et al [176] compared a preemptiveapproach (antifungal treatment initiation using both clinicaland GM evidence of IFD) with an empiric strategy (antifungaltreatment for any high-risk patient with suggestive clinical signsof IFD). The preemptive approach was associated with de-creased antifungal treatment (39.2% vs 61.3%; P < .001) andno detrimental effect on mortality.Few studies assess ed utilization of BDG or PCR to targettherapy. An RCT [177]ofAspergillus and Candida PCR com-pared survival between allogeneic stem cell transplant recipientswho received empiric antifungal treatment with those who re-ceived empiric plus P CR-bas ed antifungal treatment. The au-thors demonstrated improved 30-day su rvival in the group inwhich treatment decisions were in part based upon PCR, butsurvival did not differ by day 100.There are limited data assessing the value of fungal markersin other patient populations. Pediatric data are limited, butstudies [178] have shown that GM assay is a useful adjunctivetool when monitored twice weekly in hospitalized children withhematologic malignancies and fever.Me asurementXX. Which Overall Measures Best Reﬂect the Impact of ASPs and TheirInterventions?Recommen dation21. We su ggest monitoring antibiotic use as m easured byDOTs in preference to DDD (weak recommendation,low-quality evidence).Comment: Every ASP must measure antibiotic use, strati-ﬁed by antibiotic. DOTs are preferred, but DDDs remain analternative for sites that cannot obtain patient-level antibioticuse data. ASPs should consider measurement of appropriateantibiotic use within their own institutions by examining com-pliance with local or national guidelines, particularly when as-sessing results of a targeted intervention, and share that datawith clinicians to help inform their practice. Although ratesof CDI or antibiotic resistance may not reﬂect ASP impact (be-cause those outcomes are affected by patient population, infec-tion control, and other factors), those outcomes may also beused for measurement of targeted interventions.Evidence SummaryDOTs and DDDs are standardized methods for measu rementof antibiotic use. Both a re useful for facility-level monitoringand interfacility comparisons. DOTs have some important ad-vantages. DOTs are not impacted by dose adjustments and canbe used in both adult and pediatric populations, whereas DDDshave more limited use in pediatrics due to weight-based dosing.In addition, the Antimicrobial Use and Resistance Module ine18•CID•Barlam et al at IDSA member on May 12, 2016http://cid.oxfordjournals.org/Downloaded from

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the CDC’s National Healthcare Safety Network requires report-ing of antibiotic use by DOTs [179]. DOTs, however, require pa-tient-level antibiotic use data, which currently may not befeasible at every facility [180–182 ]. Either method can be usedto examine overall use or speciﬁc use by unit, provider, or ser-vice in the hospital. In ad dition to measurement of antibioticuse, appropriateness of prescribing can be assessed by deter-mining compliance with facility-speciﬁc antibiotic treatmentguidelines. This is particularly useful when assessing the successof a targeted intervention.Measurement of ASP impact on patient outcomes is impor-tant but is more challenging than measurement of antibiotic useor guideline compliance. For example, using CDI rates to mea-sure the effectiveness of stewardship interventions has sig-niﬁcant limitations. Although implementation of ASPs hasbeen associated wit h reduced CDI rates in quasi-experimentalstudies [18], the quantitative relationships between changes inantibiotic use and CDI incidence are largely unknown. BecauseCDI rates are affected by other practices besides antibiotic use,such as compliance with infection control measures, they maybe a relatively insensitive metric for judging the effectiveness ofASPs. Moreover, traditional statistical techniques have signiﬁ-cant limitations when applied to nonindependent events suc has CDI. Despite this, when implem enting ASP interventions di-rected at reduction of antibiotics considered to be high risk forpromoting CDI (eg, cephalosporins, clinda mycin, ﬂuoroquino-lones), including rates of healthcare-facility-onset CDI as a sec-ondary outcome measure is recommended in that population.Antibiotic resistance is an even more complex metric than CDIbecause the development and spread of resistance is impacted bymany factors. Implementation of stewardship interventions hasbeen associated with reduced resistance in both gram-positiveand gram-negative bacteria [34]; however, observed effects on re-sistance are unpredictable because of confounding variables andmany pathogen and host factors. Still, measurement of resistancemay be useful for selected bacterial pathogens and in focused pa-tient populations receiving a targeted ASP intervention.ASPs have the potential to decrease length of stay, primarilyas a consequence of timely switching from IV to oral antibioticsor by stopping unnecessar y IV antibiotics; however, the impactdepends on the preexisting contribution of prolonged adminis-tration of parenteral antibiotics to excess length of stay. Days ofhospitalization avoided is a better measure of the effectivenessof ASP. Parenteral therapy and days of ce ntral venous accessavoided are other metrics that can be useful.XXI. What is the Best Measure of Expe nditures on Antibiot ics to Assessthe Impact of ASPs and Interventions?Recommen dation22. We recommend measuring antibiotic costs based on pre-scriptions or administrations instead of purchasing data(good practice recommendation).Evidence SummaryASPs result in cost savings for facilities [ 183]. It is important tomonitor program costs in addition to measuring antibiotic useas one way to justify continued administrative suppor t for ASPactivities. Antibiotic costs should be measured based on pre-scriptions or administrations instead of purchasing data [184]and normalized to account for patient cen sus (eg, antibioticcost per patient-day) [184 ]. Program costs (eg, salary for stew-ardship personnel) [19, 185] and adjustment for inﬂation orstandardizin g costs across years [185] should be considered.Analyses that measure the effects of an intervention over timeshould compare actual costs after the initiation of the interven-tion vs projected costs in the absence of the intervention, as di-rect cost reductions tend to plateau [185, 186]. More robustanalyses include expenditures beyond drug acquisition such asthose for drug administration, therapeutic drug monitoring,and toxicities [187]. If resources are available, programs shouldanalyze broader effects on budgets, such as total hospitalizationcosts [58, 160, 188].XXII. What Measures Best Reec t the Impact of Interventions to ImproveAntibiotic Use and Clinical Outcomes in Patients With SpeciﬁcInfectious Diseases Syndromes?Recommen dation23. Measures that consider the goals and size of the syndrome-speciﬁcinterventionshouldbeused( good practicerecommendation).Evidence SummaryThe choice of metrics for syndrome-speciﬁc interventions (seeSection IV) to improve therapy can measure process or outcome(Table 3)[39, 50–57, 189–191]. For example, interventions de-signed to increase compliance with a guideline should evaluatethe proportion of patients in each period who are compliant.Evidence of unintended negative effects such as hospital read-mission or increase in rates of hospital-acquired CDI shouldalso be monitored. The major limitation to these metrics isthe availability of reliable data.Sp ecial PopulationsXXIII. Should ASPs Develop Facility-Speciﬁc Clinical Guidelines forManagement of F &N in Hem atology-Oncol ogy Patients to ReduceUnnecessar y Antibiotic Use and I mprove Outcomes?Recommen dation24 . We suggest ASPs develop facility-speciﬁcguidelinesforF&N management i n hematology-oncology patients overno such approach (weak recommendation, l ow-qualityevidence).Comment: Clinical guidelines with an implementationand dissemination strategy can be successfully used inthe care of cancer patients with F&N and are stronglyencouraged.Guideline for Implementing an Antibiotic Stewardship Program•CID•e19 at IDSA member on May 12, 2016http://cid.oxfordjournals.org/Downloaded from

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Evidence SummaryImplementing clinical pathways for management of F&N canreduce unnecessary ant ibiotic use without adverse outcomesin hematology-oncology units, although data are limited.Nucci et al [192] reported that adoption of 1997 IDSA guide-lines i n patients with h ematologic malignancies or who wereundergoing hematopoietic stem cell transpl ant was associatedwith reductions in empiric glycopeptide use (pre- vs postguide-lines: 33% vs 7% of F&N episodes; P < .0001) and total glyco-peptide use (73% vs 43% of F&N episodes; P = .0008). Successrates for empiric regimen, time to defervescence, duration of an-tibi otic therapy, an d death rates were similar before and afterguideline adoption. No deaths were attributed to infectionsdue to gram-positive organisms [192].Studies have shown that adherence to treatment guidelinesresulted in improvement in important clinical outcomes. Forexample, Pakakasama et al [193] demonstrated that implemen-tation of clinical guidelines in pediatric cancer patients resultedin statistically signiﬁcant reductions in septic shock (int erven-tion vs control: 3.5% vs 10.9%; P = .011), ICU ad missions(2.9% vs 9.4%; P = .016), and death (0% vs 6.5%; P = .0 01). I nanother study [194], adherenc e to an ASP protocol for initialantibiotic therapy base d on IDSA guidelines was associatedwith lower mortality (hazard ratio, 0.36; 95% CI, .14–.92) in169 adult patients with 307 episodes of F&N (79% with hema-tologic malignancy).XXIV. In Immunocompromised Patients Receivi ng Antifungal Therapy,do Interventions by ASPs Improve Utili zation and Outcomes?Recommen dation25. We suggest implementation of ASP interventions to im-prove the appropriate prescribing of antifungal treatmentin immunocompromised patients (weak recommendation,low-quality evidence).Comment: In facilities with large immun oco mpromisedpatient populations, ASP interventions targeting antifungaltherapy can show beneﬁt. Those interventions must be donein close collaboration with the primary teams (eg, hematology-oncology, solid organ transplant providers). Antibiotic stew-ards must develop expertise in antifungal therapy and fungaldiagnostics for the programs to be successful.Evidence SummaryPrograms that have successfully implemented antifungal steward-ship interventions have used a multipronged approach that in-cluded PAF, education, and development of clinical guidelines[195–198]. Published studies have not focused exclusively onimmunocompromised patie nts, but those patients accountedfor the largest group in most reports. Pat ients in the ICUmad e up the second-largest g roup. One study [196]reviewed636 antifungal prescriptions for 6 years after implementing anantifungal ASP, of which 72% were from the adult and pediatrichematology services. That study utilized their ASP to providefeedback to the primary teams regarding fungal diagnosis, sero-logic and radiographic investigations, drug therapeutic moni-toring, and/or starting, stopping, or m odifying antifungaltherapy. The primary teams had a high compliance rate(88%) with the ASP recommendations. Process of care mea-sures for the management of candidemia and aspergillosis(eg, optimal voriconazole monitoring, use of recommendedﬁrst-line therapy) improved. Patient outcomes were favorablein 47 of 63 (75%) patients with aspergillosis and 52 of 60(87%) with candidemia, and did not change signiﬁcantly duringthe observation period—although the study was underpoweredto demonstrate improvement. The total cost of antifungals wasconsidered to be stable and actually decreased in the year justafter the formal study ended.In a second study [197], the stewardship team focused on high-cost antifungals at a tertiary hospital in 173 patients over a 12-month period. The following antifungal agents were successfullystopped or switched: liposomal amphotericin B (51/125 [41%]),caspofungin (8/11 [73%]), micafungin (33/51 [65%]), and combi-nation therapy (5/10 [50%]). In contrast, vori conazole wasstopped or switched in only 16 of 89 (18%) patients. The total an-nual cost for these 4 antifungal agents fell from ₤1.835 million be-fore the ASP intervention to ₤1.656 million during intervention,resulting in a crude savings of ₤179 000.XXV. In Residents of Nursing Homes and Skilled Nursing Facilities, doAntibiotic Stewardship Strategi es Decrease Unnec ess ary Use ofAntibiotics and Improve Clinical Outcom es?Recommen dation26. In nursing homes and skilled nursing facilities, we suggestimplementation of antibiotic stewardship strategies to decreaseunnecessary use of antibiotics (good practice recommendation).Comment: Implementing ASPs at nursing homes andTable 3. Possible Metrics for Evaluation of Inter ventions to ImproveAntibiotic U se and Clinical Outcomes in Patients With SpecificInfectious Diseases SyndromesProcess Measures Outcome MeasuresExcess days of therapy (ie,unnecessary days of therapyavoided based on accepted targetsand benchmarks)aDuration of therapyProportion of patients compliant withfacility-based guideline or treatmentalgorithmaProportion of patients with revision ofantibiotics based on microbiologydataProportion of patients converted to oraltherapyHospital length of stay30-day mortalityUnplanned hospital readmissionwithin 30 dProportion of patients diagnosedwith hospital-acquired Clostridiumdifficile infec tion or other adverseevent(s) related to antibiotictreatmentaProportion of patients with clinicalfailure (eg, need to broadentherapy, recurrence of infection)Sources: [39, 50–57, 189–191].aThese metrics are applicable for antibiotic stewardship program interventions to reduceantibiotic treatment of asymptomatic bacteriuria, which, in most cases, should not betreated; therefore, the other metrics do not apply.e20•CID•Barlam et al at IDSA member on May 12, 2016http://cid.oxfordjournals.org/Downloaded from

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skilled nursing facilities is important and must involve point-of-care providers to be successful. The traditional physician–pharmacist team may not be available on-site, and facilitiesmight need to investigate other approaches to review and op-timize antibiotic use, such as obtaining infectious diseases ex-pertise through telemedicine consultation.Evidence SummaryNursing homes are signiﬁcant reservoirs for multidrug-resistantorganisms [199]. Developing approaches to improve antibioticuse is important; however, few studies have shown an impact onclinical outcomes.Jump et al [200] reported a decrease in sy s temic antibiotic useby 30.1% (P < .001) and fewer positive C. difﬁcile tests (P =.04)after initiating an infectious diseases consultation service at a singleVeter ans Affairs long-term care facility. The intervention included24/7 consultation availability by telephone, with weekly on-sitecase revie w by an infectious diseases physician and a nurse pra c-titioner. This model, however, may not be possible in many USnursing homes give n resour ce re s traints such as lack of ﬁnances,availability of an infectious diseases physician, and interest.Schwartz et al [201] conducted an intervention that includedphysician education, guideline implementation, and presenta-tion of local baseline antibiotic use data in a public long-termcare facility with 20 salaried internists. Antibiotic starts de-creased by 25.9%, and antibiotic DOTs decreased by 29.7%;those decreases were sustained for a 2-year fol low-up peri od.This level of physician stafﬁng, however, is not typical of mostfacilities.Stewardship interventions inclusive of the nursing staff havebeen successful in reducing antibi otic use, but the effect on clin-ical outcome is not usually reported. Fleet et al [202 ] evaluatedthe impact of the Resident Antimicrobial Management Plan at30 nursing homes in England. The nursing staff received writ-ten educational materials and used this tool to record compli-ance with good practice points at treatment initiation and 48–72hours later. Antibiotic consumption over 12 weeks decreased by4.9% (95% CI, 1.0%–8.6%; P = .02) in the inte rventi on groupand increased by 5.1% (95% CI, .2%–10.2%; P = .04) in the con-trol group. Loeb et al [189] studied a multifaceted educationalintervention for urinary tract infections that included a diagnos-tic a nd treatment algorithm at 24 nursing homes in Ontario,Canada and Idaho. Antibiotic use for suspected urinary tract in-fectionwasloweratinterventionthanatusual-carenursinghomes (1.17 vs 1.59 courses per 1000 resident-days; weightedmean difference, −0.49; 95% CI, −.93 to −.06). Zimmermanet al [203] assessed a quality improvement program at 12 nurs-ing homes in North Carolina. This multifaceted program con-sisted of guideline education for providers, sensitization toantibiotic prescribing matters for nursing staff and family mem-bers, and prescribing feedback for providers and nursing staff.Between baseline and follow-up at 9 months, prescription ratesdropped more at interventio n homes (13. 16 vs 9.51 per 1000resident-days) than at comparison homes (12.70 vs 11.80 per1000 resident-days; pooled difference in d ifferenc es, −2.75;P = .05).XXVI. In NICUs, do Antibiotic Stewardship Interventions ReduceInappropriate Antibiotic Use and/or Resistance?Recommen dation27. We suggest implementation of antibiotic stewardshipinte rventions to reduce inappropriate antibiotic use and/orresistance in the NICU (good practice recommendation).Evidence SummaryLimited evidence is available to determine the most effectiveASPstrategiesintheNICU,butgeneralprinciplesshouldapply [204].Antibiotic policy and guidelines have been shown to be effec-tive in the NICU [205]. After implementing a vancomycinguideline, Chiu et al [206] saw a 35% reduction in the initiationof vancomycin and a 65% overall decrease in exposure to van-comycin compared with the preimplementation period. Zingget al [205] evaluated antibiotic use after initiating a policy toshorten antibiotic therapy for sepsis and coagulase-negativestaphylococcal infectio n, and to stop preemptive treatment ifblood cultures were negative. They found an overall 2.8% yearlyreduction in antibiotic use (P < .001) without increasing mortal-ity. Antibiotic restriction interventions can be successful in theNICU. For example, Murki et al [207] reported that restrictingall cephalosporin classes was associated with a 22% decreased in-cidence of extended-spectrum β-lactamase–producing, gram-negative infections com pared with the previous year (P = .03).The proportion of ampicillin use increased from 12.8% to25.7% (P < .001) after the intervention, and the proportion ofcephalosporin use declined from 15.8% to 3.0% (P <.001).XXVII. Should Antimicrobial Stewardship Programs Im ple mentInterventions to Reduce Antibiotic Th erapy in Terminally Ill Patients?Recommen dation28. In terminally ill patients, we suggest ASPs provide supportto clini cal care provider s in d ecision s related to antibiotictreatment (good practice recommendation).Evidence SummaryEnd of life is deﬁned as the ﬁnal days or weeks of life in patientsunder hospice care where the primary goals are managingsymptoms, improving comfort, and optimiz ing quality of life—not prolonging survival. In contrast, palliative care is more ge-neral and can be pursued along with curative therapies.Antibiotic use, frequently with multiple antibiotics, is com-mon in patients with terminal cancer. Therapy is often contin-ued after transition to comfort care and discontinued less than 1day prior to death [208]. Patients with advanced dementia alsohave high exposure to antibiotics, especially in the weeks priorGuideline for Implementing an Antibiotic Stewardship Program•CID•e21 at IDSA member on May 12, 2016http://cid.oxfordjournals.org/Downloaded from

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to death [209]. Therefore, older adults with advanced dementiaor who are in long-term care facilities [209] and patients receiv-ing end-of-life treatment in the ICU [210] may become reser-voirs for resistant bacteria. For example, end-of-life antibiotictreatment in the ICU was independently associated with acqui-sition of resistant bacteria in a logistic regression analysis [210].For patients under hos pice care, the impact of antibiotic ther-apy on symptom alleviation should be considered in the contextof speciﬁc infections [208, 211]. For example, treating urinarytract infection may improve dysuria and treating thrush mayimprove dysphagia [211 , 212], but the impact of antibiotics onthe symptoms of respiratory tract infectio n is less clear [213–216]. Givens et al [213] reported that, compared with no antibi-otic therapy, antibiotic treatment of suspe cted pne umonia inpatients with advanced deme ntia via any route of administra-tion was associated with improved survival but less comfort(P < .001 for all comparisons) as measured by the SymptomManagement at End of Life Dementia scale. In contrast, antibi-otic treatment of pneumonia in nursing h ome residents withdementia was associated with fewer symptoms in 2 Dutch stud-ies. Van der Steen et al [214] reported that the level of discom-fort was generally higher in patients for whom a ntibiotictherapy was withheld in nonsurvivors compared with survivingpatien ts treated with antibiotics; howeve r, those n onsur vivorpatients had more discomfort before pneumonia developed.Subsequently, Van der Steen et al [215] reported fewer symp-toms if pneumonia was treated with antibiotics rather thanjust ﬂuids in patients with dementia even if death was immi-nent; the majority of patients received oral therapy. If prolong-ing survival is not a primary goa l, withholding antibiotic agentsshould be considered. If treatment is desired, antibiotic agentsshould be administered orally whenever possible.Patients and their surrogates should be engaged in the deci-sion to use antibiotic agents at end of life. Stiel et al [217] report-ed that families of terminally ill cancer patients are oftenconsulted about stopping antibiotics, but the decision to starttherapy is usually made by clinicians without much discussion.Similarly, Givens et al [218] reported that most infectious epi-sodes in nur sing home residents with advance d dementia didnot involve healthcare proxies in decision making.Given signiﬁcant treatment burdens, potential for adverse ef-fects such as CDI, and public he alth risks, antibiotic therapyshould be viewed as aggressive care in the end-of-life setting.CONCLUSIONSThis guideline discusses a broad range of possible ASP interven-tions. We have emphasized the need for each site to assess itsclinical n eeds and available resources and individualize itsASP with that assessment in mind.A powerful way to support antibiotic stewardship is to im-prove the scientiﬁc basis for ASP interventions. As outlined inSection XIII, ASPs can successfully intervene to reduce theduration of therapy for many infections because well-construct-ed, randomized controlled clinical trials have demonstrated thatclinical outcomes are equivalent. Rigorous published evidence isoften needed to convince clinicians to alter well-established, al-beit suboptimal, practice. For example, ASPs can cite high-qual-ity data to reduce unnecessary antibiotic treatment ofuncomplicated diverticulitis [219], or ASB (eg, in women 60years or younger, diabetic patients, or the elderly) [220]. Addi-tional clinical trials that incorporate consideration of antibioticstewardship in their design are critically needed.Another signiﬁcant gap is the dearth of implementation re-search in this area [28]. Although the National Action Planfor Combating Antibiotic-Resistant Bacteria [6]willrequirethe institutio n of ASPs across healthcare facilities, little effortand limited research funding have be en allocated to studyhow best to achieve large-scale implementation. Qualitative as-sessments that can examine the impact of factors such as orga-nizational culture, prescriber attitudes, and the self- efﬁcacy ofthe antibiotic steward (ie, the extent to which he/she believeshis/her goals can be reached) are lacking and are important toestablish the context in which ASP implementation occurs [221,222]. There is inadequate information on the best model for anASP. For example, should stewards use the “bundle” approachthat has been applied to ventilator-associated pneumonia [223]and central line –associated bloodstream infection with g reatsuccess [224]? Although ASPs have studied application of acombination of interventions, they are not comparable to exist-ing bundles because they require interpretation, expertise, andpersuasion [225]. A new or adapted model for ASP is likelyneeded and best developed through application of rigorous im-plementation science.Despite the recognition that much more research is needed,this guideline identiﬁes core interventions for all ASPs as well asother interventions that can be implemented based on facility-speciﬁc assessm ents of need and resources. Every healthca re fa-cility is able to perform stewardship, and institution of an ASP isattainable and of great importance to public health.NotesAcknowledgments. The expert panel expresses its gratitude to Drs Eliz-abeth Dodds Ashley, Annie Wong-Beringer, and Stan Deresinski for theirthoughtful reviews of earlier drafts of the guideline. The panel greatly appre-ciates the work of Charles B. Wessels and Michele Klein Fedyshin of theHealth Sciences Library System of the University of Pittsburgh for the de-velopment and execution of the systematic literature searches for this guide-line, and Jennifer J. Padberg, MPH, for her administrative assista ncethroughout the guideline development process.Financial support. Support for these guidelines was provided by the In-fectious Diseases Society of America (IDSA) and the Society for HealthcareEpidemiology of America.Potential conﬂicts of interest. The following list is a reﬂection of whathas been repo rted t o IDSA. To provide thorough transparency, IDSA re-quires full disclosure of all relationships, regardless of relevancy to the guide-line topic. Evaluation of such relationships as potential conﬂicts of interest isdetermined by a review process that includes assessment by the Standardsand Practice Guidelines Committee (SPGC) chair, the SPGC liaison to thee22•CID•Barlam et al at IDSA member on May 12, 2016http://cid.oxfordjournals.org/Downloaded from

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development panel, and the board of directors liaison to the SPGC, and, ifnecessary, the Conﬂicts of Interest (COI) Task Force of the Board. This as-sessment of disclosed relationships for possible COI will be based on the rel-ative weight of the ﬁnancial relationship (ie, monetary amount) and therelevance of the relationship (ie, the degree to which an association mightreasonably be interpreted by an indepen dent observer as related to thetopic or recommendation of consideration). The reader of these guidelinesshould be mindful of this when the list of disclosures is reviewed. S. E. C. hasreceived grants from Pﬁzer Grants for Learning and Change, and personalfees from Novartis, outside the submitted work. C. M. has received personalfees from Actavis Pharmaceuticals and grants from Cubist Pharmaceuticals,outside the submitted work. A. N. S. has received nonﬁnancial support fromBruker Diagnostics, outside the submitted work. C. W. H. has received pay-ments for manuscri pt preparation from IDSA, during the c onduct of thework, and payments from Cardeas, Johnson & Johnson, and Sanoﬁ Aventis,outside the submitted work. T. C. J. has been a member of an advisory com-mittee for Durata Therapeutics, outside the submitted work. P. A. L. has re-ceived personal fees from JAMA Surgery and Oakstone General Surgery,outside the submitted work. L. S. M. has received grants and nonﬁnancialsupport from, and has served on advisory boards for, Cepheid and Durata,and has received honoraria from Alere, outside the submitted work.G. J. M. has received grants from Cempra Ph armaceut icals, Cerexa, andAstraZeneca, and has participated as coauthor on a manuscript for CubistPharmaceuticals, outside the submitted work. J. G. N. has served as a con-sultant for RPS Diagnostics and has received grants from Pﬁzer, outside thesubmitted work. C. A. O. has received personal fees from Astellas and BayerPharmaceuticals, outside the submitted work. K. K. T. has received personalfees from Premier, Diatherix, the American Institutes of Research, Universityof Rochester, and Dignity Health, and has received grants from Pew Charita-ble Trusts, the CDC Foundation, and the Association of State and TerritorialHealth Ofﬁcials, outside the submitted work. All other authors report no po-tential conﬂicts of interest. All authors have submitted the ICMJE Form forDisclosure of Potential Conﬂicts of Interest. Conﬂicts that the editors considerrelevant to the content of the manuscript have been disclosed.References1. Fishman N. Policy statement on amtimicrobial stewardship b y the Society forHealthcare Epidemiology of America (SHEA ), the Infectious Diseases Societyof America (IDSA), and the Pediatric Diseases Society (PIDS). Infect ControlHosp Epidemiol 2012; 33:322–7.2. Guyatt GH, Oxman AD, Kunz R, et al. Going from evidence to recommenda-tions. 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