Interventions to improve antibiotic prescribing practices for hospital

210 Pages·2013·1.92 MB·English

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.
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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.