Interventions to improve antibiotic prescribing practices for hospital inpatients (Review) Davey P, Brown E, Charani E, Fenelon L, Gould IM, Holmes A, Ramsay CR, Wiffen PJ, WilcoxM ThisisareprintofaCochranereview,preparedandmaintainedbyTheCochraneCollaborationandpublishedinTheCochraneLibrary 2013,Issue4 http://www.thecochranelibrary.com Interventionstoimproveantibioticprescribingpracticesforhospitalinpatients(Review) Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 PLAINLANGUAGESUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 SUMMARYOFFINDINGSFORTHEMAINCOMPARISON . . . . . . . . . . . . . . . . . . . 3 BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Figure1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Figure2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Figure3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Figure4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Figure5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Figure6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Figure7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Figure8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 AUTHORS’CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 CHARACTERISTICSOFSTUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 DATAANDANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 Analysis1.1.Comparison1Intendedclinicaloutcomes,interventionsintendedtoincreaseeffectiveprescribing,Outcome 1Mortality,interventionsintendedtoincreaseappropriateantimicrobialtherapy,allinfections. . . . . . 174 Analysis1.2.Comparison1Intendedclinicaloutcomes,interventionsintendedtoincreaseeffectiveprescribing,Outcome 2Mortality,interventionsintendedtoincreaseantibioticguidelinecomplianceforpneumonia. . . . . . . 175 Analysis2.1.Comparison2Clinicaloutcomes,interventionsintendedtodecreaseexcessiveprescribing,Outcome1 Mortality,interventionsintendedtodecreaseexcessiveprescribing. . . . . . . . . . . . . . . . 176 Analysis2.2.Comparison2Clinicaloutcomes,interventionsintendedtodecreaseexcessiveprescribing,Outcome2 Readmission,interventionsintendedtodecreaseexcessiveprescribing. . . . . . . . . . . . . . . 177 Analysis2.3.Comparison2Clinicaloutcomes,interventionsintendedtodecreaseexcessiveprescribing,Outcome3Length ofstay,interventionsintendedtodecreaseexcessiveprescribing. . . . . . . . . . . . . . . . . 178 ADDITIONALTABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206 WHAT’SNEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206 HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206 CONTRIBUTIONSOFAUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207 DECLARATIONSOFINTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207 SOURCESOFSUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 INDEXTERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 Interventionstoimproveantibioticprescribingpracticesforhospitalinpatients(Review) i Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. [InterventionReview] Interventions to improve antibiotic prescribing practices for hospital inpatients PeterDavey1,ErwinBrown2,EsmitaCharani3,LyndaFenelon4,IanMGould5,AlisonHolmes6,CraigRRamsay7,PhilipJWiffen 8,MarkWilcox9 1PopulationHealthSciencesDivision,MedicalResearchInstitute,UniversityofDundee,Dundee,UK.2Bristol,UK.3TheNational CentreforInfectionPreventionandManagement,ImperialCollegeLondon,London,UK.4DepartmentofMicrobiology,StVincent’s UniversityHospital,Dublin4,Ireland.5DepartmentofMedicalMicrobiology,AberdeenRoyalInfirmary,Aberdeen,UK.6Department of Infectious Diseases and Microbiology, Imperial College of Science, Technology and Medicine, London, UK. 7Health Services ResearchUnit,DivisionofAppliedHealthSciences,UniversityofAberdeen,Aberdeen,UK.8PainResearchandNuffieldDepartment ofClinicalNeurosciences,UniversityofOxford,Oxford,UK.9DepartmentofMicrobiology,UniversityofLeeds,Leeds,UK Contact address: Peter Davey, Population HealthSciences Division, Medical Research Institute, University of Dundee, Mackenzie Building,KirstySempleWay,Dundee,Scotland,DD24BF,[email protected]. Editorialgroup:CochraneEffectivePracticeandOrganisationofCareGroup. Publicationstatusanddate:Newsearchforstudiesandcontentupdated(conclusionschanged),publishedinIssue4,2013. Reviewcontentassessedasup-to-date: 3February2009. Citation: DaveyP,BrownE,CharaniE,FenelonL,GouldIM,HolmesA,RamsayCR,WiffenPJ,WilcoxM.Interventionstoimprove antibioticprescribingpracticesforhospitalinpatients.CochraneDatabaseofSystematicReviews2013,Issue4.Art.No.:CD003543. DOI:10.1002/14651858.CD003543.pub3. Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. ABSTRACT Background ThefirstpublicationofthisreviewinIssue3,2005includedstudiesuptoNovember2003.ThisupdateaddsstudiestoDecember 2006andfocusesonapplicationofanewmethodformeta-analysisofinterruptedtimeseriesstudiesandapplicationofnewCochrane EffectivePracticeandOrganisationofCare(EPOC)RiskofBiascriteriatoallstudiesinthereview, includingthosestudiesinthe previously published version. The aim of the review is to evaluate the impact of interventions from the perspective of antibiotic stewardship.Thetwoobjectivesofantibioticstewardshiparefirsttoensureeffectivetreatmentforpatientswithbacterialinfectionand secondsupportprofessionalsandpatientstoreduceunnecessaryuseandminimizecollateraldamage. Objectives To estimate the effectivenessof professional interventions that, alone or in combination, are effectivein antibiotic stewardship for hospital inpatients, toevaluate theimpactof theseinterventions onreducing theincidence of antimicrobial-resistant pathogens or Clostridiumdifficileinfectionandtheirimpactonclinicaloutcome. Searchmethods WesearchedtheCochraneCentralRegisterofControlledTrials(CENTRAL),MEDLINE,EMBASEfrom1980toDecember2006 andtheEPOCspecializedregisterinJuly2007andFebruary2009andbibliographiesofretrievedarticles.Themaincomparisonis betweeninterventionsthathadarestrictiveelementandthosethatwerepurelypersuasive.Restrictiveinterventionswereimplemented throughrestrictionofthefreedomofprescriberstoselectsomeantibiotics.Persuasiveinterventionsusedoneormoreofthefollowing methodsforchangingprofessionalbehaviour:disseminationofeducationalresources,reminders,auditandfeedback,oreducational outreach.Restrictiveinterventionscouldcontainpersuasiveelements. Interventionstoimproveantibioticprescribingpracticesforhospitalinpatients(Review) 1 Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. Selectioncriteria Weincludedrandomizedclinicaltrials(RCTs),controlledclinicaltrials(CCT),controlledbefore-after(CBA)andinterruptedtime seriesstudies(ITS). Interventions includedanyprofessional or structuralinterventions asdefinedbyEPOC.Theintervention had toincludeacomponentthataimedtoimproveantibiotic prescribingtohospitalinpatients, eitherbyincreasing effectivetreatment orbyreducingunnecessarytreatment.Theresultshadtoincludeinterpretabledataabouttheeffectoftheinterventiononantibiotic prescribingormicrobialoutcomesorrelevantclinicaloutcomes. Datacollectionandanalysis Twoauthorsextracteddataandassessedquality.Weperformedmeta-regressionofITSstudiestocomparetheresultsofpersuasiveand restrictiveinterventions. Persuasiveinterventions advisedphysiciansabout howtoprescribeorgavethemfeedbackabouthowthey prescribed.Restrictiveinterventionsputalimitonhowtheyprescribed;forexample,physicianshadtohaveapprovalfromaninfection specialistinordertoprescribeanantibiotic.WestandardizedtheresultsofsomeITSstudiessothattheyareonthesamescale(percent changeinoutcome),therebyfacilitatingcomparisonsofdifferentinterventions.Todothis,weusedthechangeinlevelandchangein slopetoestimatetheeffectsizewithincreasingtimeaftertheintervention(onemonth,sixmonths,oneyear,etc)asthepercentchange inlevelateachtimepoint.Wedidnotextrapolatebeyondtheendofdatacollectionaftertheintervention.Themeta-regressionwas performedusingstandardweightedlinearregressionwiththestandarderrorsofthecoefficientsadjustedwherenecessary. Mainresults Forthisupdateweincluded89studiesthatreported95interventions.Ofthe89studies,56wereITSs(ofwhich4werecontrolled ITSs),25wereRCT(ofwhich5werecluster-RCTs),5wereCBAsand3wereCCTs(ofwhich1wasacluster-CCT). Most (80/95, 84%) of the interventions targeted the antibiotic prescribed (choice of antibiotic, timing of first dose and route of administration).Theremaining15interventionsaimedtochangeexposureofpatientstoantibioticsbytargetingthedecisiontotreator thedurationoftreatment.Reliabledataaboutimpactonantibioticprescribingdatawereavailablefor76interventions(44persuasive, 24restrictiveand8structural).Forthepersuasiveinterventions,themedianchangeinantibioticprescribingwas42.3%fortheITSs, 31.6%forthecontrolledITSs,17.7%fortheCBAs,3.5%forthecluster-RCTsand24.7%fortheRCTs.Therestrictiveinterventions hadamedianeffectsizeof34.7%fortheITSs, 17.1%fortheCBAsand40.5%fortheRCTs. Thestructuralinterventions hada medianeffectof13.3%fortheRCTsand23.6%forthecluster-RCTs.Dataaboutimpactonmicrobialoutcomeswereavailablefor 21interventionsbutonly6ofthesealsohadreliabledataaboutimpactonantibioticprescribing. Meta-analysisof52ITSstudieswasusedtocomparerestrictiveversuspurelypersuasiveinterventions.Restrictiveinterventionshad significantlygreaterimpactonprescribingoutcomesatonemonth(32%,95%confidenceinterval(CI)2%to61%,P=0.03)and onmicrobial outcomesat6months(53%,95%CI31%to75%, P=0.001) buttherewerenosignificant differencesat12or24 months.InterventionsintendedtodecreaseexcessiveprescribingwereassociatedwithreductioninClostridiumdifficileinfectionsand colonizationorinfectionwithaminoglycoside-orcephalosporin-resistantgram-negativebacteria,methicillin-resistantStaphylococcus aureusandvancomycin-resistantEnterococcusfaecalis.Meta-analysisofclinicaloutcomesshowedthatfourinterventionsintendedto increaseeffectiveprescribingforpneumoniawereassociatedwithsignificantreductioninmortality(riskratio0.89,95%CI0.82to 0.97),whereasnineinterventionsintendedtodecreaseexcessiveprescribingwerenotassociatedwithsignificantincreaseinmortality (riskratio0.92,95%CI0.81to1.06). Authors’conclusions Theresultsshowthatinterventionstoreduceexcessiveantibioticprescribingtohospitalinpatientscanreduceantimicrobialresistance orhospital-acquiredinfections,andinterventionstoincreaseeffectiveprescribingcanimproveclinicaloutcome.Thisupdateprovides moreevidenceaboutunintendedclinicalconsequencesofinterventionsandabouttheeffectofinterventions toreduceexposure of patients to antibiotics. The meta-analysis supports the use of restrictive interventions when the need is urgent, but suggests that persuasiveandrestrictiveinterventionsareequallyeffectiveaftersixmonths. PLAIN LANGUAGE SUMMARY Improvinghowantibioticsareprescribedbyphysiciansworkinginhospitalsettings. Antibioticsareusedtotreatinfections,suchaspneumonia,thatarecausedbybacteria.Overtime,however,manybacteriahavebecome resistanttoantibiotics.Antibioticresistanceisaseriousproblemforindividualpatientsandhealthcaresystems;inhospitals,infections Interventionstoimproveantibioticprescribingpracticesforhospitalinpatients(Review) 2 Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. causedbyantibiotic-resistantbacteriaareassociatedwithhigherratesofdeath,illnessandprolongedhospitalstay.Bacteriaoftenbecome resistantbecauseantibioticsareusedtoooftenandincorrectly.Studieshaveshownthatabouthalfofthetime,physiciansinhospital are not prescribing antibiotics properly.Hospital physicians may be unclear about the benefits and risks of prescribing antibiotics, includingwhethertoprescribeanantibiotic,whichantibiotictoprescribe,atwhatdoseandforhowlong. Many differentmethodsofimproving theprescribing of antibiotics inhospitals havebeenstudied. Inthisreview, 89 studiesfrom 19countrieswereanalyzedtodeterminewhatmethodswork.Themaincomparisonwasbetweenpersuasiveandrestrictivemethods. Persuasivemethodsadvisedphysiciansabouthowtoprescribeorgavethemfeedbackabouthowtheyprescribed.Restrictivemethods putalimitonhowtheyprescribed;forexample,physicianshadtohaveapprovalfromaninfectionspecialistinordertoprescribean antibiotic. Overall,the89studiesshowedthatthemethodsimprovedprescribing.Inaddition,21studiesshowedthatthemethods decreasedthenumberofinfectionsinhospital.Therestrictivemethodsappearedtohavealargereffectthanpersuasivemethods.In conclusion,thisreviewhasfoundalotofevidencethatmethodscanimproveprescribingofantibioticstopatientsinhospital,butwe needmorestudiestofullyassesstheclinicalbenefitsofthesemethods. Interventionstoimproveantibioticprescribingpracticesforhospitalinpatients(Review) 3 Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. SUMMARY OF FINDINGS FOR THE MAIN COMPARISON [Explanation] Interventionscomparedwithnonetoimproveantibioticprescribing Patientorpopulation:Healthcareprofessionals Settings:Secondarycare(inpatientsinacute,notlongtermcareonly) Intervention:Anyintendedtoimproveantibioticprescribing Comparison:Usualcare Outcomes Effectmeasure Number of studies and health Qualityoftheevidence professionals (GRADE) RestrictiveversusPersuasiveinterventions Appropriate prescribing of an- 32% difference in effect size 53comparisonsfrom40studies Low ⊕⊕OO tibiotics (restrictive-persuasive) at one (allITS)in46hospitals Indirect comparison between month studies that provide data about 95%CI2to61% effectofeitherpersuasiveorre- strictiveinterventions Nosignificantdifferenceat6,12 or24months Microbialoutcomes 53% difference in effect size 20comparisonsfrom14studies Low ⊕⊕OO (restrictive-persuasive) at 6 (allITS)in14hospitals Indirect comparison between months studies that provide data about 95%CI31to75% effectofeitherpersuasiveorre- strictiveinterventions Nosignificantdifferenceat12or 24months Interventionsintendedtodecreaseunnecessaryantibioticprescribing Patientoutcomes Riskofmortalityforintervention 11comparisonsfrom11studies Moderate⊕⊕⊕O versuscontrol (7RCT,3cluster-RCT,1cluster- High risk of bias especially 0.92(95%CI0.81to1.06) CCT)in20hospitalswith9,817 aroundstudydesign patients Difference(indays)inlengthof 6 comparisons from 6 studies VeryLow⊕OOO stayforinterventionversuscon- (4 RCT, 2 cluster-RCT) in 8 Studies areveryheterogeneous trol hospitalswith8,071patients andhavehighriskofbias -0.04days(95%CI-0.34to0. 25) Riskofreadmissionforinterven- 5 comparisons from 5 studies VeryLow⊕OOO tionversuscontrol (4 RCT, 1 Cluster-RCT) in 12 Studies areveryheterogeneous 1.26(95%CI1.02to1.57) hospitalswith5,856patients andhavehighriskofbias Interventionsintendedtoincreaseeffectiveantibioticprescribingforpneumonia Interventionstoimproveantibioticprescribingpracticesforhospitalinpatients(Review) 4 Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. Patientoutcomes Riskofmortalityforintervention 4 comparisons from 4 studies Low⊕⊕OO versuscontrol (3CBA,1RCT)in104hospitals High risk of bias especially 0.89(95%CI0.82to0.97) with22,526patients aroundstudydesign GRADEWorkingGroupgradesofevidence Highquality:Furtherresearchisveryunlikelytochangeourconfidenceintheestimateofeffect. Moderatequality:Furtherresearchislikelytohaveanimportantimpactonourconfidenceintheestimateofeffectandmaychange theestimate. Lowquality: Further research isverylikelytohaveanimportant impact onourconfidence intheestimate ofeffect and islikelyto changetheestimate. Verylowquality:Weareveryuncertainabouttheestimate. Abbreviations CBA: controlled before and after; CCT: controlled clinical trial; CI: confidence interval; ITS: interrupted time series; RCT: randomized controlledtrial. xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx BACKGROUND infarction or breast, colon and lung cancer combined (Robson Antibiotic resistance is now regarded as a major public health 2008),anddelayineffectiveantibiotictreatmentisassociatedwith problem.Incomparisonwithinfectionscausedbysusceptiblebac- increasedmortality(Daniels2010;Kumar2006).Theterm’an- teria,thosecausedbymultidrug-resistant bacteriaareassociated tibioticstewardship’isusedtocapturethetwinaimsofensuring with higherincidences ofmortalityandprolongedhospital stay effectivetreatmentofpatientswithinfectionandminimizingcol- (deKraker2010;deKraker2011a;deKraker2011b;Wolkewitz lateraldamagefromantimicrobial use(Allerberger2009;Davey 2010).Clostridiumdifficileinfectionisanother manifestation of 2010;Dellit2007;MacDougall2005). thecollateraldamagecausedbyantimicrobialprescribing(Davey 2010). Such infections are also associated with increased costs, Thereisevidencethatantibioticusageinhospitalsisincreasing, arisingfromtheneedtousemoreexpensiveantibioticsastherapy, and that over a third of prescriptions are not compliant with prolongedhospitalstay(deKraker2011a)andexpensesrelatedto evidence-based guidelines (Zarb 2011). In Denmark, antibiotic screeningandsurveillance,eradicationregimensandconsumables usage in hospitals increased by 18% between 1997 and 2001 (the gloves, gowns and aprons used to prevent cross-infection). (Muller-Pebody2004).AsimilarstudycarriedoutintheNether- Theemergenceofmultidrug-resistantorganismslimitsthechoice lands revealed that hospital antibiotic usage between 1997 and oftherapyforpatientswithhospital-acquiredinfectionsand,omi- 2000 increasedby 10.6%. However,more recentdatafromthe nously,forthefirsttimesinceantibioticswereintroducedweare Netherlandshowedthatthenumberofhospitaladmissionsaswell facedwiththeprospectofnothavingeffectivetreatmentforsome asthe antibiotic use hasincreased by22% from2003 to2010. patientswithbacterialinfections(So2010).Anumberofreports Theauthorsinterpretedtheseresultsasshowingthattotaluseand haveproposedarangeofmeasuresdesignedtoaddresstheprob- clinicalactivitieswereincreasinginparallel.However,theynoted lemof increasing resistance (Behar2000; EU2002; Goldmann thattheuseofpenicillinswithextendedspectrumandquinolones 1996;HouseofLords1998;HouseofLords2001;Lawton2000; increasedfrom2008to2011andthatthiswasnotfullyexplained Shlaes1997;SMACS1998).Common toalltherecommenda- byincreasedclinicalactivity(SWAB2011).Finally,asurveyof22 tionsisthechallengetoreduceinappropriateantibioticprescrib- USacademiccentresfoundthattherewasastatisticallysignificant ing, the implication being that antibiotic resistance is largely a increaseintotalantibacterialusebetween2002and2006,froma consequenceoftheselectivepressuresofantibioticusageandthat meanof798daysoftherapy(DOTs)per1000patientdays(PDs) reducingthesepressuresbythejudiciousadministrationofantibi- toameanof855DOTsper1000 PDs(Polk2007).TheEuro- oticswillfacilitateareturnofsusceptiblebacteriaor,atleast,will peanSurveillanceofAntimicrobialConsumption(ESAC)hases- preventorslowthepaceoftheemergenceofresistantstrains.At tablishedamethodforpointprevalenceofantibioticprescribing thesametime,sepsiskillsmorepeopleannuallythanmyocardial in hospitals (Amadeo 2010; Ansari 2008) and the 2009 survey Interventionstoimproveantibioticprescribingpracticesforhospitalinpatients(Review) 5 Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. included data from 172 hospitals in 25 countries (Zarb 2011). Typesofparticipants Thesesurveyshaverevealedimportanttargetsforimprovingthe Healthcareprofessionalswhoprescribeantibioticstohospitalin- qualityofantimicrobialprescribingtohospitalinpatients.Inthe patientsreceivingacutecare(includingelectiveinpatientsurgery). 2009surveytheindicationfortreatmentwasnotrecordedincase Thereviewexcludesinterventionstargetedatresidentsinnursing notesof24%ofpatientsandwhenanindicationwasrecordedit homesorotherlong-termhealthcaresettings. wasnotcompliantwithlocalornationalguidelinesin38%ofpa- tients.Therewasalsoevidenceofexcessivetreatmentofcommu- nity-acquiredinfectionsandunnecessaryprolongationofsurgical Typesofinterventions antibioticprophylaxis(Zarb2011). ThefollowingprofessionalinterventionsintheEffectivePractice andOrganisationofCareGroup(EPOC)scopewereincluded: Whatshouldbedonetoimproveantibioticstewardshipinhospi- 1. Persuasiveinterventions:distributionofeducational tals?TheInfectiousDiseasesSocietyofAmericaandtheSociety materials;educationalmeetings;localconsensusprocesses; ofHospitalEpidemiologistsofAmericahaverecommendedmea- educationaloutreachvisits;localopinionleaders;reminders surestoimproveantibioticprescribinginhospitals(Dellit2007). providedverbally,onpaperoroncomputer;auditandfeedback. However,therecommendationsarebasedononlyasmallpropor- 2. Restrictiveinterventions:selectivereportingoflaboratory tionofthepublishedliterature,andtheliteraturethatwasassessed susceptibilities,formularyrestriction,requiringprior wasnotsubjectedtocriticalevaluationorsystematicreview.We authorizationofprescriptionsbyinfectiousdiseasesphysicians, havethereforereviewedtheliteratureforevidenceoftheimpactof microbiologists,pharmacistsetc,therapeuticsubstitutions, interventionsontheappropriatenessofantimicrobialprescribing automaticstopordersandantibioticpolicychangestrategies andontheprevalenceofantimicrobialresistanceand/orclinical includingcycling,rotationandcross-overstudies. outcome. 3. Structural:changingfrompapertocomputerizedrecords, Thisreviewofinterventionsintendedtoimproveprescribingof rapidlaboratorytesting,computerizeddecisionsupportsystems antibioticstohospitalinpatientscomplementsareviewofinter- andtheintroductionororganizationofqualitymonitoring ventionstoimproveprescribingofantibioticstopatientsinam- mechanisms. bulatorycare(Arnold2005). Studiesthatwereclinicaltrialscomparingtheeffectivenessofan- tibiotictreatments(forexampleintravenous(IV)versusoralad- ministrationofantibiotics)wereconsideredinvalidforthisreview. OBJECTIVES The primary aim is to identify interventions that, alone, or in Typesofoutcomemeasures combination,areeffectiveinimprovingantibioticprescribingto • Antibioticprescribingprocessmeasures(decisiontotreat, hospitalinpatients.Wehaveusedtheterm’antibioticstewardship’ choiceofdrug,dose,routeordurationoftreatment); toaddresstwoobjectives.Thefirstobjectiveistoensureeffective • Clinicaloutcomemeasures(mortality,lengthofhospital treatmentforpatientswithbacterialinfection.Thesecondobjec- stay); tiveistoprovideconvincingevidenceandinformationtoeducate • Microbialoutcomemeasure(colonizationorinfectionwith andsupportprofessionalsandpatientstoreduceunnecessaryuse Clostridiumdifficileorantibiotic-resistantbacteria). andminimizecollateraldamage.Collateraldamagemeansthein- creasedriskofinfectionwithantibiotic-resistantbacteria,andan- tibioticresistantbacteria,whicharisesfromdamagetothenormal Searchmethodsforidentificationofstudies bacterialfloraafterantibiotictreatment. For this update, we searched the Cochrane Central Register of Controlled Studies (CENTRAL), PubMed, EMBASE in 2006. METHODS Weusedsearchterms:antibiotics,premedication,guideline,clin- icalprotocols,criticalpathways,evidencebasedmedicine,inter- vention. WealsosearchedtheEPOCRegisterinJuly2007 and Criteriaforconsideringstudiesforthisreview February2009(Appendix1). Thenextupdateofthisreviewwill includefullydocumentedsearchstrategies. Typesofstudies Datacollectionandanalysis Weincludedallrandomizedandnonrandomizedcontrolledtrials (RCTsandCCTs),controlledbefore-afterstudies(CBAs)andin- terruptedtimeseriesstudies(ITSs)(withatleastthreedatapoints beforeandafterimplementationoftheintervention). Selectionofstudies Interventionstoimproveantibioticprescribingpracticesforhospitalinpatients(Review) 6 Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. Two authors (EB and PD) reviewed citations and abstracts re- torycare(Arnold2005).Theseinterventionsinvolveachangeto trievedinthesearchtoidentifyallreportsthatincludedoriginal theantibioticformularyorpolicyimplementedthroughanorga- dataaboutinterventionstochangeantibioticprescribing.Ifeither nizationalchangethatrestrictsthefreedomofprescriberstoselect authorhadanydoubtabouteligibility,thenbothauthorsreviewed some antibiotics. We identified four distinct types of restrictive thefullpapers.Theauthorswerenotblindedtostudyauthoror interventions: location.Weresolveddisagreementsbydiscussionandconsensus. 1. Compulsoryorderform-prescribershadtocompletea Wethenexcludedstudiesthathadnorelevantandinterpretable formwithclinicaldetailstojustifyuseoftherestricted data presented or obtainable. ’Relevant data’ was defined as an antibiotics; intervention that included a change in antibiotic treatment for 2. Expertapproval-theprescriptionforarestrictedantibiotic hospital inpatients and at least one of the study’s reported out- hadtobeapprovedbyanInfectionspecialistorbytheHeadof comeswasdirectlyattributabletochangeinantibiotictreatment. Department; ’Interpretable data’ was definedas follows: CBA, CCT or RCT 3. Restrictionbyremoval-arestrictivepolicywasimposedin designshadtoincludesufficientdatatoestimateeffectsizewith targetwards,unitsoroperatingtheatres,forexampleby 95% confidence interval (CI) as change in at leastone relevant removingrestrictedantibioticsfromdrugcupboards; outcomeaftertheintervention.Forproportionsthiswaseitherthe 4. Reviewandmakechange-thedifferencebetweenthis numeratoranddenominatorortheriskdifference(orriskratioor interventionandreviewandrecommendchange(educational oddsratio).Forcontinuousvariablesthiswaseitherthemeanplus outreach)isthatthereviewerchangedtheprescriptionrather standarddeviationorstandarderror,plusnumberineachgroup. thangivinghealthprofessionalseitheraverbalorwritten ITSstudieshadtoincludeaclearlydefinedinterventionpoint. recommendationthattheyshouldchangetheprescription. Wedidnotexcludestudiesbecauseofhighriskofbias. Inadditionsomestudiesincludedautomaticstoporders(termina- Wereachedalldecisionsaboutminimummethodologicalcriteria tionofprescriptionsafteraspecifiedintervalunlessauthorization by consensus betweentheauthors, andhadthemconfirmedby wasobtainedtocontinue)butautomaticstoporderswerenever therevieweditor,LisaBero. usedasthemainintervention. Noneoftherestrictiveinterventionsinourreviewincludedfinan- cialincentivesorpenalties. Dataextractionandmanagement Tworeviewauthorsindependentlyperformeddataabstractionus- ingatemplatewhichincludedinformationon:studydesign,type Structuralinterventions ofintervention,presenceofcontrols,typeoftargetedbehaviour, Inthiscategoryweincludedtheintroductionofnewtechnology participants, setting, methods(unit of allocation, unit of analy- for laboratory testingor changestolaboratory turnaround time sis,studypower,methodologicalquality,consumerinvolvement), thatrequiredsubstantivechangestotheworkpatternsofthemi- outcomes,andresults. crobiologylaboratory,orcomputerizeddecisionsupportthatre- quiredsubstantivechangestothehospital’sinformationsystems. Explanationoftermsusedtodescribeinterventions Assessmentoftheimpactofinterventions Persuasiveinterventions Wehaveusedmeta-analysistomakethefollowing comparisons inassessingtheimpactofinterventionsonantibioticprescribing WeappliedtheEPOCdefinitionsforeachintervention,withad- andoutcomes: ditionaldetailrelevanttothecontextofthisreview.Thepersuasive Comparison1:effectofpersuasiveversusrestrictiveinterventions interventionsconsideredwere: onantibioticprescribing; 1. Disseminationofeducationalmaterialsinprintedformor Comparison2:effectofpersuasiveversusrestrictiveinterventions viaeducationalmeetings; onmicrobialoutcomes; 2. Reminders; Comparison3:effectofinterventionsintendedtoincreaseeffec- 3. Auditandfeedback; tive antibiotic treatment versus no intervention on clinical out- 4. Educationaloutreach(academicdetailingorreviewand comes; recommendchange). Comparison4:effectofinterventionsintendedtoreduceunnec- essaryantibiotictreatmentversusnointerventiononclinicalout- Restrictiveinterventions comes. RestrictiveinterventionscorrespondtotheEPOCcategoryof’fi- nancialandhealthcaresystemchanges’usedintheCochranere- Assessmentofriskofbiasinincludedstudies viewofinterventionstoimproveantibioticprescribinginambula- Interventionstoimproveantibioticprescribingpracticesforhospitalinpatients(Review) 7 Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd. Weappliedthe2009revisedEPOCriskofbiascriteriatoallpapers Measuresoftreatmenteffect in the review, including articles in the 2003 review (Cochrane DataarereportedinnaturalunitsintheCharacteristicsofincluded EPOC 2013). We scored each study for risk of bias as ’Low’ if studies tables and the Results section. We calculated the effects allcriteriawerescoredas’Done’,’Medium’ifoneortwocriteria ofinterventionsbystudydesigns.Whenthereismorethanone werescoredas’Unclear’or’NotDone’,and’High’ifmorethan study of the same study design, we calculated the effectsize by twocriteriawerescoredasUnclear’or’NotDone’. takingthemedianvalueacrossstudies.Wehavedividedoutcomes TheEPOCgroupcriteriaforareliableprimaryoutcomemeasure intofourmaingroups:prescribing,clinical,microbiologicaland include“Whenthereweretwoormoreraterswithatleast90% financial.’Prescribing’includesthedecisionwhetherornottopre- agreementorkappagreaterthanorequalto0.8”.However,kappa scribeanantibiotic,choiceofdrug,dosage,routeofadministra- valuesmaybeaslowas0.39forcompositequalityindicatorseven tion,dosingintervalanddurationoftreatment.’Clinical’includes whendataabstractioniscarriedoutbytrainedabstractors,sothe lengthofhospitalstay,incidenceofreadmissions, mortalityand inter-raterreliabilityislikelytobethebestpossible(Scinto2001). theoccurrenceofspecificinfectionsdefinedbyclinicaldiagnosis Thekeyissueiswhetherornottheactualagreementissufficientfor (e.g.woundinfection)withoutinformationaboutmicrobiological theapplicationofthequalityindicator,soforcompositemeasures cause.’Microbial’includesincidenceofinfectioncausedbyspecific suchasqualityortimingofantibiotictherapyweacceptedkappa bacteria(e.g.Clostridiumdifficileandcolonizationwithorinfec- valuesaslowas0.6(Marwick2007;Williams2006). tioncausedbyantimicrobial-resistantbacteria).Onestudy(Micek We applied three additional criteria to studies with microbial 2004)usedthenumberofinfectionsintheintensivecareunitas riskofoutcome,basedontheORIONstatement:Guidelinesfor abalancingmeasureofunintendedconsequencesofachangein transparentreportingofoutbreakreportsandinterventionstud- antibiotic policy.We havenotincluded thisasamicrobial out- ies of nosocomial infection (Stone 2007, http://www.idrn.org/ come.’Financial’includesstudiesthatprovideinformationabout orion.php). The most important of these is the distinction be- boththecostofdevelopingorimplementingtheinterventionand tweenplannedandunplannedintervention.Anunplannedinter- aboutsavingsarisingfromtheintervention. ventionismadeinresponsetoaproblem,whichmakesinterpreta- FortheincludedRCTorCBAstudies,whenpossiblewereport tionoftheeffectoftheinterventiondifficultbecauseofregression pre-interventionandpostinterventionpercentagesforbothstudy tothemean,whichisthenaturaltendencyforextremeresultsto andcontrolgroups,andcalculatetheabsolutechangefrombase- befollowedbyareturntonormal.Regressiontothemeanisan linewith95%confidenceintervals(CIs). importantriskofbiasforanyunplannedinterventionbutisapar- WeexaminedthemethodsofanalysisofITSdatacritically.The ticularproblemforstudiesofinfectionbecauseoftheshapeofthe preferredmethodisastatisticalcomparisonoftimetrendsbefore epidemiccurve(Cooper2003;Davey2001).Aclassicexampleis andaftertheintervention. Iftheoriginal paper didnot include the1854choleraepidemicinGoldenSquare,London,whenthe ananalysisofthistype,weextractedthedatapresentedintables numberofdeathsperdayfellfrom140to20infivedayswithout or graphs in the original paper and used them to perform new any intervention (Davey 2001). The additional Microbial Out- analyseswherepossible.Weusedsegmentedtime-seriesregression comeCriteriawere: analysistoestimatetheeffectoftheinterventionwhilsttakingac- 1. Casedefinition:scoreasDONEifthereisacleardefinition countoftimetrendandautocorrelationamongtheobservations. eitherofinfectionorofcolonizationandtherewerenomajor Weobtainedestimatesforregressioncoefficientscorrespondingto changesinlaboratorydiagnosticmethodsduringthestudy twostandardisedeffectsizesforeachstudy:achangeinleveland period. achangeintrendbeforeandaftertheintervention.Achangein 2. Plannedintervention:scoreasDONEiftheintervention levelwasdefinedasthedifferencebetweentheobservedlevelat wasplannedtoreduceendemicratesofcolonizationorinfection thefirstinterventiontimepointandthatpredictedbythepre-in- andwasnotimplementedinresponsetoanoutbreak. terventiontimetrend.Achangeintrendwasdefinedasthediffer- 3. Otherinfectioncontrolmeasures:scoreasDONEif encebetweenpost-andpre-interventionslopes(Ramsay2003).A infectioncontrolpractices(handhygiene,gowningorother negativechangeinlevelandslopeindicatesaninterventioneffect personalprotection)andisolationorcohortingpoliciesare intermsofareductionininfectionrates.Weevaluatedthedirect describedandtherewerenochangescoincidentwiththe effectoftheinterventionusingresultsreportedonemonthafter interventiontochangeantibioticprescribing. theinterventionstarted.Wealsoreportedtheleveleffectsatsix Intheriskofbiastablesthesecriteriaarelistedunder’otherbias’. months,andyearlythereafterwhenpossible.Westandardizedthe IntheEPOCriskofbiastables,themicrobialcriteriacountintwo resultsof some ITS studies so thatthey wereon the same scale of the criteria: ’intervention independent of other changes’ and (percentchangeinoutcome),therebyfacilitatingcomparisonsof ’otherbiases’.IntheresultstablesofMicrobialOutcomes(17a-d) different interventions. To do this, we used the change in level wehaveincludedanassessmentofmicrobialriskofbiasbasedon andchangeinslopetoestimatetheeffectsizewithincreasingtime theORIONcriteria:lowhasnorisks,mediumhasoneandhigh aftertheintervention(one month,sixmonths,oneyear,etc)as hastwoorthreemicrobialrisksofbias. thepercentchangeinlevelateachtimepoint.Wedidnotextrap- Interventionstoimproveantibioticprescribingpracticesforhospitalinpatients(Review) 8 Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
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