Assessment of an intervention aimed at early discontinuation of intravenous antimicrobial therapy in a Brazilian University hospital

w w w . e l s e v ie r . c o m / l o c a t e / b j i d

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

Original

article

Assessment

of

an

intervention

aimed

at

early

discontinuation

of

intravenous

antimicrobial

therapy

in

a

Brazilian

University

hospital

Gislaine

Ferraresi

Bonella

,

Astrídia

Marília

de

Souza

Fontes

,

Miguel

Tanús

Jorge

,

Alexandre

Barcelos

Morais

da

Silveira

a_{UniversidadeFederaldeUberlândia,FaculdadedeMedicina,ProgramadePós-Graduac¸ãoemCiênciasdaSaúde,Uberlândia,MG,Brazil}

b_{UniversidadeFederaldeUberlândia,HospitaldeClínicas,DepartamentodeFarmáciaHospitalar,Uberlândia,MG,Brazil}

c_{UniversidadeFederaldeUberlândia,HospitaldeClínicas,Servic¸odeControledeInfecc¸ãoHospitalar,Uberlândia,MG,Brazil}

d_{UniversidadeFederaldeUberlândia,InstitutodeCiênciasBiomédicas,DepartamentodeAnatomiaHumana,Uberlândia,MG,Brazil}

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Articlehistory:

Received29March2016 Accepted3July2016

Availableonline8August2016

Keywords: Antibiotics Intravenousadministration Oraladministration Inappropriateprescribing

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Manyinterventionsdemonstratesuccessinadaptingthedurationofintravenousantibiotic therapy,butfewstudieshavebeenconductedindevelopingcountries.Theaimofthisstudy wastoevaluatetheeffectivenessofaninterventionintheinductionofearlydiscontinuation ofintravenousantimicrobialtherapyand/oritsswitchtooraltherapy.Thestudyemployed abefore–afterinterventiondesignthatconsistedofdisplayingamessageinthe comput-erizedprescriptiononthethirddayandsuspensionoftheprescriptiononthefifthdayof intravenousantimicrobialtherapy.Atotalof465patientswerefollowedduringthecontrol period(CP)and440intheinterventionperiod(IP).Theintravenoustherapywasswitched tooraltherapyfor11(2.4%)patientsduringtheCPand25(5.7%)intheIP(p=0.011),and wasdiscontinuedfor82(17.6%)patientsduringtheCPand106(24.1%)intheIP(p=0.017). DuringtheIPtherewasasignificantincreaseofpatientswhohadtheirantimicrobial treat-mentdiscontinuedbeforetheseventhdayofintravenoustreatment,37.40%(49/131)inthe IPand16.13%(15/93)intheCP(p=0.0005).Thedurationofintravenousantimicrobialtherapy decreasedbyoneday,butitwasnotsignificant(p=0.136).Itisconcludedthattheproposed interventioniseffectiveinpromotingtheearlydiscontinuationofantimicrobialtreatment and/orswitchtooraltherapy.Aslongasacomputerizedsystemforprescriptionalready exists,itiseasyandinexpensivetobeimplemented,especiallyinhospitalsindeveloping countries.

©2016SociedadeBrasileiradeInfectologia.PublishedbyElsevierEditoraLtda.Thisisan openaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/ by-nc-nd/4.0/).

∗ _{Correspondingauthor.}

E-mailaddresses:gibonella@hotmail.com,abonella@ufu.br(G.F.Bonella).

http://dx.doi.org/10.1016/j.bjid.2016.07.002

1413-8670/©2016SociedadeBrasileiradeInfectologia.PublishedbyElsevierEditoraLtda.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Apart from causing therapeutic injury and unnecessary toxicity to the patient, the frequent use of inappropri-ateantimicrobialsfoundinhospitals1–5_{generatesincreased}

costsand has agreat impacton bacterial resistance.6 _The

implementationofprograms aimingtoimprove the use of antibioticsinhospitalsiswidelyrecommended,especiallyin developingcountries.7_{However,problemssuchasscarcityof}

financialresourcesandpoorinfrastructure,deficiencyof spe-cializedtraining,lackofcontroloverthesupplyandqualityof antibiotics,poorhygiene,overcrowding,andculturalhabitsof physiciansandpatientshindertheimplementationofthese programsindevelopingcountries.8,9

InBraziland otherdevelopingcountries, theavailability anduseofantimicrobialsarepoorlycontrolled,whichfurther aggravatestheproblemofbacterialresistance.10_Ontheother

hand,becausethepublicUnifiedHealthSystem(SUS–Sistema

UnificadodeSaúde)isuniversalandfree,healthauthoritiesare

concernedwiththeproperuseofantibiotics.11–13

Reassessmentofantimicrobialtherapybythethirddayisa recommendedmeasureinantimicrobialstewardship.Atthis time,theidentificationofmicroorganismsandtheir suscep-tibilityallowtargetedtherapy,andclinicalevaluationofthe patientmayleadtodiscontinuation,changeintherapy dura-tion,and/orswitch to oraltherapy.14–17 _{Doctorshave often}

ignoredthisrevaluationduetoseveralfactorssuchastime constraint,changeofthephysicianresponsibleforthepatient duringthefirstdaysofhospitalization,reluctancetochange theempiricaltherapyinapatientwhohasshownsatisfactory improvement,orevenduetopooreducation.18

When correctly recommended, the switch from intra-venoustooraltherapyreducesthepotentialforcomplications duetotheuse ofintravenousdevices,the lengthof hospi-tal stay, and hospital costs with the treatment.19,20_Among

thecriteriaforswitchingtooraltherapyareimprovementof clinicalandhemodynamicstatus,abilitytoingestdrugs,and normalgastrointestinalfunction.21–23

Awiderangeofinterventionswithcontributionsbyclinical pharmacistsisdescribedintheliteratureanddemonstrating successinimproving theprescriptionofantibioticsin hos-pitalizedpatients, especiallyininducingthe switch tooral therapyanddecreaseddurationofintravenoustherapy.24–28

However, few studies have been conducted in developing countriesandthereisrelativelylittleknowledgeoneffective strategiestoimproveantimicrobialuseinthiscontext.7_The

aimofthisstudywastoevaluatetheeffectivenessofaneasy toimplementinterventionintheinductionofearly discontin-uationofintravenousantimicrobialtherapyand/oritsswitch tooraltherapy.

Methods

Thepresentstudyadoptedthehistoricallycontrolled prospec-tivemodelunderthebeforeandafteraninterventiontype.It wasconductedattheClinicalHospitaloftheFederal Univer-sityofUberlândia(HCU,HospitaldeClínicasdeUberlândia), a publictertiaryteachinghospital,holding525bedsandentirely

dedicated to SUS. Theprojectfor this study wasapproved bytheResearchEthicsCommitteeoftheFederalUniversity ofUberlândia(UFU,UniversidadeFederal deUberlândia)under processnumber379467.

The HCU has a computerized prescription system that allowstheexchangeofinformationbetweenthephysician, clinicalpharmacies,andtheHospitalInfectionControl Com-mission (CCIH, Comissão de Controle de Infecc¸ão Hospitalar).

Amongother functions, thesystem providesa dailylistof patientswhoareinitiatingtreatmentwithantimicrobialsand onlyallowstheprescriptionofthesedrugswhenthe physi-cianfills inan“antimicrobialrequest form”inthe system, justifyingtheneedforitsuse.

Data collectionand evaluationsofthe medical prescrip-tionsand“antimicrobialrequestforms”werecarriedoutby tworesearchers,apharmacistandaninfectiousdisease physi-cianattheHospitalInfectionControlService(SCIH,Servic¸ode

ControledeInfecc¸ãoHospitalar),inthecontrolperiod(CP)–

Octo-berandNovember2013–andintheinterventionperiod(IP)– AugustandSeptember2014.Thesamemethodologyfordata collectionwasusedinbothperiods.Allpatientswhoinitiated intravenousantibioticsduringhospitalizationinthe301beds oftheMedicalandSurgicalwards,intheadultIntensiveCare Unit (ICU),and inthe EmergencyRoomwere consecutively followeduntildischarge,death,orfor60days.

Patientswhowerealreadyusingintravenousantimicrobial onthefirstdayofthestudyandthosewhoweredischargedor diedinthefirstthreedaysofintravenousantimicrobial ther-apywere excludedfromevaluation.Patientswhohad their intravenousantimicrobialtherapydiscontinuedorswitched tooralbeforethethirddayoftreatmentwerealsoexcluded.

Intervention

Interventionconsistedofmessagesonthepatient’selectronic prescription bythethirddayofintravenoustreatment and suspension ofantimicrobialprescribing bythe fifth dayof intravenoustreatment.Thephysicianssawthemessageonly onthefourthdayoftreatment,uponanewprescription.It pointed to the evaluation of possibleappropriateness (tar-getedtherapy),discontinuationoftheantimicrobialtreatment or switch tooraltherapyin casethepatient was hemody-namically stable, afebrile, presented clinical and leukocyte countimprovement,andwasabletoingestand/orabsorbthe antimicrobial. Incase the thirddayof intravenous antimi-crobial therapy occurred over the weekend or holiday, the messagewasdisplayedonthefollowingbusinessday.

Suspension ofthe antimicrobialsprescription ofby the pharmaceuticalresearcherwasonlyconductedonthefifth day of treatmentwith intravenous antimicrobial. The sus-pensiontook intoaccountpredeterminedcriteriabased on national and international protocols and dataavailable on thelocalantimicrobialresistance.Whennecessary,the treat-ingphysicianswerecontactedbytelephoneforclarification ofthe patients’condition. Tocontinueprescribingthe sus-pended intravenous antimicrobial, the physicianin charge for the patient had to fill in a computerized form justify-ing thecontinuationofthetreatment. Incasethefifthday ofthe injectableantimicrobialtreatmentoccurred over the

weekendorholiday,suspensionoftheprescriptionwasmade onthefollowingbusinessday.

Outcomes

Thefrequencyofprematurediscontinuationofintravenous antimicrobialtherapyorswitchtooraltherapywere consid-eredasprimaryoutcome,andthe reductioninduration of intravenoustherapyandofhospitalstayassecondary out-comes.Toevaluatesafety and efficacyofthe antimicrobial treatment the following were considered: need to resume intravenous antimicrobial therapy, mortality, and readmis-sions over a periodof 60 days followingpatient’s hospital discharge.

Statistical

analysis

Statisticalanalysisofthedatawasperformedwiththehelp ofJMP®_{software(SASInstitute,1995).Becausethedatawere}

notnormallydistributed,asverifiedbytheShapiro–Wilktest at5%significancelevel,differencesbetweenthemediansof hospitalstayanddurationofintravenoustherapyindayswere evaluatedusingthenon-parametricMann–Whitneytest.

ThePearson’schi-squaretestwasappliedtoevaluatethe potentialassociationbetweencategoricalvariablesassessed inthetwostudy periods(CPandIP).Thebinomial testfor comparingtwoproportionswasappliedfornon-categorical variables.Alevelof5%significancewasconsidered.

Thefollowingoutcomes were considered indata analy-sis:switchtooraltherapywhenitoccurredbythefifteenth dayofintravenousantimicrobialtreatment;discontinuation of intravenous antimicrobial therapy without switching to oraltherapy, when all antimicrobials usedwere discontin-uedbeforethefifteenthdayofuseandthepatientremained hospitalized;maintenanceofintravenoustreatmentuntil dis-charge, when intravenous antimicrobial therapy was used throughoutthehospitalstay.Thepatient’slengthofhospital staywasconsidered fromthe firstday intravenous antimi-crobialwereprescribeduntildischarge,death,or60daysof hospitalization.

Results

Thestudy included465patientsintheCPand 440patients intheIP.Thepatients’meanageinyearswassimilarinboth studyperiods,48±23.69yearsintheCPand48±23.74intheIP (p=0.9253).IntheCP,264patientsweremale(56.8%)compared to282(64.1%)intheIP(p=0.0271).Clinicalfeatures,wards,and themostcommonlyusedclassesofantimicrobialsinbothCP andIPareshowninTable1.

Themedianpatients’lengthofhospitalstaywas11days intheCP(interquartilerange6and21.5days)similartothe IP(11;7and21days)[p=0.8853].Thedurationofintravenous therapywasonedaylower inthe IP(median:9; interquar-tilerange 6and 17 days)comparedtothe CP (median:10; interquartilerange 6and18 days),anon significant differ-ence(p=0.1360).Theproportionofreadmittedpatientswas significantlyhigherintheIP(11.6%)comparedtotheCP(7.1%)

Table1–Characteristicsoftheassessedpatientsand classesofcommonlyusedantimicrobialsinthecontrol period(CP)andinterventionperiod(IP).

CP IP p-value

Ward/Hospital–No.(%)

Surgicalward 102(21.9%) 82(18.6%) 0.2448a

AdultICU 52(11.2%) 40(9.1%) Generalmedicalward 25(5.4%) 19(4.3%) Emergencyroom 286(61.5%) 299(68.0%)

Likelysourceofinfection–No.(%)

Urinarytractinfection 109(23.4%) 85(19.3%) 0.0551a

Respiratorytract infection 84(18.1%) 99(22.5%) Intra-abdominal infection 82(17.6%) 73(16.6%) Skinandsofttissue

infection

61(13.1%) 53(12%) Infectionofthe

osteoarticularsystem

56(12%) 63(14.3%) Centralnervoussystem

infection

10(2.2%) 11(2.5%) Sepsis 56(12.1%) 38(8.7%) Prophylaxis 7(1.5%) 18(4.1%)

Total 465(100%) 440(100%)

Classesofantimicrobials–No.(%)

Beta-lactams Cephalosporins 466(32.9%) 355(29.2%) 0.0389c Penicillinsb _{160(11.3%) 204(16.8%) <0.0001}c Carbapenems 148(10.5%) 112(9.2%) 0.284118 Glycopeptides 150(10.6%) 138(11.3%) 0.540815 Nitroimidazole 115(8.1%) 77(6.3%) 0.077461 Quinolones 11(7.8%) 114(9.4%) 0.161931 Antifungals 90(6.4%) 67(5.5%) 0.358115 Lincosamides 79(5.6%) 73(6%) 0.645597 Sulfonamides 27(1.9%) 27(2.2%) 0.573581 Aminoglycosides 20(1.4%) 17(1.4%) 0.973036 Others 50(3.5%) 33(2.7%) 0.230188 Total 1416 1217

a _{Pearson’schi-squaretest.}

b _{Beta-lactams associated with beta-lactamase inhibitor are}

includedinthepenicillinclass.

c _{Significancelevel(p<0.05)basedonthebinomialtestfor}

compar-isonofproportions.

[p=0.0199].However,there wasno significant differencein patientswhoswitchedtooraltherapy,9.1%(1/11)intheCPand 8%(2/25)intheIP(p=0.9131).Thesameoccurredinpatients who had theirintravenousantimicrobialtreatment discon-tinued,10.98%(9/82)intheCPand10.38%(11/106)intheIP [p=0.8950].Atotal of19.51%(16/82)ofthe patientshad to resumeintravenousantibioticsinCPand22.64%(24/106)in theIP[p=0.6031].Twenty-sevenpercent(3/11)ofthepatients resumedintravenousantibioticsafterswitchingtooral ther-apyintheCPand20%(5/25)intheIP[p=0.6287].

Therewasnodifferenceinthepercentageofpatientswho usedotheroralmedicationsconcomitantlywithintravenous antimicrobialsinbothperiods,361patients(77.6%)intheCP and325(73.9%)intheIP(p=0.1856).

Theinterventionwasassociatedwithasignificantincrease inthenumberofpatientswhohadtheirintravenous antimi-crobialtherapy stoppedeitherbyswitchingtooraltherapy

Table2–Frequencyandtypeofchangesinthe antimicrobialintravenoustreatmentinpatients

evaluatedduringthecontrolperiod(CP)andintervening period(IP).

CP IP p-value

Variable–No.(%)

Switchtooraltherapy 11(2.37%) 25(5.68%) 0.0107a Discontinuationof intravenous treatmentwithout switchingtooral therapy 82(17.63%) 106(24.09%) 0.0167a Maintenanceof intravenous

treatmentuntildayof discharge

372(80.0%) 309(70.23%) 0.0007a

Total 465(100%) 440(100%) Discontinuationof

intravenous treatmentbeforethe seventhdayof antimicrobial therapyb

15(16.13%) 49(37.40%) 0.0005a

Totalc _{93(100%) 131(100%)}

a _{Significancelevel(p<0.05)basedonthebinomialtestfor}

compar-isonofproportions.

b _{Discontinuationofintravenousantimicrobialtreatmentbefore}

theseventhday,eitherduetoswitchtooraltherapyor discontin-uationoftreatmentwithoutswitchingtooraltherapy.

c _{Totalnumberofpatientswhohadtheirintravenousantimicrobial}

therapydiscontinued,eitherduetoswitchingtooraltherapyor duetodiscontinuationwithoutswitchingtooraltherapy.

orbydiscontinuationwithoutswitchingtooraltherapy.The interventionwasalsoassociatedwithasignificantincreasein thenumberofpatientswhohadtheirintravenous antimicro-bialtherapydiscontinuedbeforetheseventhday(Table2).

Discussion

Theresultsindicatethat thetestedinterventionwas effec-tive,sinceit ledtoasignificant increaseinthe number of patients who had their intravenous antimicrobial therapy stoppedbyswitchingtooraltherapyorbyhavingthe treat-ment discontinued without switching to oraltherapy. The resultsalsoindicatethatthenumberofpatientswhohadtheir intravenousantimicrobialtreatmentdiscontinuedbeforethe seventhdayincreasedsignificantlyby21.27%duringthe inter-vention.

Thesignificantincreaseinswitchingtooraltherapywas lessthanimpressive(3%).Thispercentageismuchlowerthan thatfoundinotherstudiesconductedinother partsofthe world.24,25,28_{Thelowswitchingfrequencytooraltherapyin}

theHCUwasalreadyknown.29_{Thisstudydoesnotaddtothe}

understandingofthisfact.Thismayoccurdueto organiza-tionalproblemsandmedicalpractice,whichcouldbereduced byeducational interventionor structuralchanges. Further-more, since the study design was not intended to follow patientsaftertheirdischarge,thenumberofpatientswhohad

theirantimicrobialtherapyswitchedtooraltherapymayhave beenunderestimated.IntheHCU,aswellasinotherBrazilian hospitals,problemssuchasovercrowdingandwaitinglistsfor admissionencourageearlydischargeofpatients.30_Itislikely

thatassoonasthehospitalizedpatientcanstopthe treat-mentwithintravenousantimicrobialsoruseitorally,heor sheisdischargedandoraltherapyisstartedathome.

Amongthecriteria forswitchingtooraltherapyare the abilitytoingestdrugsandthenormalgastrointestinal func-tion.Sinceinthetwoperiodsofthestudymostofthepatients were using oral drugs from other pharmacological groups concomitantly with intravenous antibiotics, these patients probablydidnothavegastrointestinalintolerance,thusable toingestandabsorboralantibiotics.Therefore,by hypothe-sis,gastrointestinalintolerancemustnothavebeenthecause formaintainingintravenousantimicrobialtreatmentinmost cases.

Although the duration of the intravenous antimicrobial therapydecreasedbyoneday,thereductionwasnot signif-icant.However,asthecriteriaforswitchingtooraltherapy ordiscontinuingthetreatmentwereonlyevaluatedintheIP, it was notpossibletoassess the effectofthe intervention onthedurationofintravenousantimicrobialtherapyjustin patientswhometthecriteria.Thus,theeffectofthe interven-tiononthedurationofintravenousantimicrobialtreatment wasdilutedsincetheanalysisalsoincludedpatientswhodid notmeetthecriteria,whichwasalimitationofthestudy.

Whileonemightthinkthatthegoodresultsof interven-tionsevaluatedinotherstudiesareduetothefactthatthey werecarriedonmoredevelopedcountries,withmore orga-nizedhealthcarefacilitiesvanNiekerketal.31_demonstrated

thatdespitefacingdifficulties,interventionsinadeveloping countryhaveledtoanincreasednumberofpatientswhohad intravenoustherapyswitchedtooraltherapy,risingfrom16% to43.9%.Therewasalsoadecreaseinthedurationofthe intra-venous therapy and costs. This probablyoccurred because feedbacktophysiciansanddirectattempttoconvincethem tochangethetherapywerealsopartoftheintervention.31

Although the two study periods occurred in different monthsoftheyear,allowingforpossibleseasonalbias,the demographic and clinical characteristics found were sim-ilar among the populations studied in the two different periods.

Asnotedinotherstudiesinwhichinterventionstoreduce the durationofintravenousantimicrobialtherapywas suc-cessful, wealsoobservednoindicationthattherewas any interference with the effectiveness of the treatment and patient safety.23,24,26 _{There was no difference between the}

twoperiodsregardingthefrequencyofresumingintravenous antimicrobial treatment and mortality.In this context, the detectedincreaseintheglobalpercentageofreadmissionsin theIPcouldindicateaharmfuleffectoftheintervention. How-ever,whenweanalyzethepercentagerelatedonlytothegroup ofpatientswhoswitchedtooraltherapy,orwhohad antimi-crobialtreatmentstopped,therewasnosignificantdifference. Then,theglobalincreaseprobablyoccurredforreasonsother thantheinterventionitself.Wedonothaveenoughdatato explainthereasonforsuchglobalincrease.

Thedifferencefoundinbothperiodsregardingcommonly usedantimicrobialclassesmaybeduetoepisodesofshortage

ofsomeantimicrobials,whichoccurredinbothstudyperiods. However,therewasnolackofantimicrobialsusedorallyin neitheroftheperiods.

Thesignificantresultofthisstudycontrastswitha previ-ousstudycarriedoutinthesamehospital,inwhichstrategies involvingpreparation,presentationanddistributionof guide-lines,anddailyreminderstophysiciansthroughlabelsaffixed onnoncomputerizedprescriptionsturnedoutineffective.29

Thedifference isprobablydue tothe use ofcomputerized featuresinthepresentstudythatdeliveredthemessagesat thetimetheprescriptionwerepreparedand,aboveall,due toprescriptionsuspension,whichrequiredphysicianstofill inthejustificationforcontinueduseofintravenous antimi-crobials.Theseresourceshavebeensuccessfullyusedforthe appropriatenessofantimicrobialsuse.14,32

Itmustbeconsideredthat,despitethemodestbenefitof theinterventionevaluatedinthisstudy,itsimplementationin placeswheretheprescriptionsystemissimilar,issimpleand comesatalowcost.Otherstudiesmaytestthisintervention withsomemodifications.Asthisinterventionwasinterrupted withthephysician’sjustification,onecouldarguewhetherit wouldbemoreeffectiveifthejustificationwasassessedandif itwasnotconvincingthereshouldbeanattempttopersuade the physicianin charge. Perhapsa directcontact withthe prescriberswouldproduceevenmoresignificantoutcomes. However,thisstudywaslookingforaneffective,inexpensive, andeasytomaintainstrategy.

Aslongascomputerization alreadyexists, theproposed interventioncanbeeasilyimplementedandenforcedbythe pharmacistindailypracticewithgoodacceptanceby physi-cians.ArecentacknowledgmentbyCochranerecognizedthat duetothecomplexityofhealthcareorganizations,individual hospitalswillalwayshavetoevaluatetheirowninterventions andthatmulti-facetedandcomplexinterventionsarenot nec-essarilymoreeffectivethansimpleinterventions.33

Conclusion

Weconcludethattheinterventioncarriedoutinthisstudy iseffectivewithregardtotheearlydiscontinuationof intra-venous antibioticsand/or switch tooral therapy. Although this conclusion is not necessarily valid for all types of hospitals, this study suggests it is worthwhile at least testing the evaluated strategy in hospitals that wish to deploysomeinterventiontowardthatend.Thecost/benefit ratio of the intervention should be ascertained, including whethercomputerizationand/orappropriatenessofthe pre-scription system already exists or whether they are still necessary.

Other approaches related to the rationaluse of antimi-crobialagentscanalsobeaddedtotheinterventionaswell asfeedbacktophysiciansforappropriatenessof antimicro-bialtherapy.Thisstudyindicatesthatdespitethedifficulties facedindevelopingcountries,pharmacistscancontributeto animprovementintheuseofantimicrobialsinhospitals,and simpleinterventionssuchastheoneproposedhereareoflow costand easy toimplement,which isespeciallyimportant withregardtotheirmaintenanceandsustainability.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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