Decontamination Strategies and Bloodstream Infections With Antibiotic-Resistant Microorganisms

126 Pages·2017·1.35 MB·English

Research
JAMA | OriginalInvestigation | CARINGFORTHECRITICALLYILLPATIENT
Decontamination Strategies and Bloodstream Infections
WithAntibiotic-ResistantMicroorganismsinVentilatedPatients
A Randomized Clinical Trial
BastiaanH.Wittekamp,MD,PhD;NienkeL.Plantinga,MD,PhD;BenS.Cooper,PhD;JoaquinLopez-Contreras,MD,PhD;PereColl,MD,PhD;
JordiMancebo,MD;MattP.Wise,MD,PhD;MattP.G.Morgan,MD,PhD;PieterDepuydt,MD,PhD;JerinaBoelens,MD,PhD;ThierryDugernier,MD,PhD;
ValérieVerbelen,PhD;PhilippeG.Jorens,MD,PhD;WalterVerbrugghe,MD;SurbhiMalhotra-Kumar,PhD;PierreDamas,MD,PhD;CécileMeex,PhD;
KrisLeleu,MD;Anne-MarievandenAbeele,MD;AnaFilipaGomesPimentadeMatos,MSc;SaraFernándezMéndez,MD;AndreaVergaraGomez,Msc;
ViktorijaTomic,MD,PhD;FrancSifrer,MD;EstherVillarrealTello,MD;JesusRuizRamos,PhD;IreneAragao,MD;ClaudiaSantos,MD;
RobertaH.M.Sperning,Msc;PatriziaCoppadoro,BSc;GiuseppeNardi,MD;ChristianBrun-Buisson,MD,PhD;MarcJ.M.Bonten,MD,PhD
VisualAbstract
IMPORTANCETheeffectsofchlorhexidine(CHX)mouthwash,selectiveoropharyngeal
Editorialpage2081
decontamination(SOD),andselectivedigestivetractdecontamination(SDD)onpatient
outcomesinICUswithmoderatetohighlevelsofantibioticresistanceareunknown. Supplementalcontent
OBJECTIVE TodetermineassociationsbetweenCHX2%,SOD,andSDDandtheoccurrence
ofICU-acquiredbloodstreaminfectionswithmultidrug-resistantgram-negativebacteria
(MDRGNB)and28-daymortalityinICUswithmoderatetohighlevelsofantibioticresistance.
DESIGN,SETTING,ANDPARTICIPANTS RandomizedtrialconductedfromDecember1,2013,toMay
31,2017,in13EuropeanICUswhereatleast5%ofbloodstreaminfectionsarecausedbyextended-
spectrumβ-lactamase–producingEnterobacteriaceae.Patientswithanticipatedmechanicalventilation
ofmorethan24hourswereeligible.Thefinaldateoffollow-upwasSeptember20,2017.
INTERVENTIONS StandardcarewasdailyCHX2%bodywashingsandahandhygiene
improvementprogram.Followingabaselineperiodfrom6to14months,eachICUwasassigned
inrandomorderto3separate6-monthinterventionperiodswitheitherCHX2%mouthwash,
SOD(mouthpastewithcolistin,tobramycin,andnystatin),orSDD(thesamemouthpasteand
gastrointestinalsuspensionwiththesameantibiotics),allapplied4timesdaily.
MAINOUTCOMESANDMEASURES TheoccurrenceofICU-acquiredbloodstreaminfectionwith
MDRGNB(primaryoutcome)and28-daymortality(secondaryoutcome)duringeach
interventionperiodcomparedwiththebaselineperiod.
RESULTS Atotalof8665patients(medianage,64.1years;5561men[64.2%])wereincluded
inthestudy(2251,2108,2224,and2082inthebaseline,CHX,SOD,andSDDperiods,
respectively).ICU-acquiredbloodstreaminfectionwithMDRGNBoccurredamong144
patients(154episodes)in2.1%,1.8%,1.5%,and1.2%ofincludedpatientsduringthebaseline,
CHX,SOD,andSDDperiods,respectively.Absoluteriskreductionswere0.3%(95%CI,
−0.6%to1.1%),0.6%(95%CI,−0.2%to1.4%),and0.8%(95%CI,0.1%to1.6%)forCHX,
SOD,andSDD,respectively,comparedwithbaseline.Adjustedhazardratioswere1.13(95%
CI,0.68-1.88),0.89(95%CI,0.55-1.45),and0.70(95%CI,0.43-1.14)duringtheCHX,SOD,
andSDDperiods,respectively,vsbaseline.Crudemortalityrisksonday28were31.9%,
32.9%,32.4%,and34.1%duringthebaseline,CHX,SOD,andSDDperiods,respectively.
AuthorAffiliations:Author
Adjustedoddsratiosfor28-daymortalitywere1.07(95%CI,0.86-1.32),1.05(95%CI, affiliationsarelistedattheendofthis
0.85-1.29),and1.03(95%CI,0.80-1.32)forCHX,SOD,andSDD,respectively,vsbaseline. article.
CorrespondingAuthor:BastiaanH.
CONCLUSIONSANDRELEVANCE AmongpatientsreceivingmechanicalventilationinICUswith Wittekamp,MD,PhD,JuliusCenter
moderatetohighantibioticresistanceprevalence,useofCHXmouthwash,SOD,orSDDwas forHealthSciencesandPrimaryCare,
UniversityMedicalCenterUtrecht,
notassociatedwithreductionsinICU-acquiredbloodstreaminfectionscausedbyMDRGNB
HuispostnummerStr6.131,
comparedwithstandardcare. POBox85500,3508GA,Utrecht,
theNetherlands(b.h.j.wittekamp
TRIALREGISTRATION ClinicalTrials.govIdentifier:NCT02208154 @umcutrecht.nl.).
SectionEditor:DerekC.Angus,MD,
JAMA.2018;320(20):2087-2098.doi:10.1001/jama.2018.13765 MPH,AssociateEditor,JAMA
PublishedonlineOctober22,2018. ([email protected]).
(Reprinted) 2087
©2018AmericanMedicalAssociation.Allrightsreserved.
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Research OriginalInvestigation EffectsofDecontaminationStrategiesonDrug-ResistantBloodstreamInfectionsinVentilatedPatients
C
areofpatientsinintensivecareunits(ICUs)isfre-
quentlycomplicatedbyinfections,whichareassoci- KeyPoints
atedwithincreasedmorbidity,mortality,andhealth
Question Isuseofchlorhexidine2%mouthwash,selective
care costs.1,2 Selective digestive tract decontamination oropharyngealdecontamination(SOD),orselectivedigestivetract
(SDD)andselectiveoropharyngealdecontamination(SOD) decontamination(SDD)associatedwithreducedriskof
consistoftopicalantimicrobialagentstargetingaerobic bloodstreaminfectionsduetomultidrug-resistantgram-negative
gram-negative pathogens, Staphylococcus aureus, and bacteriaamongventilatedpatientsinintensivecareunits(ICUs)
withmoderatetohighprevalenceofantibioticresistance?
yeastsinthegastrointestinaltract(SDD)andoropharynx
(SDD/SOD),andtheyaimtopreventinfections.InICUswith Findings Inthisrandomizedtrialof8665patients,theuseof
lowlevelsofantibioticresistance,SDDandSODhavebeen chlorhexidine1%mouthwash,SOD,orSDDwasnotassociated
associatedwithimprovedpatientoutcomes,3,4withSDD withsignificantdifferencesinICU-acquiredbloodstreaminfections
beingmoreefficaciousthanSOD.5,6Currently,SDDandSOD withmultidrug-resistantgram-negativebacteria(adjustedhazard
ratios,1.13,0.89,and0.70,respectively),comparedwithabaseline
areroutinelyusedinICUsintheNetherlands,buttheiruse
periodofchlorhexidinebodywashingandahandhygiene
hasnotbeenwidelyadoptedinothercountries,7mainly
improvementprogram.
becauseoflimitedefficacydatainsettingswithhigherlev-
Meaning AmongventilatedpatientsinICUswithmoderateto
elsofantibioticresistanceandconcernaboutemergenceof
highprevalenceofantibioticresistance,useofchlorhexidine1%
antibioticresistance,althoughthelatterisnotsupportedby
mouthwash,SOD,orSDDwasnotassociatedwithasignificant
meta-analyses.8Incontrast,chlorhexidine(CHX)mouth-
differenceinbloodstreaminfectionswithmultidrug-resistant
washiswidelyusedinICUpatientsanditsusehasbeen gram-negativebacteriacomparedwithstandardcare.
associatedwithalowerincidenceofventilator-associated
pneumonia,9,10withCHX2%beingmoreefficaciousthan
lowerconcentrations.9Yet,inmeta-analyses,CHXmouth- withvancomycin-resistantenterococci(alldefinedas>10%
wash was associated with higher mortality in ICU pa- ofICU-acquiredbacteremiawiththatspecies)wereexcluded
tients.11,12SDDandSODhaveneverbeencomparedheadto fromparticipation.
headwithCHXmouthwashinICUpatients. Allhospitalsstartedwithabaselineperiodofatleast6
Giventheequipoiseontheeffectivenessandecological months,whichincludeddailyCHX-digluconate2%body
safetyofthesedecontaminationstrategiesinICUswithmod- washing(CHX-BW)forallICUpatientsuntilICUdischarge
eratetohighlevelsofantibioticresistance,arandomizedtrial andimplementationoftheWorldHealthOrganizationhand
wasconductedin6Europeancountriestoquantifytheasso- hygieneprogram,includingweeklyobservations.13CHX
ciationbetweenCHXmouthwash,SOD,andSDDandICU- mouthwash(0.12%or0.20%)wasallowedaspartofstan-
acquiredbloodstreaminfections(BSIs)withmultidrug- dardcareifthiswaspartofregularcarebeforethestudy.
resistantgram-negativebacteria(MDRGNB),patientmortality, UniversalCHX-BWandmonitoringofhandhygienecontin-
andunitwideprevalenceofantibioticresistance. uedthroughoutthe3followinginterventionperiods.After
thebaselineperiod,the3studyinterventions(CHXmouth-
wash,SOD,andSDD)wereimplementedinasequential
computer-generatedrandomizedorderineachparticipating
Methods
center.Randomizationoftheorderofinterventionsaimed
StudyDesign toreduceeffectsofchangesintimeinantibioticresistance
Anonblindedmulticentertrialwithclusterrandomization orclinicalpracticethatmightaffectstudyoutcomes.All
andcrossoverofinterventionswasconductedin13ICUs studyperiodswereintendedtolast6monthsandwere
fromBelgium,Spain,Portugal,Italy,Slovenia,andtheUnited separatedbya1-monthwashout/inperiod.
KingdombetweenDecember1,2013,andMay31,2017.
Thefulltrialprotocolandstatisticalanalysisplansarein Patients
Supplement1.Thecharacteristicsoftheparticipatingcenters Patientswithanexpecteddurationofinvasivemechanicalven-
areineTable1inSupplement2.Institutionalreviewboard tilationofatleast24hourswereeligible.Exclusioncriteriain-
approvalfordatacollectionwasobtainedpriortostudy cludedageyoungerthan18years,pregnancy,andallergyto
start,and,whererequired,nationalregulatoryauthorities anystudyinterventioncomponent.Eligiblepatientsadmit-
approvedthestudyprotocolpriortorandomizationofinter- tedduringthefirst2weeksofthewashout/inperiodreceived
ventions.Allhospitalsobtainedawaiverforindividual thenewinterventionbutwerenotpartofthestudypopula-
patientinformedconsentbecauseinterventionsaimedto tion;patientsadmittedduringthesecond2weeksreceivedthe
achieveward-levelecologiceffects(andpatient-basedran- newinterventionandwereanalyzedassuch.
domizationmightleadtocontaminationofeffects)andinter-
ventionswereconsideredtohaveminimalrisksofharm. Interventions
Only ICUs with an extended-spectrum β-lactamase CHX2%mouthwash,SOD,andSDDweremanufacturedby
prevalenceofatleast5%amongEnterobacteriacea-causing thepharmacyoftheUniversityMedicalCenterUtrecht,the
BSIwereeligible(studyprotocolinSupplement1).ICUswith Netherlands.CHX2%mouthwashwasreplacedbyCHX1%
endemiclevelsofcarbapenem-resistantEnterobacteriaceae, oralgelinMarch2015afterthereportingoforalmucosal
multidrug-resistantPseudomonasorAcinetobacterspeciesor adverseeffectsin29of295patients(9.8%)treatedin2
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EffectsofDecontaminationStrategiesonDrug-ResistantBloodstreamInfectionsinVentilatedPatients OriginalInvestigation Research
hospitals.14TheoropharyngealpasteusedduringSODand dayofICUadmissionbeingdesignatedasday0.Onlythefirst
SDDcontained0.19millionunitsofcolistinsulfate,10mgof episodeperpatientwasusedintheanalyses.Microorganisms
tobramycinsulfate,and0.1millionunitsofnystatinper excludedfromthedefinitionofBSIarelistedineTable2in
dosage(0.5g)andthegastrointestinalsuspensioncon- Supplement2.DefinitionsofMDRGNBandHRMOarelisted
tained1.9millionunitsofcolistinsulfate,80mgoftobra- ineTable3inSupplement2andmainlyincludeEnterobacte-
mycinsulfate,and2.0millionunitsofnystatinperdosage riaceaeresistanttothird-generationcephalosporinsandGNB
(10mLthroughnasogastrictube).AlthoughtheSDDregi- resistanttocarbapenems,colistin,or3ormoreantibiotics.15
men,whereusedroutinely(eg,theNetherlands),3-5usually
includesa4-daycourseofintravenouscephalosporin,pro- SampleSizeandStatisticalAnalyses
phylacticuseoftheseantibioticswasnotconsideredappro- TodeterminetheeffectsofCHX,SOD,andSDDasifthese
priateinsettingswithamoderatetohighprevalenceofanti- wereimplementedinICUsinadditiontostandardcare,each
bioticresistance,andwasthereforenotpartofthestudy interventionwascomparedwithstandardcare(baseline
protocol.CHXmouthwash,SOD,andSDDwereinitiated period)foralloutcomes.Studyfundingwasobtainedfroma
afterstudyinclusionandapplied4timesdailyafterregular grantcallthatspecificallyaskedforevaluationofinterven-
oralcareuntilmechanicalventilationwasstopped.Adher- tionsinICUsthatcouldreducetheincidenceofICU-acquired
encetodecontaminationstrategieswasmonitoredwith BSIwithMDRGNB.We,therefore,usedthisastheprimary
monthlyadherencemeasurementsandrecordingofinter- outcome,butbasedthesamplesizecalculationon28-day
ruptionsinindividualpatients. mortality,consideredtobeamoreclinicallyrelevantout-
Rectumandrespiratorysurveillancesamples(endotra- come.A10%(relative)reductionin28-daymortalityanda
chealaspirate,whenpossible,orthroatswabs)wereob- 50%relativereductionintheincidenceofICU-acquired
tainedtwiceweeklyfromstudypatients,andoncemonthly MDRGNBBSIwereconsideredclinicallyrelevant.4Todem-
fromallpatientspresentintheunitonthatdayforpointpreva- onstratea10%relativedifferencein28-daymortalityfor
lencesurveys.MicrobiologymethodsaredescribedineAp- eachinterventioncomparedwithbaseline,10800patients
pendix1inSupplement2.Asafetycommitteeconsistingof3 wererequired(usingabaseline28-daymortalityof27.5%;
independentexpertsreviewedtheresultsofmonthlypoint α=.05;80%power),includingamarginof600patientsper
prevalencesamplesat3-monthintervals,butnotclinicalout- studyarmtoincludeclustereffectsanddifferencesinbase-
comes.Thecommitteememberswereblindedtotheinter- linecharacteristics.However,anerrorinthecalculationof
ventionsappliedandcouldrecommendinterruptionofthe variancebetweenstudygroupswasdiscoveredafterstudy
studyinaparticipatingICUifanincreaseinantibioticresis- completion,whichhadledtolowerpatientnumbersthan
tancewasapparent. requiredforthepowerof80%.Detailsofthesamplesizecal-
culationareineAppendix2inSupplement2.
Outcomes Threecohortswerecreatedfortheanalysesofclinical
TheprimaryoutcomewastheincidenceofICU-acquired outcomes:uniqueICUadmissionsforICUmortalityand
BSIwithMDRGNBinstudypatientsduringuseofCHX,SOD, ICU-acquiredBSI(withMDRGNB,HRMO,andanypatho-
orSDDcomparedwithstandardcare.Secondaryoutcomes gen),uniquehospitaladmissionsforhospitalmortality,and
wereICU-acquiredBSIwithhighlyresistantmicroorganism uniqueICUadmissionswithnopriorICUadmissionwithin
(HRMO), defined as MDRGNB or methicillin-resistant 30daysfor28-daymortality(Figure).Allanalyseswereper-
Saureusorvancomycin-resistantenterococci;mortalityat formedoncaseswithoutmissingcovariatesoroutcomes.
day28fromICUadmission,atICUdischarge,andathospital Toadjustfordifferencesinpatientcharacteristicsbetween
discharge(allprespecified);andICU-acquiredBSIwithany studyperiods,propensityscoreswerecalculatedusinggen-
pathogen(posthoc).Othersecondaryoutcomesaresubject eralizedboostedmethods,16andinverseprobabilityweight-
tofutureanalysesandnotreportedinthisarticle:cross- ingwasusedtobalancethedistributionoftheconfounders
transmission rates of MDRGNB, the occurrence of ICU- center,age,sex,CharlsonComorbidityIndexscore,17dis-
acquiredrectumandrespiratorytractMDRGNBcolonization, easeseverity,admissiontype(medicalorsurgical),antibi-
and associations between colonization and BSI. Ward- oticuseonICUadmission,andlocationbeforeICUadmis-
levelexploratoryoutcomesincludedtheunitwidepreva- sion(samehospital,otherhospitalorlong-termcarefacility,
lenceofHRMOmeasuredbymonthlypointprevalencesur- orhome).BecauseICUsuseddifferentdiseaseseverityscor-
veysoftherectumandrespiratorytractofallpatientsinthe ingsystems,separatepropensityscoremodelsweremade
ICUtomonitorecologicsafety,andtheunitwideuseofsys- forICUsusingeitherAcutePhysiologyandChronicHealth
temicantibiotics(descriptiveanalyses),expressedasdefined Evaluation (APACHE) II or Simplified Acute Physiology
dailydosesperpatientday.Asaposthocexploratoryanaly- Score(SAPSII)scores,andthederivativeweightsusedin
sis,carriagerateswithantibiotic-resistantGNBintherectum thefinalmodels.ICU-acquiredBSIandICUandhospital
andrespiratorytractweredeterminedbasedontheresults mortality were analyzed with Cox-proportional hazard
of surveillance cultures plated on extended-spectrum analysesstratifiedforcenter,withdischargeanddeathas
β-lactamaseselectivemediaandobtainedtwiceweeklyfrom competingeventswhereapplicable.TheSchoenefeldGood-
studypatients. nessofFittestwasusedtotesttheproportionalityassump-
ICU-acquiredBSIwasdefinedasbacteremiaorcandi- tionandtherewasnoevidencetorejecttheproportional
demiadiagnosedfromday2ofICUstayonwards,withtheinitial hazardassumptionat5%significancelevel.
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Research OriginalInvestigation EffectsofDecontaminationStrategiesonDrug-ResistantBloodstreamInfectionsinVentilatedPatients
Figure.FlowchartandCohortsforAnalyses
56ICUs assessed for eligibility
43Excluded (did not meet inclusion
criteria or for logistical reasons)
13ICUs randomized
13ICU clusters randomized to 13ICU clusters randomized to 13ICU clusters randomized to selective 13ICU clusters randomized to selective
standard care (median cluster chlorhexidine mouthwash oropharyngeal decontamination digestive track decontamination
size: 122 patients; range: 45-352) (median cluster size: 109 (median cluster size: 104 patients; (median cluster size: 129 patients;
patients; range: 46-338) range: 36-349) range: 41-346)
8106Patients screened 7898Patients screened 8407Patients screened 8522Patients screened
5855Excludeda 5790Excludeda 6183Excludeda 6440Excludeda
4212No MV 3963No MV 4166No MV 4460No MV
1483Estimated MV <24 h 1642Estimated MV <24 h 1758Estimated MV <24 h 1725Estimated MV <24 h
84Aged <18 y 102Aged <18 y 93Aged <18 y 100Aged <18 y
211Other reasons 224Other reasons 296Other reasons 284Other reasons
2251ICU admissions included in 2108ICU admissions included in 2224ICU admissions included in 2082ICU admissions included in
the analysis the analysis the analysis the analysis
2251ICU admissions 2108ICU admissions 2224ICU admissions 2082ICU admissions
2214Hospital admissionsb 2066Hospital admissionsb 2185Hospital admissionsb 2044Hospital admissionsb
220628-d mortalityc 206728-d mortalityc 218528-d mortalityc 203828-d mortalityc
Abbreviations:ICU,intensivecareunit;MV,mechanicalventilation. cThecohortfor28-daymortalityincluded8496uniqueICUadmissions
aSomepatientshadmultiplereasonsforexclusion. withnopriorICUadmissionwithin30days,56withmissing28-day
mortalitystatus.
bThecohortforhospitalmortalityincluded8509uniquehospitaladmissions,
37withmissinghospitalmortalitystatus.
Fortheanalysisof28-daymortality,amixed-effects come;thesespecificmodelsincludedcorrectionforunderly-
logisticregressionmodelwasusedwithafixedeffectforcen- ingtimetrendsperICUandestimatedameantimetrendper
terandarandomeffectforthe52center-periodcombina- studyperiod(asanexploratoryanalysis).Becausethepoten-
tions(4periodorders[A-B-C-D]×13ICUs).Allmodelswere tialfortypeIerrorduetomultiplecomparisonswasnotad-
adjustedfortheconfoundersandmeanhandhygienecom- dressed,secondaryanalyseswereconsideredexploratory.
plianceperstudyperiodpercenter.Asensitivityanalysiswas A2-sidedsignificancelevelof.05wasusedforallanaly-
performedonthemortalityoutcomesexcludingpatients ses.SPSS(IBM,version21)andRsoftware,version3.3.2
whostayedfewerthan3daysintheICUbecausetheymight (RProjectforStatisticalComputing)wereusedfordata
havebeenoverrepresentedinthebaselineperiod.Basedon preparationandstatisticalanalyses,respectively.
thestudyfindings,anadditionalposthocsensitivityanalysis
wasperformedtoexplorepotentialconsequencesofnot
includingprophylaxiswiththird-generationcephalosporins
Results
in the SDD regimen and of stopping SDD at the end of
mechanicalventilation(ratherthanatICUdischarge),ashad BetweenDecember1,2013,andMay31,2017,32933ICU
beenperformedinpreviousDutchstudies.3-5Inthisanalysis, admissionswerescreened,ofwhich8665wereincluded,
allSDD-treatedpatientswithICU-acquiredBSIcausedbya yielding8509uniquehospitaladmissionsand8496inclu-
pathogensusceptibletothird-generationcephalosporinsdur- sionsfor28-daymortality(Figure;seeeTable4inSupplement
ingthefirst4daysand/orwithICU-acquiredBSIwithany 2forbaselinecharacteristicsofscreenedpatients).The
pathogenaftertheendofmechanicalventilationwerecon- mediandurationsofstudyperiodswere6months(range,
sideredaliveforallmortalityoutcomes,therebymaximizing 6-14.5)forbaselineand6(range,4.6-6),6(range,5-8.5),and
thepotentiallymissedeffectsofbothchangestoprevious 6(range5-7)monthsfortheCHX,SOD,andSDDperiods,
protocols.Asathirdposthocsensitivityanalysis,head-to- respectively(Table1).ProportionsofBSIcausedbyHRMO
headcomparisonsbetweentherandomizedintervention andEnterobacteriaceaeresistanttothird-generationcephalo-
groupswereperformedforallpatient-leveloutcomes. sporins,bothamongallBSIepisodes,were25.5%and15.1%,
TheunitwideprevalenceofHRMOcarriagebasedonpoint respectively.Perstudyperiod,26.7%to29.7%ofscreened
prevalencesurveyswasanalyzedseparatelyforrectumandre- patientswereeligibleand91%to94%ofthesepatientswere
spiratorytract,withbinomialmodels(loglink)foreachout- enrolled.Ofthe8665includedpatients,5561weremale
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EffectsofDecontaminationStrategiesonDrug-ResistantBloodstreamInfectionsinVentilatedPatients OriginalInvestigation Research
Table1.BaselineCharacteristicsoftheStudyPopulation
No.(%)
Characteristic Baseline(n=2251) CHX(n=2108) SOD(n=2224) SDD(n=2082)
PatientCharacteristics
Age,mean(SD),y 62.0(15.6) 61.4(15.7) 61.6(15.7) 62.8(15.5)
Sex
Male 1420(63.1) 1358(64.4) 1439(64.7) 1344(64.6)
Female 831(36.9) 750(35.6) 785(35.3) 738(35.4)
APACHEIIscores 20.3(8.6) 19.8(8.2) 20.5(9.3) 21.8(8.7)
for5hospitals,
mean(SD)a
Abbreviations:APACHE,Acute
SAPSIIscores 53.0(18.0) 54.8(17.9) 54.4(17.5) 55.0(18.0) PhysiologyandChronicHealth
for8hospitals,
mean(SD)b Evaluation;CHX,chlorhexidine
mouthwash;ICU,intensivecareunit;
TypeofICUadmission
SAPS,SimplifiedAcutePhysiology
Medical 1464(65.3) 1323(63.0) 1442(64.9) 1385(66.6) Score;SDD,selectivedigestivetract
Traumawithsurgery 138(6.2) 142(6.8) 156(7.0) 115(5.5) decontamination;SOD,selective
oropharyngealdecontamination.
Trauma,nosurgery 113(5.0) 88(4.2) 104(4.7) 88(4.2)
aTheAPACHEIIdiseaseseverity
Surgical,scheduled 198(8.8) 173(8.2) 173(7.8) 178(8.6) scorerangesfrom0to71,with
Surgical,unscheduled 328(14.6) 374(17.8) 346(15.6) 314(15.1) higherscoresindicatingincreased
severityandanincreased
Surgical,unspecified 10(0.4) 8(0.4) 3(0.1) 2(0.1)
probabilityofin-hospitaldeath.
Locationbefore ApatientwithanAPACHEIIscoreof
ICUadmission
20wouldhaveanestimated
Samehospital 1020(45.3) 1032(49.0) 1025(46.1) 1035(49.7) probabilityofin-hospitaldeath
Anotherhospitalor 400(17.8) 312(14.8) 316(14.2) 301(14.5) rangingfrom6.3%to71%,
longtermcarefacility dependingonthereasonforICU
Home(directlyor 831(36.9) 764(36.2) 883(39.7) 746(35.8) admissionandtheneedfor
viaemergency emergencysurgery.18
department) bTheSAPSIIdiseaseseverityscore
Antibioticatthetime 943(41.9) 832(39.5) 992(44.6) 744(35.8) rangesfrom0to163,withhigher
ofICUadmission
scoresindicatingincreasedseverity
Sitesoforganfailure andanincreasedprobabilityof
Respiratoryillness 1023(45.5) 990(47.0) 998(44.9) 985(47.3) in-hospitaldeath.Apatientwitha
SAPSIIscoreof52wouldhavean
Cardiovascularillness 828(36.8) 811(38.5) 835(37.5) 792(38.0)
estimatedprobabilityofin-hospital
Neurologicillness 686(30.5) 674(32.0) 615(27.7) 603(29.0) deathof50%.19
Otherillness(renal, 633(28.1) 617(29.3) 742(33.4) 676(32.5) cTheCharlsonComorbidityIndex
hepatic,metabolic, rangesfromrangesfrom0
hematologic, to37,withhigherscoresassociated
and/orother)
withahigherprobabilityof
CharlsonComorbidity 2.15(2.42) 2.38(2.49) 2.35(2.42) 2.42(2.56) 1-yearmortality.17
Indexscore,
mean(SD)c dICUsarenumberedininorderof
studystartdate(eTable1in
0 738(32.8) 631(29.9) 653(29.4) 626(30.1)
Supplement2).
1-2 759(33.7) 674(32.0) 718(32.3) 654(31.4)
eA,B,C,andDrepresentthefirst,
3-4 399(17.7) 398(18.9) 461(20.7) 410(19.7) second,third,andfourthstudy
>4 355(15.8) 405(19.2) 392(17.6) 392(18.8) periods,respectively.
ICUCharacteristics(Type,No.ofbeds)d OrderofStudyArmsperICU(Duration,mo)[No.ofStudyPatients]e fSuspensionofCHX2%intervention
periodduetooromucosal
ICU1(mixed,36beds) A(6)[212] B(5.6)[214]f C(6)[245] D(6)[229]
adverseeffects.
ICU9(mixed,42beds) A(6)[333] B(6)[338] C(5)[309]h D(6)[317] gProlongationofstudyperiod,
ICU2(mixed,24beds) A(6)[77] B(4.6)[59]f D(6)[101] C(6)[80] pendingapprovalfortheamendment
ICU11(mixed,8beds) A(9)[63]g B(6)[50] D(6)[70] C(5)[54]k fortheswitchfromCHX2%
mouthwashtoCHX1%oralgel.
ICU5(mixed,30beds) A(6)[169] C(6)[277] B(8.5)[349]g D(6)[248]
hInterruptionofSODperioddueto
ICU12(mixed,22beds) A(8)[352]i C(6)[272] B(6)[248] D(6)[237] increaseinantibiotic-resistant
ICU4(mixed,42beds) A(6)[266] C(6)[285] D(6)[334] B(7)[346]g bacteria.
ICU7(mixed,10beds) A(14.5)[297]i C(6)[109] D(6)[104] B(6)[129] iProlongationofbaselineperiod,
pendingapprovalfromthe
ICU8(mixed,15beds) A(6)[85] D(6)[92] B(6)[85] C(6)[75]
regulatoryagenciesforthe
ICU3(medical,12beds) A(6)[45] D(6)[46] B(6)[36] C(6)[41] introductionofstudyinterventions.
ICU10(medical,24beds) A(8)[113]j D(6)[85] C(6)[85] B(6)[92] jProlongationofbaselineperiodfor
ICU6(mixed,12beds) A(6)[122] D(6)[177] C(3.5+2.5)[155]h B(6)[144] locallogisticreasons.
kShortenedstudyperiodfor
ICU13(mixed,9beds) A(7)[117]i D(6)[104] C(6)[103] B(6)[90]
logisticalreasons.
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Research OriginalInvestigation EffectsofDecontaminationStrategiesonDrug-ResistantBloodstreamInfectionsinVentilatedPatients
(64.2%)andtheirmedianagewas64.1years(range,18-98). periods,respectively(Table3).Incidencespercentercanbe
Patientcharacteristicsdifferingbetweenbaselineandinter- foundineTable8inSupplement2.
ventionperiodsincludedthemeanAPACHEIIandSAPSII ICU-acquiredBSIwithHRMOoccurredin169patients(182
scoresandtheproportionofpatientsreceivingantibioticsat episodes)(Table2).RisksforICU-acquiredBSIwithHRMOwere
ICUadmission(Table1;eTable5inSupplement2). 2.4%,2.1%,1.7%,and1.6%duringthebaseline,CHX,SOD,and
Amongstudypatients,themeanproportionsreceivingde- SDDperiods,respectively.Absoluteriskreductionswere0.3%
contaminationaccordingtoprotocol,determinedbymonthly (95%CI,−0.6%to1.2%),0.6%(95%CI,−0.2%to1.5%),and
compliancemeasurements,were92.5%,92.4%,and94.2% 0.7%(95%CI,−0.1%to1.6%)forCHX,SOD,andSDD,com-
duringtheCHX,SOD,andSDDperiods,respectively(eTable paredwithbaseline,respectively.CorrespondingaHRsof
6inSupplement2).Therewere23ICUadmissionswithmiss- HRMOBSIduringstudyinterventions,comparedwithbase-
ingcovariatesand1,37,and56patientswithamissingICU, line,were1.07(95%CI,0.58to1.99),0.83(95%CI,0.46to1.51),
hospital,and28-daymortalitystatus,respectively.Average and0.77(0.38to1.52)duringCHX,SOD,andSDD,respec-
handhygienecompliancewas64.1%duringthebaselinepe- tively(Table3).
riodandrangedfrom72.2%to72.5%duringtheintervention
periods(eTable7inSupplement2).FiveICUsusedCHX0.12% Mortality
and6used0.20%mouthwashaspartofstandardcare.The Theriskratesformortalityonday28were31.9%,32.9%,32.4%,
intraclustercorrelationcoefficientwas0.001. and34.1%duringthebaseline,CHX,SOD,andSDDperiods,
respectively.Absoluteriskreductionswere−1.1%(95%CI,
DeviationsFromStudyProtocol −3.9%to1.8%),−0.5%(95%CI,−3.3%to2.3%),−2.2%(95%
Thestudywastemporarilyinterruptedin2centers.Inonecen- CI,−5.0%to0.7%)forCHX,SOD,andSDD,respectively,com-
ter,anincreasedprevalenceofcolistin-resistantKlebsiellapneu- paredwithbaseline.Correspondingadjustedoddsratiosfor
moniaewasidentifiedbythesafetycommittee,whichledto 28-daymortalitywere1.07(95%CI,0.86to1.32),1.05(95%
theidentificationofaclonaloutbreakafterSODhadbeenused CI,0.85to1.29),and1.03(95%CI,0.80to1.32)duringCHX,
for3.5months.Aftera7-monthperiodofoutbreakcontain- SOD,andSDD,respectively(Table3).TheriskratesforICUmor-
ment,SODwasreintroduced.Inanothercenter,thehospital talitywere30.7%,31.5%,30.8%,and31.0%duringthebase-
infectioncontrolcommitteeinterruptedthestudyafterSOD line,CHX,SOD,andSDDperiods,respectively.Absoluterisk
hadbeenusedfor5months,pendingevaluationsofanin- reductionswere−0.8%(95%CI,−3.6%to1.9%),−0.1%(95%
creasedprevalenceofcarbapenem-resistantEnterobacteri- CI,−2.8%to2.6%),and−0.3%(95%CI,−3.0%to2.5%)forCHX,
aceae.Furtherinvestigationrevealedthattheoutbreakwas SOD,andSDD,respectively,comparedwithbaseline.Corre-
polyclonalandoccurringinmultiplehospitalwardssimulta- spondingaHRswere1.03(95%CI,0.92to1.16),1.00(95%CI,
neously.Afteraninterruptionof7months,thenextrandom- 0.89to1.14),and0.95(95%CI,0.81to1.11)duringtheCHX,
izedstudyphase(beingSDD)wasintroducedafterinstitu- SOD,andSDDperiods,respectively.Theriskratesforhospi-
tionalreviewboardapproval.Duringbothinterruptions,SOD talmortalitywere38.0%,38.1%,38.7%,and40.3%duringthe
wasnotappliedandpatientsincludedintheintervalswerenot baseline,CHX,SOD,andSDDperiods,respectively.Absolute
includedintheanalyses. riskreductionswere0.0%(95%CI,−2.9%to2.9%),−0.7%(95%
CI,−3.5%to2.2%),and−2.2%(95%CI,−5.2%to0.7%)forCHX,
AdverseEvents SOD,andSDD,respectively,comparedwithbaseline.Corre-
CHX2%mouthwashwasreplacedbyCHX1%oralgelafterad- spondingadjustedoddsratioswere0.97(95%CI,0.85-1.11),
verseevents,mainlyconsistingoforomucosallesions,re- 1.00(95%CI,0.87-1.14),and0.96(95%CI,0.82-1.12)during
cordedinatotalof29(9.8%)of295patientstreatedwithCHX theCHX,SOD,andSDDperiods,respectively.
2%inthe2centersthatfirstimplementedCHX2%.14Nose-
riousadverseeventswerereportedduringtheuseofCHX1%, AntibioticUseandResistance
SOD,andSDD. Theunitwideconsumptionofsystemicantibioticswas1.1,1.0,
1.0,and1.1defineddailydosesperpatientdayduringthebase-
ICU-AcquiredBSIs line,CHX,SOD,andSDDperiods,respectively(eTable9in
ICU-acquiredBSIwithMDRGNB(primaryoutcome)occurred Supplement2).
in144patients(154episodes),mostfrequentlywithKpneu- Intotal,5536respiratoryand5441rectalsampleswereob-
moniae(n=56),Enterobactercloacae(n=20),Pseudomonas tainedfrom5706surveyparticipantsduring329-pointpreva-
aeruginosa(n=17),andEscherichiacoli(n=15)(Table2).These lencesurveys(Table4;eTable10inSupplement2).Complete-
occurredin2.1%,1.8%,1.5%,and1.2%ofthepatientsin- nessofsusceptibilitytestingwasgreaterthan95%(eTable11
cludedinthebaseline,CHX,SOD,andSDDperiods,respec- inSupplement2).Basedonthepointprevalencesurveys,the
tively.Absoluteriskreductionswere0.3%(95%CI,−0.6%to overallprevalenceofcarriagewithMDRGNBrangedfrom17.1%
1.1%),0.6%(95%CI,−0.2%to1.4%),and0.8%(95%CI,0.1% to25.3%inrectumsamplesandofcarriagewithMDRGNBfrom
to1.6%)forCHX,SOD,andSDD,respectively,comparedwith 10.2%to15.2%inrespiratorytractsamples,withoutstatisti-
thebaselineperiod.Correspondingadjustedhazardratios callysignificantdifferencesbetweenstudygroups(Table5).
(aHRs)ofICU-acquiredMDRGNBBSI,comparedwithbase- Theprevalenceofcolistinresistancedidnotincreaseduring
line,were1.13(95%CI,0.68to1.88),0.89(95%CI,0.55to1.45), the intervention periods (Table 5; eTables 10 and 12 in
and0.70(95%CI,0.43-1.14)duringtheCHX,SOD,andSDD Supplement2).
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Table2.ICU-AcquiredBloodstreamInfectionsperStudyGroup
Baseline(n=2251) CHX(n=2108) SOD(n=2224) SDD(n=2082)
Proportion Proportion Proportion Proportion
No.of ofBSI No.of ofBSI No.of ofBSI No.of ofBSI
StudyGroup Episodes Episodes,% Episodes Episodes,% Episodes Episodes,% Episodes Episodes,%
PrimaryOutcome:ICU-AcquiredBSIsWithMultidrug-ResistantGram-NegativeBacteria(MDRGNB)a,b
BSIwithMDRGNB, 52(47) 41(38) 34(33) 27(26)
No.ofepisodes,
(No.ofpatients)
Enterobacteriaceae 39 75.0 29 70.7 26 76.5 24 88.9
Resistantto 35 25 24 24
third-generation
cephalosporins
Resistanttocolistin 2 2 5 5
Glucosenonfermenting 9 17.3 10 24.4 5 14.7 3 11.1
gram-negativebacteria
Pseudomonas 4 9 3 2
species
Otherglucose 4 7.7 2 4.9 3 8.8 0 0.0
nonfermenting
gram-negative
bacteriac
SecondaryOutcomes:ICU-AcquiredBSIsWithHighlyResistantMicroorganisms(HRMOs)a,d
BSIwithHRMO, 58(53) 49(44)e 40(38)e 35(34)
No.ofepisodes
(No.ofpatients)
MDRGNB, 52(47) 89.7 41(38) 83.7 34(33) 85.0 27(26) 77.1
No.ofepisodes
(No.ofpatients)
Highlyresistant 6(6) 10.3 8(8) 16.3 6(6) 15.0 8(8) 22.9
Gram-positivebacteria,
No.ofepisodes
(No.ofpatients)
Vancomycin-resistant 3 4 3 0
enterococci
Methicillin-resistant 3 4 3 8
Staphylococcus
aureus
ICU-AcquiredBSIsWithAnyPathogena,f
BSIwithanypathogen, 199(154) 201(156) 172(140) 141(123)
No.ofepisodes
(No.ofpatients)
Enterobacteriaceae 99 49.7 90 44.8 77 44.8 51 36.2
Intrinsiccolistin 30 13 14 10
resistant
Glucosenonfermenting 31 15.6 19 9.5 20 11.6 15 10.6
gram-negative
bacteria
Pseudomonas 21 16 15 9
species
Gram-positivebacteria 43 21.6 61 30.3 47 27.3 50 35.5
Enterococcus 27 32 34 32
faecium/faecalis
Staphylococcus 13 25 12 17
aureus
Yeasts 15 7.5 22 10.9 23 13.4 18 12.8
Otherg 11 5.5 9 4.5 5 2.9 7 5.0
Abbreviations:BSI,bloodstreaminfection;CHX,chlorhexidinemouthwash; dHRMOsincludeMDRGNB,methicillin-resistantStaphylococcusaureus,
ICU,intensivecareunit;SDD,selectivedigestivetractdecontamination; andvancomycin-resistantenterococci(completedefinitionineTable3
SOD,selectiveoropharyngealdecontamination. inSupplement2).
aBSIdefinedasfirstoccurrenceofuniquespeciesonday2ofICUstayonwards, eTwopatientsintheCHXperiodand1patientintheSODperiodhadaBSIboth
withtheinitialdayofICUadmissionbeingdesignatedasday0.ICU-acquired withMDRGNBandgram-positiveHRMO.
BSIswithanypathogenwasaposthocoutcome. fExcludingcoagulase-negativeStaphylococcus,Micrococcus,andClostridium
bInbrief,MDRGNBincludeEnterobacteriaceaeresistanttothird-generation speciesandnonpneumococcalStreptococci(eTable2inSupplement2),
cephalosporins,gram-negativebacteriaresistanttocarbapenems,colistin, alsoincludingHRMO.
or3ormoreantibioticsfromseparateclasses(completedefinitionineTable3 gTheseincludedBSIwithBacteroidesspp(18),Parabacteroidesspp(2),
inSupplement2). Haemophilusinfluenzae(3),andStreptococcuspneumoniae(9).
cStenotrophomonasspp,Burkholderiaspp,andAchromobacterspp.
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Table3.AssociationsBetweenInterventionsandICU-AcquiredBSIandPatientMortality
CrudeAnalyses AdjustedAnalyses,AdjustedHazardRatio(95%CI)a
Baseline CHX SOD SDD CHXvs SODvs SDDvs
(n=2251) (n=2108) (n=2224) (n=2082) Baseline Baseline Baseline
PrimaryOutcome
Patientswith
ICU-acquiredBSI
withMDRGNB
Incidence,No.(%) 47(2.1) 38(1.8) 33(1.5) 26(1.2)
Absoluteriskreduction 0.3(−0.6to1.1) 0.6(−0.2to1.4) 0.8(0.1to1.6)
vsbaseline,%(95%CI)
Rate(per1000 1.62 1.34 1.14 0.94 1.13 0.89 0.70
patientdaysatrisk) (0.68to1.88) (0.55to1.45) (0.43to1.14)
SecondaryOutcomes
Patientswith
ICU-acquiredBSI
withHRMOb
Incidence,No.(%) 53(2.4) 44(2.1) 38(1.7) 34(1.6)
Absoluteriskreduction 0.3 0.6 0.7
vsbaseline,%(95%CI) (−0.6to1.2) (−0.2to1.5) (−0.1to1.6)
Rate(per1000 1.84 1.56 1.32 1.24 1.07 0.83 0.77
patientdaysatrisk) (0.58to1.99) (0.46to1.51) (0.38to1.52)
Patientswith
ICU-acquiredBSI
(anypathogen)
Incidence,No.(%) 154(6.8) 156(7.4) 140(6.3) 123(5.9)
Absoluteriskreduction −0.6 0.5 0.9
vsbaseline,%(95%CI) (−2.1to1.0) (−0.9to2.0) (−0.5to2.4)
Rate(per1000 5.69 5.95 5.12 4.67 1.08 0.94 0.79
patientdaysatrisk) (0.85to1.39) (0.76to1.17) (0.60to1.05)
MortalityinICUc
Incidence,no./No.(%) 691/2251(30.7) 664/2107(31.5) 685/2224(30.8) 645/2082(31.0)
Absoluteriskreduction −0.8 −0.1 −0.3 1.03 1.00 0.95
vsbaseline,%(95%CI) (−3.6to1.9) (−2.8to2.6) (−3.0to2.5) (0.92to1.16) (0.89to1.14) (0.81to1.11)
Mortalityinhospitald
Incidence,no./No.(%) 839/2206 782/2055 845/2184 816/2027
(38.0) (38.1) (38.7) (40.3)
Absoluteriskreduction 0.0 −0.7 −2.2 0.97 1.00 0.96
vsbaseline,%(95%CI) (−2.9to2.9) (−3.5to2.2) (−5.2to0.7) (0.85to1.11) (0.87to1.14) (0.82to1.12)
Mortalityat28d
fromICUadmissione
Incidence,no./No.(%) 701/2198 675/2049 703/2171 689/2022
(31.9) (32.9) (32.4) (34.1)
Absoluteriskreduction −1.1 −0.5 −2.2 1.07 1.05 1.03
vsbaseline,%(95%CI) (−3.9to1.8) (−3.3to2.3) (−5.0to0.7) (0.86to1.32)f (0.85to1.29)f (0.80to1.32)f
Otheroutcomes,
median(IQR),d
ICU 10(5to18) 10(6to19) 10(6to18) 11(6to18)
Inhospital 23(11to45) 24(12to45) 23(12to43) 24(12to44)
Onmechanical 6(3to13) 7(4to13) 6(3to12) 7(3to12)
ventilationinICU
Abbreviations:BSI,bloodstreaminfection;CHX,chlorhexidinemouthwash; bIncludesMDRGNBandhighlyresistantgram-positivemicroorganisms
HRMO,highlyresistantmicroorganism;ICU,intensivecareunit; (methicillin-resistantSaureusandvancomycin-resistantEfaecium/Efaecalis),
IQR,interquartilerange;MDRGNB,multidrug-resistantgram-negative accordingtodefinitionsineTable3inSupplement2.
bacteria;SDD,selectivedigestivetractdecontamination;SOD,selective cOnemissingoutcome.
oropharyngealdecontamination.
dThecohortincluded8509uniquehospitaladmissions,ofwhich37were
aAllmodelsaccountedforclusteringusingafixedeffectonICUandarandom missinghospitalmortalitystatus.
effectonstudyperiod(13ICUs×4studyperiods)andwereadjustedforage,
eThecohortfor28-daymortalityincluded8496uniqueICUadmissions
sex,CharlsonComorbidityIndexscore,APACHEIIorSAPSIIscore,admission
withnopriorICUadmissionwithin30days,ofwhich56weremissing28-day
type,antibioticuseonICUadmission,locationbeforeICUadmission(inboth
mortalitystatus.
propensityscoreandfinalmodels),andmeanhandhygienecomplianceper
studyperiod(onlyinfinalmodels). fAdjustedoddsratio(95%CI).
SensitivityAnalyses sultsforSDD(eTable13inSupplement2).Sensitivityanaly-
PosthocsensitivityanalysesinwhichBSIswereassumedto sesexcludingpatientswhostayedinanICUfewerthan3days
havebeenpreventedbythird-generationcephalosporinsand ledtosimilarresultsforallmortalityoutcomes(eTable13in
SDDtreatmentuntiltheendofICUstayyieldedsimilarre- Supplement2).
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Table4.DescriptiveStatisticsofPointPrevalenceSurveysforUnitwideCarriageofAntibiotic-Resistant
MicroorganismsintheRectumandRespiratoryTract
DescriptiveStatisticsPoint
PrevalenceSurveys Baseline CHX SOD SDD
Proportionofpatientsintheunit 93.1 94.3 92.2 92.3
screened,%
No.ofpatientssampled 1456 1424 1469 1407
Includedinstudypopulation, 63.0 61.7 60.7 59.8
%ofpatientssampled
Abbreviations:CHX,chlorhexidine
No.ofrectalsamples 1392(95.6) 1370(96.2) 1419(96.6) 1355(96.3) mouthwash;SDD,selective
(%ofpatientssampled)
digestivetractdecontamination;
No.ofrespiratorysamples 1381(94.8) 1333(93.6) 1408(95.8) 1319(93.7) SOD,selectiveoropharyngeal
(%ofpatientssampled)
decontamination.
Table5.PrevalenceofUnitwideCarriageofAntibiotic-ResistantMicroorganismsintheRectumandRespiratoryTract(ExploratoryOutcome)
Baseline CHX SOD SDD
Prevalence,% Prevalence,% aRR(95%CI)a Prevalence,% aRR(95%CI)a Prevalence,% aRR(95%CI)a
Rectum
HRMOenterobacteriaceae 16.1 21.7 1.07(0.99-1.16) 19.7 1.04(0.96-1.13) 13.9 1.05(0.95-1.16)
Third-generation 15.8 21.5 1.07(0.99-1.16) 19.2 1.04(0.96-1.13) 13.7 1.07(0.97-1.18)
cephalosporinresistance
Carbapenemresistance 3.2 3.1 0.68(0.54-0.86) 2.9 0.85(0.71-1.03) 2.6 0.80(0.64-1.01)
Resistanceto≥3antibiotics 10.8 15.5 1.07(0.97-1.19) 14.2 1.06(0.96-1.17) 10.0 1.10(0.97-1.24)
(orclasses)
Colistinresistanceb 0.5 1.6 0.81(0.54-1.21) 1.8 0.97(0.65-1.45) 1.3 0.96(0.60-1.54)
HRMOglucose 3.2 3.2 0.77(0.62-0.95) 3.3 0.93(0.76-1.14) 2.3 0.81(0.63-1.04)
nonfermentingGNB
MDRGNB,regardlessof 1.0 1.5 0.80(0.50-1.27) 1.1 0.80(0.49-1.30) 1.6 1.01(0.64-1.58)
antibioticsusceptibility
AnyMDRGNB 19.3 25.3 1.03(0.96-1.11) 23.0 1.03(0.96-1.11) 17.1 1.04(0.96-1.14)
(aggregate)
VRE 2.2 1.5 0.96(0.74-1.24) 1.8 0.94(0.73-1.21) 4.2 1.03(0.84-1.27)
RespiratoryTract
HRMOEnterobacteriaceae 6.6 7.6 0.94(0.81-1.09) 4.2 0.93(0.80-1.09) 4.7 0.94(0.78-1.13)
Third-generation 6.4 7.4 0.95(0.82-1.10) 4.2 0.93(0.80-1.09) 4.5 0.94(0.78-1.13)
cephalosporinresistance
Carbapenemresistance 1.4 1.1 0.71(0.47-1.07) 0.9 0.68(0.48-0.94) 0.5 0.59(0.37-0.97)
Resistanceto≥3antibiotics 4.0 5.2 1.02(0.84-1.23) 3.3 0.92(0.76-1.12) 3.5 1.04(0.83-1.31)
(orclasses)
Colistinresistanceb 0.1 0.8 0.57(0.29-1.14) 0.9 0.66(0.36-1.21) 0.3 0.61(0.30-1.22)
HRMOglucose 3.4 2.9 0.80(0.64-1.00) 3.8 0.84(0.70-1.00) 2.7 0.75(0.58-0.96)
nonfermentingGNB
MDRGNB,regardlessof 3.8 5.2 1.16(0.94-1.44) 3.2 0.97(0.77-1.22) 3.6 1.04(0.83-1.31)
antibioticsusceptibility
AnyMDRGNB 12.9 15.2 0.98(0.88-1.08) 10.3 0.93(0.84-1.04) 10.2 0.94(0.83-1.06)
(aggregate)
MRSA 1.7 1.1 0.95(0.66-1.36) 1.3 0.77(0.59-1.00) 1.7 0.73(0.54-0.97)
Abbreviations:aRR,adjustedrelativerisk;CHX,chlorhexidinemouthwash; aaRRpermonth,allmodelswerecorrectedforunderlyingtimetrends
GNB,gram-negativebacteria;HRMO,highlyresistantmicroorganism; percenter.
MDRGNB,multidrug-resistantgram-negativebacteria(eTable3in bExcludingEnterobacteriaceaewithintrinsiccolistinresistance(Proteusspp,
Supplement2);MRSA,methicillin-resistantSaureus;SDD,selective Morganellaspp,Serratiaspp,Providenciaspp,andHafniaalvei).
digestivetractdecontamination;SOD,selectiveoropharyngeal
decontamination;VRE,vancomycin-resistantEfaecium/Efaecalis.
PostHocOutcomes to1.0%),0.5%(95%CI,−0.9%to2.0%),and0.9%(95%CI,
Overall,573patientshad713episodesofICU-acquiredBSI −0.5%to2.4%)forCHX,SOD,andSDD,respectively,com-
withanypathogen,mostfrequentlycausedbyEnterococ- paredwithbaseline.Ascomparedwithbaseline,theaHRs
cus spp (n=125), Klebsiella spp (n=121), Candida spp were1.08(95%CI,0.85to1.39),0.94(95%CI,0.76to1.17),
(n=69),Saureus(n=67),andPseudomonasspp(n=61) and0.79(95%CI,0.60to1.05)forCHX,SODandSDD,
(Table2).Theseoccurredin6.8%,7.4%,6.3%,and5.9% respectively(Table3).SDDwasassociatedwithlowerriskof
duringthebaseline,CHX,SOD,andSDDperiods,respec- ICU-acquiredMDRGNBBSIcomparedwithCHX(aHR,0.62;
tively.Absoluteriskreductionswere−0.6%(95%CI,−2.1% 95%CI,0.39-0.98)(eTable14inSupplement2).Therewere
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nostatisticallysignificantdifferencesinanyofthemortality reducedtheeffectsofSDD.DuringSDD,therewere48epi-
outcomes in the post hoc head-to-head comparisons sodesofICU-acquiredBSIsoccurringwithinthefirst4daysof
betweeninterventions(eTable14inSupplement2).There inclusion,17ofwhichinvolvedpathogenssusceptibletothird-
werenostatisticallysignificantassociationsbetweeninter- generationcephalosporins.AbsenceofcefotaximeduringSDD
ventionsandcompetingendpointsinanyoftheseanalyses cannotexplainthediscrepantfindingsforSOD,whichwasalso
(eTable15inSupplement2). associatedwithareductioninmortalityandICU-acquiredBSI
Inanexploratoryanalysisbasedontheresultsofsurveil- inapreviousDutchstudy.4
lanceculturesplatedonextended-spectrumβ-lactamase Third,interventionswerediscontinuedattheendof
selective media and obtained twice weekly from study mechanicalventilation,insteadofatICUdischarge.Inapre-
patients,carriagerateswithantibiotic-resistantGNBinthe viousDutchstudy,SDDandSODwereadministeredduring
rectumduringSDDandintherespiratorytractduringSDD/ morethan95%ofpatients’days,4,5whereasinthecurrent
SODappearedtoremainstable,incomparisonwithother study,mechanicalventilationdaysaccountedfor69.2%of
studygroupswherethereappearedtobeagradualincrease ICUdaysinstudypatients,reflectingthemaximumpropor-
incolonizationduringICUstay(eFigureinSupplement2).On tionoftimeduringwhichpatientsreceivedstudyinterven-
day14ofICUstay,theproportionofrectalculturesgrowing tions.Infact,duringCHX,SOD,andSDD,therewere32,23,
GNBfromselectivemediawas14.8%duringSDDand28.3% and33ICU-acquiredBSIepisodesthatoccurredondays
duringthebaselineperiod. without mechanical ventilation. A post hoc sensitivity
analysisinwhichBSIswereassumedtohavebeenpre-
ventedbythird-generationcephalosporinsandSDDtreat-
mentuntiltheendofICUstayyieldedsimilarresultsfor
Discussion
SDD.Itis,therefore,unlikelythattheseprotocolvariations
Inthisclusterrandomizedmulticenterstudyin13European explainthediscrepantfindingswithregardtoSDDefficacy
ICUs,decontaminationstrategieswitheitherantibiotics forpatientoutcomecomparedwithpreviousstudies.
(SDDorSOD)orCHXmouthwashwerenotassociatedwith Fourth,standardcareinthecurrentstudyincludedstrat-
reductionsinICU-acquiredBSIwithMDRGNB,normortal- egiesthatmayhaveinfluencedcarriageandtransmissionof
ity,inventilatedICUpatientswhencomparedwithstandard HRMOandwerenotimplementedinpreviousDutchstudies,
care,whichincludeduniversaldailyBWswithCHXduring suchasoralcarewithantiseptics(CHXmouthwash0.12%or
ICUstayandahandhygieneprogram.Furthermore,the 0.20%)in11of13centers,implementationoftheWorldHealth
unitwideprevalenceofcarriagewithantibiotic-resistant OrganizationhandhygieneprogramanddailyCHX2%BWs
bacteriadidnotchangeduringtheinterventions,whichis forallpatientsintheICUuntildischarge.Althoughtheef-
consistentwithresultsobtainedinalllargeSDDtrialsofthe fectsofthesestrategiesoncolonizationandinfectionwithGNB
last20years.8 cannotbeassessedwithinthecurrentstudy,theymayhave
ThestrengthsofthisstudyincludeparticipationofICUs reducedthepotentialofthe3interventionstoofferaddi-
in6Europeancountries,withresistanceratesthatbetterre- tionalbenefits.20
flecttheaverageEuropeanorAmericansettingthanDutch
ICUs,therebyimprovingexternalvalidityandgeneralizabil- Limitations
ityoffindings,aswellasthedetailedunitwideresistancemoni- Thisstudyhasseverallimitations.First,itsdesigninvolvesthe
toringwithmonthlypointprevalencestudies. inherentriskof(selection)biasduetoclusterrandomization
The findings of the current study differ in several andthefixedstartwiththebaselineperiod,precludingad-
aspectsfromthoseobtainedinsimilarstudiesinDutch justmentforchangesinICUorganization,ecology,orunmea-
centers.3-5First,thecurrentstudyaimedtotestdecontami- suredpatientcharacteristicsovertime.Thestudywasalsode-
nationregimensinICUswithhigherprevalenceofantibiotic signedtocompareeachinterventionwithstandardcare,but
resistance.Indeed,theobserved17.6%unitwiderectalcar- notwitheachother.Thehead-to-headcomparisonsofthe3
riage rate of third-generation cephalosporin-resistant interventionsforprimaryandsecondaryoutcomes,asre-
Enterobacteriaceae and an overall proportion of 25.5% ported,werebasedonaposthocanalysis.
ofICU-acquiredBSIscausedbyHRMOareconsiderably Second,theoriginallytargetedsamplesizeof10800
higherthaninpreviousDutchstudies.3-5Decontamination patientswasnotreached,andaccordingly,thestudymay
strategiesusingconventionalSDDorSODregimensmaybe havebeenunderpoweredtodetectaclinicallyrelevantdif-
lesseffectiveinthiscontext,especiallyinareaswithhigh ferenceintheprimaryoutcome.However,posthocpower
prevalence of resistance to aminoglycosides or colistin calculationrevealedthatthisstudyhad80%powertodetect
amongGNB.Theunitwideprevalenceofcolonizationwith anabsolutereductioninhospitalmortalityof4.2%,whichis
gentamicin-resistantGNBwas8.3%intherectumand4.5% within the 2.9% to 5.3% range that was suggested by
intherespiratorytract,whichistwiceashighasinaprevi- meta-analyses,12and78.7%powertodetecta50%relative
ousDutchstudyperformedbetween2004and2006,4but reductioninICU-acquiredBSIcausedbyMDRGNB.Thecon-
comparablewiththemorerecentDutchstudyperformed fidenceintervalsfortheprimaryoutcome,BSI,doleave
between2009and2013.5 roomforapotentialeffectofSDDinalargerstudy.Yet,as
Second,SDDdidnotincludea4-daycourseofintrave- mosthazardratesforthemortalityoutcomeswereclosetoor
nousthird-generationcephalosporins,whichmighthave evenabove1,alargerstudypopulationwouldprobablynot
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