The impact of Clostridium difficile infection on resource use and costs in hospitals in Spain and Italy: a matched cohort study

The

impact

of

Clostridium

difficile

infection

on

resource

use

and

costs

in

hospitals

in

Spain

and

Italy:

a

matched

cohort

study

Angel

Asensio

a,b,

*

,

Stefano

Di

Bella

c

,

Andrea

Lo

Vecchio

d

,

Santiago

Grau

e

,

Warren

M.

Hart

f

_,

_Beatriz

_Isidoro

g

_,

_Ricardo

_Scotto

d

_,

_Nicola

_Petrosillo

c

_,

Maureen

Watt

h

,

Jameel

Nazir

h

a

HospitalUniversitarioPuertadeHierro,C/ManueldeFalla1,Majadahonda28222,Madrid,Spain

b

UniversityFranciscodeVitoria,Madrid,Spain

c

NationalInstituteforInfectiousDiseases‘‘L.Spallanzani’’,Rome,Italy

d

DepartmentofTranslationalMedicalScience,UniversityofNaples‘‘FedericoII’’,Naples,Italy

e

HospitaldelMar,UniversitatAuto`nomadeBarcelona,Barcelona,Spain

f

EcoStatConsultingUKLtd,London,UK

g_{HMHospitales,Madrid,Spain} h

AstellasPharmaEMEA,Chertsey,UK

1. Introduction

Clostridium difficile infection (CDI), which is caused by an anaerobic,Gram-positive, spore-forming bacillus,is theleading causeofinfectiousdiarrhoeainhospitalizedadultpatients,causing infections ranging from mild diarrhoea to pseudomembranous colitis.1–3_{ThemostimportantriskfactorforCDIispriororongoing}

antimicrobial therapy, which can disrupt the normal intestinal floraandallowC.difficiletocolonizethegut.1–3_{Otherriskfactors}

includechemotherapy,solidorganandbonemarrow transplanta-tion, and chronic treatment with proton pump inhibitors.2,4

Specific patient groups are also considered to be at risk, e.g. elderly, chronically ill, and immunocompromised patients.2,3 However, CDI is becoming an increasingly common cause of community-acquired diarrhoeain low-riskpopulations,suchas children,healthyadults,andpregnantwomen.1,4

Although viral infections (rotavirus, norovirus) remain the leadingcausesofdiarrhoeainthepaediatricpopulation,CDIisalso considered to be an increasingly common cause of hospital-acquireddiarrhoeaandanemergingcauseofcommunity-acquired diarrhoeainchildren.2,5_{Incontrasttoadults,norelationshipwith}

antibioticexposureorcomorbidconditionshasbeenobservedin childrenwithcommunity-acquiredCDI.2–4,6

ManyreportshaveshownthattheincidenceandseverityofCDI areincreasingandthatitisassociatedwithincreasingmorbidity and mortality; however,most studies have been performed in

ARTICLE INFO Articlehistory:

Received27November2014 Receivedinrevisedform12May2015 Accepted14May2015

CorrespondingEditor:EskildPetersen, Aarhus,Denmark

Keywords:

Clostridiumdifficileinfection CDI

Hospitallengthofstay Costburden

Matchedcohortanalysis

SUMMARY

Objective:ToassesstheimpactofClostridiumdifficileinfection(CDI)onhospitalresourcesandcostsin SpainandItaly.

Methods:CDIdatawerecollectedfrominstitutionsinSpainandItaly.Eachpatientwasmatchedwith tworandomlyselecteduninfectedcontrolsinthesameinstitution.Patientoutcomeswereassessedfor thefirstandsecondepisodesofCDIandforpatientsaged65and>65years.TheimpactofCDIon hospitallengthofstay(LOS)wasusedtocalculateCDI-attributablecosts.Amultivariateanalysisusing durationofstayasthecontinuousoutcomevariableassessedtheindependenteffectofCDIonhospital costsandLOS.

Results:LOSattributabletoCDIrangedfrom7.6–19.0daysinadultsandwas5.0daysinchildren;the increasesweregreaterinadultsinItalythaninSpain.Attributablecostsperadultpatientrangedfrom

s_{4396inMadridto}s_{14023inRome,withthemajorityofthecostbeingduetohospitalization.For}

children,thetotalattributablecostwass3545/patient.

Conclusions: ThesedatashowthattheburdenofCDIisconsiderableinSpainandItaly.Treatmentsthat canreduceLOS,diseaseseverity,andrecurrencerates,aswellaseffectiveinfectioncontrolmeasuresto preventtransmission,havethepotentialtoreducetheburdenofCDI.

ß2015TheAuthors.PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases. ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(

http://creativecommons.org/licenses/by-nc-nd/4.0/).

* Correspondingauthor.Tel.:+34911917413. E-mailaddress:aasensiov@salud.madrid.org(A.Asensio).

ContentslistsavailableatScienceDirect

International

Journal

of

Infectious

Diseases

j o urn a l hom e pa ge : ww w. e l s e v i e r. c om/ l o ca t e / i j i d

http://dx.doi.org/10.1016/j.ijid.2015.05.013

North America or northern Europe.7–9 _{A pan-European study}

conducted by the European Centre for Disease Prevention and Controlin2008showedthattheincidenceofCDIdiffersbetween countries; the reported rates in Italy and Spain were 3.6 and 4.3episodesper10000patient-days,respectively.10Althoughthe studyhadauniformdesignwithafixed3-monthfollow-up,some studieshavesuggestedthatthediagnostictestingapproachused causes variations in estimates of the incidence of CDI.11–13

However,country-specificstudiesinSpainandItalyindicatethat theprevalenceofCDIisincreasing:between1999and2007,the prevalencerateincreasedfrom3.9–12.2per100000populationin Spain,14_{withmorerecentdataindicatingthatratesremainhigh}

(13.4–22.5 per 100 000) and suggesting that CDI is under-diagnosedduetothediagnosticmethodsused;15,16_{inItaly, the}

incidence of CDI in five large hospitals in Rome increased significantly (p<0.001) over the 6-year period between 2006and2011(from0.3–2.3episodesper1000patient-days).17

The resource burden of CDI is considerable. A retrospective cohortstudyofinfected(n=38)andmatchednon-infected(n=76) patientsconductedduringanoutbreakofnosocomialCDIinSpain in 2006, demonstrated that patients who developed CDI were exposed to more antibiotics, had higher mortality, and were hospitalizedforlonger.18_{Aretrospectivecross-sectionalstudyin}

ItalyshowedthatCDIisassociatedwithconsiderablecostsinan Italianhospitalsetting,withlengthofstay(LOS)beingthemost importantfactorindeterminingcosts,19_{althoughthisstudyhad}

methodologicallimitations.CDIinhospitalizedchildrenhasbeen shown to increase the risk of death, extend hospital LOS, and increasehospitalcosts.20_{Thegeneralconclusion that CDIhasa}

considerableresource impactis supportedby a reportshowing thatCDIis associatedwitha significantincreaseinattributable healthcare costs.21 _{The increasing economic burden of CDI in}

healthcare facilities in Europe has been demonstrated, with incrementalcostsof infectionintherange of

s

_1857–

s

_4266.22

However,thisstudyincludedonlylimiteddatafromSpainandno informationfromItaly.22

As evidence regarding the impact of CDI on healthcare resourcesinsouthernEuropeisgenerallyscarce,theaimofthis studywastoanalysedataontheburdenofCDIintermsofhospital resources and costs, and in particular CDI-attributable LOS, in SpainandItaly.

2. Methods 2.1. Patientselection

PatientswithCDIwerediagnosedbasedonapositiveC.difficile toxinimmunoassayorpositiveculturefortoxigenicC.difficileand signsandsymptomscompatiblewithCDI(threeormoreunformed stoolswithin24h).AllpatientswithCDIdiagnosedattheHospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain (tertiarycarereferralhospitalwithalargesolidorgan transplan-tationprogramme and approximately650beds; periodof data collection January 2011–November 2013), Hospital del Mar, Universitat Auto`noma de Barcelona, Barcelona, Spain (tertiary carehospital withapproximately 400 beds, including 18 in an intensivecareunit;datacollectedFebruary–November2011),and DepartmentofTranslationalMedicalScience,UniversityofNaples ‘‘Federico II’’, Naples, Italy (tertiary care hospital, including specialist paediatric medical and surgical departments with 50beds;data collected2006–2012) wereincluded.Patientsfor inclusion in thestudy were selectedrandomly at theNational Institute for Infectious Diseases ‘‘L. Spallanzani’’, Rome, Italy (tertiary care hospital with medical, surgical, and diagnostics departmentsandapproximately200beds;datacollectedJanuary 2011–August2013).

2.2. Dataextractionprotocol

A protocol for data extraction from patient records was developedandusedtocollectdata.Foreachinstitution,datafor hospital-onset cases of CDI (infected cohort) and uninfected control patients (non-infectedcohort) werecollected. Hospital-onset wasdefined as>48h afteradmission or <4 weeks after dischargefromahealthcarefacility(Naplesonly).

2.3. Matchedcohortdesign

Each patient in the infected cohort wasmatched withtwo randomly selected uninfected control patients in the same institution.Patientswerematchedbywardandperiodofhospital admission (15 days). Foreach patient inthe infectedand non-infectedcohorts,dataregardingmaindiseasediagnosisathospital admission,demographics,hospitaldepartmentinwhichtheywere treated, and other factors potentially associated to LOS were collected. This matchedcohort designwas usedto overcome the problemofhowtoassignhospitalLOSdatadirectlytoC.difficile.

For the patients in the infected cohort, the index day was definedasthedayofhospitalstaywhenthepatientwasdiagnosed with CDI. For those in the non-infected cohort, patients were selectedrandomlyfromthosewhosedurationofstaywasatleast aslongasthatfromthedateofadmissiontotheindexdayforthe casewithwhichtheywerematched.Forthesepatients,theindex daywasdefinedasthesamedayofhospitalizationastheindexday ofthecasewithwhichtheywerematched.

2.4. Datacollected

To control for severity of illness before CDI infection, data requiredforthecalculationofamodified AcutePhysiologyand ChronicHealthEvaluationIII(APACHE)score23_{werecollectedfor}

allpatients48hbeforetheindexday.ThemodifiedAPACHEscore didnotincludebloodpH,pulmonaryarterialoxygensaturation, pulmonaryarterialgradient,urineoutput,orscoringfor neuro-logicalabnormalities,becausethesedatawerenotavailableforall patientsinthestudy,particularlythosenotintheintensivecare unit (ICU). To control for underlying disease, the Charlson comorbidityindexwascalculatedusingpatientmedicalhistory.24 Itshouldbenotedthatwhiledataforthesetwomeasureswere collectedforthepaediatricpatients,thevalidityofthemeasures forpaediatricpatientsisuncertain.

To control for prognosis of primary disease, the McCabe– Jacksonindexwasestimated.25_{Finally,informationaboutprevious}

antibioticusewascollectedfromthedateofhospitaladmissionto dateofinfectionforcases,andfromthedateofhospitaladmission totheindexdayforcontrols.

ThefollowingdataonCDIwerecollected:durationofdiarrhoea, treatmentforCDI,hospitalLOS(includingICUandisolationdays), whethersigmoidoscopy/colonoscopywasperformed,andclinical outcomes, including cure, mortality at 30 days, attributable mortality,and recurrence. Based on the guidelines available at thetimethatpatientswerediagnosed,26_{recurrencewasdefinedas}

a secondepisodeofCDI basedon clinicalsymptoms,apositive diagnostictestforC.difficile,orboth,occurringwithin2–8weeksof theindexcaseandwithinthehospitalstay.

2.5. Treatmentprotocols

125–500mgevery6hfor10daysorfidaxomicin200mgtwice dailyfor10days.

Paediatric patients withmild-to-moderate CDI were usually treatedwithmetronidazole125or250mgevery8haccordingto body weight for 7–14 days; patients with severe or recurrent infections received vancomycin 10 mg/kg/dose every 6h(to a maximumof1500mg/day).

2.6. Costs

In Spain, the costs of metronidazole and vancomycin were

s

_{1.08 (20 units of 250 mg) and}

s

_{3.45 (1 unit of 125 mg),}

respectively.27 _{The daily cost of a hospital in-patient stay was}

s

443.59andthedailycostofICUwas

s

1156.07.27_Anestimated

averagedailycostofstaywascalculatedbycomparingthetotal numberofdayspatientsspentintheICUwiththetotaldaysspent inhospitalandcalculatingaweightedaveragecost.

InItaly, costsof

s

_{708.54 and}

s

_{1214.64wereusedfordaily}

adulthospitalizationandICUcosts.Thesearebasedonthevalue reported by Magalini etal.19_{inflated to2013 values using the}

Italian ConsumerPriceIndex.28_{Thecostsof metronidazoleand}

vancomycinwere

s

1.30(perg)and

s

4.60(perg),respectively. Thecostofhospitalizationperdayinchildrenwas

s

708.54,also basedonthevaluereportedbyMagalinietal.19

2.7. Analysesperformed

Intheadultpopulation,thefollowinganalyseswereperformed. First,patientoutcomeswereassessedbothforthefirstandsecond episodesofCDIandbytherapyused.TheimpactofCDIonhospital LOS,includingtimeintheICU,wasalsocalculated.Furthermore, thenumberofisolationdays(contactprecautions)wasassessed. Each of these outcomes was analysed both in the overall population and in patients aged 65 and >65 years. These measureswereusedtocalculateCDIattributablecosts.

Forthepaediatricpatients,thetypeandoutcomeoftherapywas capturedforthefirstandsubsequentepisodesofCDI.Theimpact ofCDIonhospitalLOS,isolationdays,andcostswasanalysed. 2.8. Statisticalanalyses

ToanalysetheindependenteffectofCDIonhospitalcostsand LOS,amultivariateanalysisusingacontinuousoutcomevariableof durationofstay(post-infectiondurationofhospitalizationforthe infectedcohortanddurationofhospitalizationaftertheindexday forthenon-infectedcohort)wasperformed.Potentialconfounding variables were taken into account: modified APACHE III score (incorporates age), Charlson comorbidity index score, and McCabe–Jacksondiseaseclassification.

Medianrather thanmeanvalueswereusedfortheoutcome measurestoreducetheinfluenceofextremeoroutliervalues.This approach was considered more appropriate than using mean values,whichhavebeenusedinotherstudies.Bynotadjustingfor skewed data, the use of mean values tends to overestimate difference.Thealternative–logtransformationofdata–tendsto underestimatedifference.

Median regression analysis using the qreg function in the statistical programStataversion12 (StataCorp.,CollegeStation, TX,USA)wasregardedasvalid.

3. Results

3.1. Patientanddiseasecharacteristics

Intotal,datawerecollectedfor232adultinfectedpatientsand 426matchednon-infectedpatientsinMadrid(n=94),Barcelona (n=12), and Rome (n=126). Nineteen patients in Madrid had community-onset CDI and were not matched to non-infected patients.Inaddition,datafor19paediatricinfectedpatientsand 38matchednon-infectedpatientswerealsocollectedinNaples.

Table1

Patientanddiseasecharacteristics

Institution

Madrid Barcelona Rome Naples

Characteristic Infected Non-infected Infected Non-infected Infected Non-infected Infected Non-infected Adult/paediatric Adult Adult Adult Adult Adult Adult Paediatric Paediatric

n 94 150 12 24 126 252 19 38

Meanage,years(range) 70.4 (21–98) 65.7 (20–100) 55.3 (21–80) 53.8 (25–80) 65.8 (19–95) 55.2 (18–101) 9.0 (0.8–17) 11.1 (1–18) Male(%) 50.0 62.0 58.3 58.3 57.1 54.4 68.4 36.8 Priorantibioticuse(%) 74.5 75.0 91.3 43.4

Admissionservice(%)

Medical 71 67 75 75 89 77 –a _–a

Surgical 23 28 8 8 6 20

ICU 4 5 17 17 5 3

Other 2 1 0 0 0 0

Meanserumalbumin,g/l(range) 3.05 (0.3–4.0) 3.42 (2.0–5.2) 2.70 (1.4–4.2) 3.13 (1.2–4.0) 2.86 (0.1–4.3) 4.1 (2.8–4.9) 4.46 (3.5–4.9) McCabe–Jacksondiseaseclassification(%)

Non-fatal 59.6 62.7 66.7 70.8 82.5 94.1 100.0 36.8 Rapidlyfatal 17.0 12.7 0.0 4.2 4.0 1.6 0

Ultimatelyfatal 23.4 24.7 33.3 25.0 13.5 4.4 0 63.2b

MeanCharlsoncomorbidityindexscore(range)c

6.3 (0–14) 5.33 (0–12) 2.8 (0–9) 2.7 (0–10) 6.0 (0–18) 3.7 (0–13) NR NR MeanAPACHEscore(range)d

34.7 (0–68) 28.8 (0–73) 9.3 (2–16) 11.5 (0–35) NR NR NR NR

ICU,intensivecareunit;NR,notreported.

a _{Allpaediatricpatientswereadmittedtothepaediatricdepartment.} b

Forpaediatricpatients,diseasewasclassifiedasnon-fatalorultimatelyfatalonly.

c

Usedtoassesstheriskof10-yearmortalitybasedonthescoringof19medicalconditions,whichareweightedtoprovideascoreintherange0–45;higherscoresare associatedwithahigherriskofdeath.

d

Patient and disease characteristics are shown in Table 1. Differences in age were observed, most likely because the matching criteria used did not specify age, and probably contributedtothedifference inCharlson indexscoresobserved inItaly.DataonantibioticusepriortothediagnosisofCDIare shownintheSupplementaryMaterial(OnlineResources1and2). 3.2. FirstepisodeofCDI

3.2.1. Adults

Dataregardingthediseasecharacteristicsoftheinitialepisode ofCDI,itstreatment,andtheoutcomesoftreatmentfortheoverall population and patients aged 65 and >65 years (Madrid and Romeonly)areshowninTable2(dataforpatientswhodidnot havearecurrenceandthosewhohadarecurrenceareshowninthe SupplementaryMaterial(OnlineResources3and4)).Itshouldbe noted that a proportion of patients received non-oral therapy: 26patients in Madrid(intravenousmetronidazolen=19, intra-colonicvancomycinn=2,bothn=5),fourinBarcelona (intrave-nous metronidazole n=3, intracolonic vancomycin n=1), and 16 inRome (allintravenous metronidazole).Disease character-isticsweregenerallysimilarforadultpatientsatthedifferentsites, bothfortheoverallpopulationandthepatientsaged>65years, althoughtheincidenceofulcerationandcolonicwallthickening appearedtobelowerinItalythanineitherMadridorBarcelona. However,this couldbedue todifferences intheproportionsof patients who underwent computed tomography in different institutions. Finally, while outcomes in Spain were generally similarforpatientsaged>65 and65years,patientsaged>65 yearshadworseoutcomesthanthoseaged65yearsinRome. 3.2.2. Children

Dataregardingthediseasecharacteristicsoftheinitialepisode ofCDI,itstreatment,andtheoutcomesoftreatmentforpaediatric

patients inNaplesareshowninTable2.Diseasecharacteristics weregenerallycomparabletothoseinadults,buttheincidenceof ulcerationandcolonicwallthickeningwashigherthanthatinthe adult patients in Rome. In contrast to adult patients, the first episode of CDI in children was exclusively treated with oral therapy.NodeathsduetothefirstepisodeofCDIwerereported. 3.3. CDIrecurrence

Atotalof34adultpatients(12.5%)andtwopaediatricpatients (10.5%)experiencedafirstrecurrenceofCDI.Threeofthe34adult patients and one of the two paediatric patients had a further recurrence.Althoughfidaxomicinwas includedinthe treatment protocolsforrecurrentCDIinSpainandItaly,nopatientwastreated with this agent. Two deaths occurred in patients with a first recurrence,bothattributabletoCDIandbothoccurringinRome.No deathswerereportedin thispatient groupin theother centres, whetherattributabletoCDIornot.NoCDI-attributablemortality wasreportedinpatientswithasecondCDIrecurrence.Nostatistical analysisofpotentialdifferencesinoutcomeswasperformeddueto thesmallsamplesizeoftherecurrentCDIgroups.

3.4. AttributablehospitalLOS

DataforhospitalLOS,includingdaysspentinisolationandthe ICU,andhospitalLOSattributabletoCDIareshowninTables3– 5.LOSattributabletoCDIwasgenerallysimilarinadultsaged65 and>65years.However,thedatasuggestthattheLOSattributable toCDIwaslongerinadultswithCDIinItalythaninadultswithCDI inSpain.LOSattributabletoCDIinchildrenwasshorterthanin adultsinbothSpainandItaly.

InMadrid,theLOSattributabletoCDIwasshorterforthefirst episode (6.4 days) than for the first recurrence (45 days) (Tables4 and 5). Thiswasalsothecasein Rome, althoughthe

Table2

InitialCDI,treatment,andoutcomes

Institution

Madrid Barcelonaa

Rome Naples

All 65years >65years All All 65years >65years Paediatric

n 94 33 61 12 126 54 72 19

Meandurationofdiarrhoea,days(range) 10.1(1–48) 8.7(2–33) 10.9(1–48) 11.8(2–25) 12.9(2–50) 11.5(2–50) 14.0(2–42) 7.8(0–30) Diarrhoeacontainsblood(%) 15.0 15.6 14.7 16.7 6.3 7.4 5.6 36.8 Fever(%) 15.0 18.8 13.1 8.3 18.2 22.2 15.3 21.0

Ileus(%) 3.2 3.1 3.3 8.3 2.4 1.9 2.8 0.0

Leukocytecount15109

/l(%) 31.2 37.5 27.9 25.0 32.5 24.1 70.8 36.8 Serumcreatinineincrease>50%(%) 24.7 12.5 31.1 0.0 21.4 11.1 29.2 0.0 Sigmoidoscopy/colonoscopy(%) 7.5 9.4 6.6 8.3 7.1 5.6 8.3 15.8 Pseudomembranes(%) 8.6 9.4 8.2 8.3 0.0 0.0 0.0 0.0 Ulceration(%) 3.2 3.1 3.3 0.0 3.2 1.8 4.2 10.5 Colonicwallthickening(%) 14.0 21.9 9.8 33.3 7.1 5.6 8.3 5.3 Pericolonicfat(%) 4.3 3.1 4.9 0.0 0.8 0.0 1.4 0.0 Treatment,n(%)b Metronidazole,oral 79(84.0) 27(81.8) 53(86.9) 10(83.3) 83(65.9) 39(72.2) 44(61.1) 10(52.6) Metronidazole,intravenous 24(25.5) 7(22.6) 17(25.0) 3(25.0) 16(12.7) 3(5.6) 13(18.1) 0 Vancomycin,oral 13(13.8) 5(15.2) 8(13.1) 1(8.3) 36(28.6) 12(22.2) 24(33.3) 5(26.3) Vancomycin,intracolonic 7(7.5) 4(12.1) 3(4.9) 1(8.3) 0 0 0 0 Outcomes(%)c Cure 75(80.6) 26(81.3) 49(80.3) 12(100.0) 79(64.8) 42(80.8) 37(52.9) 17(89.5) Failure 13(14.0) 5(15.6) 8(13.1) 0(0.0) 5(4.1) 3(5.8) 2(2.9) 1(5.3) 30-daymortality 14(15.1) 5(15.6) 9(14.8) 1(8.3) 18(14.8) 4(7.7) 14(20.0) 0(0.0) 1-yearmortality 19(20.4) 6(18.8) 13(21.3) 1(8.3) 19(15.6) 4(7.7) 15(21.4) 0(0.0) Attributablemortality 4(4.3) 1(3.1) 3(4.9) 0(0.0) 7(5.7) 1(1.9) 6(8.6) 0(0.0) Recurrenced 7(7.5) 2(6.3) 5(8.2) 2(16.7) 25(20.5) 6(11.5) 19(27.1) 2(10.5) CDI,Clostridiumdifficileinfection.

a

Notanalysedbyageduetosmallpatientnumbers.

b

Patientsmayhavereceivedmorethanoneantibiotic.

c

OutcomesdatanotavailableforonepatientinMadridandfourpatientsinRome.

d

difference was much smaller (20 and 24 days, respectively) (Tables4and5).However,itshouldbenotedthatpatientnumbers fortheseanalysesweresmall.

3.5. CostsattributabletoCDI

ThecostsassociatedwithCDIdifferedbetweensites.InMadrid, theestimatedaveragecostperdayvariedbetween

s

480.28and

s

_{610.58basedon5.2%and23.4%ofthetotalhospitalstaybeingin}

theICUforthosepatientsaged65and>65years,respectively. Therefore, the attributable hospitalization costs were

s

4265,

s

2882,and

s

4885perpatientforallpatientsandthoseaged65 and>65years,respectively.Drugcostsaddapproximately

s

131 perpatient(basedonatotalmetronidazoledoseof12958mgand a total vancomycin dose of 3728 mg per patient). Assuming 7601 cases per year,27 the annual cost of CDI would be

s

33413971.

In Rome,thetotalcostattributabletoCDIwas

s

14023per patient (19.0 days 

s

738.06) for all patients. The cost was

s

_{15668forthoseintheagegroup65yearsand}

s

_13862for

those aged>65 years,withthedifference in costbeingdue to differencesinlengthofstay(21vs.19days,respectively)andcost perday.Forsubgroupsaged18–64,65–79,and>79yearsthecosts were

s

15668,

s

16487,and

s

11112,respectively.Forpatients withrecurrence,thetotalcostattributabletoCDIwas

s

17714per patient(attributableLOS25days),whileforpatientswithasingle episode of CDI, the cost was

s

14 936. Drug costs add approximately

s

51perpatient(basedon atotalmetronidazole dose of 6504mg anda totalvancomycin doseof 9173mg per patient). Based on the most recent epidemiological data for Rome,18_{thistranslatestoanestimatedcostofCDIof}

_s

_32371per

10000patient-days.

ForthepaediatricpatientsinNaples,thetotalcostattributable toCDIwas

s

3545perpatient(5.0days

s

709),withdrugcosts

Table3

HospitalLOSforallCDIepisodes,includingfirstepisodeandfirstorsecondrecurrence Institution Madrid Barcelonab Rome Naples All (n=75)a 65 years (n=26) >65years (n=49) All (n=12) All (n=126) 65years (n=54) >65years (n=72) Paediatric (n=19) MeanLOS,days(range)

Infected 20.6(1–85) 23.3(1–85) 19.2(2–80) 42.1(5–161) 36.0(5–154) 39.1(5–154) 33.7(5–126) 7.4(0–41) Non-infected 11.0(0–227) 13.8(0–227) 8.5(0–56) 7.9(1–26) 18.0(0–391) 17.0(0–391) 19.7(0–368) 0.3(0–8) MedianLOS,days

Infected 13.0 12.5 13.0 26.5 29.5 27.5 29.5 5.0

Non-infected 5.5 7.0 4.0 7.5 8.0 7.0 8.0 0

MeanICUstay,days(range)

Infected 3.4(0–126) 1.2(0–28) 4.5(0–126) 7.9(0–69) 2.1(0–57) 2.9(0–46) 1.4(0–57) 0 Non-infected 0.5(0–29) 0.8(0–29) 0.3(0–12) 1.3(0–14) 0.6(0–35) 0.3(0–11) 1.2(0–35) 0 MedianICUstay,days

Infected 0 0 0 0 0 0 0 0

Non-infected 0 0 0 0 0 0 0 0

IncreaseinLOSattributabletoCDI,daysc _{7.6 6.0 8.0 20.0 19.0 21.0 19.0 5.0}

Meanlengthofisolation,days(range) 9.3(0–53) 9.8(0–41) 9.0(0–53) 8.8(0–16) 11.9(0–52) 10.9(0–39) 12.5(0–52) 3.5(0–30) Medianlengthofisolation,days 7.0 8.0 7.0 10.0 10 10 10 0 LOS,lengthofstay;CDI,Clostridiumdifficileinfection;ICU,intensivecareunit.

a

Numberofpatientsreferstotheinfectedcohort;theuninfectedcohortincludedtwiceasmanypatientsastheinfectedcohort.

b

Notanalysedbyageduetosmallpatientnumbers.

c

CalculatedusingmultivariatelinearregressionanalysiswithLOSasthecontinuousoutcomevariableandbasedonmedianvalues.

Table4

HospitalLOSforpatientswithafirstepisodeofCDI Institution Madrid Barcelonab Rome Naples All (n=71)a 65years (n=24) >65years (n=47) All (n=10) All (n=101) 65years (n=61) >65years (n=40) Paediatric (n=17) MeanLOS,days(range)

Infected 17.9(1–80) 19.7(1–65) 17(2–80) 46.0(5–161) 34.4(5–126) 35.3(5–141) 33.6(5–126) 7.7(0–41) Non-infected 11.3(0–227) 14.4(0–227) 8.6(0–56) 8.2(1–26) 11.8(1–59) 10.6(1–59) 14.2(0–62) 0.3(0–8) MedianLOS,days

Infected 13.0 11.5 13.0 26.5 28.0 26.5 30.0 5.0

Non-infected 6.0 7.0 4.0 7.5 8.0 7.0 11.0 0

MeanICUstay,days(range)

Infected 2.2(0–57) 1.3(0–28) 2.7(0–57) 9.5(0–69) 2.6(0–46) 3.3(0–46) 1.9(0–57) 0 Non-infected 0.5(0–29) 0.8(0–29) 0.3(0–12) 1.6(0–14) 0.3(0–8) 0.3(0–9) 0.4(0–8) 0 MedianICUstay,days

Infected 0 0 0 0 0 0 0 0

Non-infected 0 0 0 0 0 0 0 0

IncreaseinLOSattributabletoCDI,daysc _{6.4 5.0 8.0 20.0 20.0 20.0 19.0 5.0}

Meanlengthofisolation,days(range) 8.0(0–33) 8.8(0–30) 7.6(0–33) 8.9(0–16) 10.1(0–39) 10.0(0–39) 10.2(0–46) 3.8(0–30) Medianlengthofisolation,days 7.0 8.0 7.0 10.0 10.0 10.0 10.0 0 LOS,lengthofstay;CDI,Clostridiumdifficileinfection;ICU,intensivecareunit.

a

Numberofpatientsreferstotheinfectedcohort;theuninfectedcohortincludedtwiceasmanypatientsastheinfectedcohort.

b

Notanalysedbyageduetosmallpatientnumbers.

c

contributing <

s

100 per patient. Based on the most recent epidemiological data for Rome, this translates to an estimated costof

s

8154per10000patient-days.

4. Discussion

ThisstudyshowsthattheburdenofCDIinSpainandItalyin termsoftheuseofhospitalresourcesandcosts,andinparticular CDI-attributableLOS,isconsiderable,withcostsofupto

s

14023 perpatient.BasedondatafromItaly,costsappearedtobehigher for adults with recurrent disease than for those with a first infection(

s

17 714vs.

s

14936;differenceof

s

2778),withthe majorityofthecostdifferencelikelybeingduetoanincreasein LOSwiththefirstrecurrence,highlightingthepotentialvalueof preventingrecurrence.InbothSpainandItaly,themajorityofthe CDI-associatedcostsinbothadultsandchildrenwereduetoexcess hospitalization.However,theattributableLOSforadultsdiffered betweenthetwocountries,at6–10daysinSpaincomparedto19– 21daysinItaly.Thisdifferenceresultedinadifferenceincosts betweenthecountries(

s

4396perpatientinSpainvs.

s

14023per patient in Italy). Drug-related costs were relatively low and resulted from vancomycin and metronidazole therapy. Despite beingpartoftreatmentprotocolsinbothcountries,fidaxomicin wasnotused,probablybecauseitwasapprovedonlyforthird-line useinSpain,wherefewpatientshadasecondrecurrence,andwas approved for use in Italy only after data had been collected (November2013).

Asinthepresentstudy,previousstudiesinadultshavereported varyingdata for attributable LOSdue to CDI. A study in Spain reported anattributable LOSof 4days,18_{withotherstudies in}

EuropeandtheUSAprovidingsimilarestimates.29,30_Incontrast,a

literaturereviewof European dataprovided estimates ofup to 18daysdependingonthecountry,22_{andattributableLOSofupto}

16.09dayswasreportedin astudyin fourEuropean countries, including Spain (13.56 days), although this study focused on patientsatincreasedriskofCDI.31_{Thereasonsforthesedifferences}

arelikely toinclude differences in patient populations,patient history,underlyingseverityofdisease,andcomorbidities.31_Data

onsomeofthesefactorswerecollectedinthepresentstudyforthe adultpatients, andfor underlyingseverityof diseaseusing the McCabe–JacksondiseaseclassificationandCharlsoncomorbidity indexin particular. These data indicated that adult patients in SpainhadmoresevereunderlyingdiseasethanthoseinItalyanda

similarlevelofcomorbidity.Thesefactorsarethereforeunlikelyto explain the longer attributable LOSin Italy. Similarly, the CDI disease characteristics, although different, did not reveal any differencesthatmightexplainthedifferencesinattributableLOS. OnefactorthatcouldinfluenceLOSispriorantibioticuse:the durationofnon-CDI-relatedantibioticexposurehasbeenshownto berelatedtoadverseoutcomes.32_{Unfortunately,whiledataonthe}

type and dose of antibioticused prior to CDI diagnosis,which appearedtodifferinSpainandItaly,werecollectedinthepresent study,nodataregardingthedurationofusewerecollected,which wouldhaveprovidedgreaterinsight.However,theuseofisoniazid, ethambutol, and rifampicin (Supplementary Material, Online Resources1and2)suggeststhatmorepatientsinItalythanSpain hadtuberculosis,whichmayinpartexplainthelongerLOSinItaly. Furthermore, we did not collect information on the C. difficile serotypes implicated in CDI and it is therefore possible that patientsinItalyweremorelikelytobeinfectedwithhypervirulent serotypes,whichwouldalsoinfluenceLOS.

InrelationtoLOS,itisalsointerestingtonotethatthemedian duration ofisolation ofadultpatients wassimilarinSpainand Italy.Thus,whileonaverageadultpatientsinSpainwereisolated for mostor allof theCDI-attributable LOS, those in Italywere isolatedforonlyapproximatelyhalfoftheirCDI-attributableLOS. Thereasonforandeffectofthisaredifficulttoassess,butcould alsoberelatedtothesuggestionthatmorepatientsinItalythan Spainhadtuberculosis.

An additional observation in relation to LOS was that attributableLOSwithafirstrecurrencewasincreasedcompared totheinitialepisodeinbothMadridandRome.Thisconfirmsthe burden of recurrent disease for patients with CDI and for healthcare systems. Although the attributableLOS appeared to be considerably higher in Madridthan in Rome, small patient numbersmeanthatnoconclusionsshouldbedrawnbasedonthis. Data on the burden of CDI in children are very limited. Furthermore, specific considerations relating to asymptomatic colonizationandtheuseofdiagnostictestingmeanthatestimates oftheincidenceofCDIinpaediatricpatientsareuncertain.33Inthe presentstudy,themajorityofcasesofCDIinchildrenoccurredin thecommunityratherthanthehospitalsetting.Thiscontrastswith thesituationinadults,wherehospitalizationisariskfactorforCDI, althoughtheincidenceofinfectionsoccurringinthecommunityis increasing.2,26,34 _{Furthermore, in the children included in this}

study,themedianCDI-attributableLOSappearedtobelessthan

Table5

HospitalLOSforpatientswithonerecurrentepisodeofCDI Institution Madrida

Barcelonaa

Romea

Naples Allpatients All(n=5) All(n=2) All(n=23) Paediatric(n=1) All(n=31) MeanLOS,days(range)

Infected 63.5(50–77) 22.5(15–30) 44.3(5–154) 0.0(0–0) 42.5(0–154) Non-infected 8.5(0–23) 6.3(2–9) 46.3(1–391) 0.0(0–0) 37.1(0–391) MedianLOS,days

Infected 63.5 22.5 34.0 0.0 34.0

Non-infected 5.0 7.0 9.5 0.0 8.0

MeanICUstay,days(range)

Infected 25.2(0–126) 0.0(0–0) 0.0(0–1) 0 4.2(0–126) Non-infected 0.0(0–0) 0.0(0–0) 2.0(0–35) 0 1.6(0–35) MedianICUstay,days

Infected 0 0 0 0 0

Non-infected 0 0 0 0 0

IncreaseinLOSattributabletoCDI,daysb _{45.0 NP 24.0 NP 26.0}

Meanlengthofisolation,days(range) 19.8(7–53) 8.5(7–10) 17.5(5–35) 0.0(0–0) 16.7(0–53) Medianlengthofisolation,days 11.0 8.5 18.0 0 15.0 LOS,lengthofstay;CDI,Clostridiumdifficileinfection;ICU,intensivecareunit;NP,notpossibleduetosmallsamplesize.

a

Notanalysedbyageduetosmallpatientnumbers.

b

thatinadultsinItaly(5vs.19daysinRome),asdidisolationand ICU use. Therefore, although daily costs of care are higher for childrenthanadults,theoverallburdenofCDIinthepaediatric populationinItalyislowerthanthatinadults.

As the costs of CDI in Spain and Italy are driven by the attributableLOS,itisimportanttonotethatthemethodologyfor assessmentinthepresentstudydifferedfromthatusedinother studies. To account for the excess stay attributable to CDI, comparisonsofinfectedandnon-infectedpatientsmusttakeinto account the potential effect of confounding factors. Matching basedon thesepotentialconfoundingfactorscanbedifficultto achieve,soit is more efficienttocontrolfor themthrough the analysis.Inaddition,thedistributionofLOSwasnotnormal.This precludedtheuseofmultiplelinearmodels.Forthis reason,an adjustedcomparisonofmedianLOSwasperformed.Inlinewith thedataforSpainobtainedin thisstudy,arecentretrospective cohortstudyfoundanadjustedmedianexcessLOSattributableto CDIof6days.35

Variouslimitationsofthisstudycanbeidentified.First,there were differences in data collection and reporting between the different institutions. Thus, the observed differences in CDI severitybetweenSpainand Italycouldhavebeeninfluencedby datacollectioninthedifferentinstitutions.Furthermore,cureand recurrence were not recorded homogeneously in the available medicalrecords,againpotentiallyaffectingthereportedrates.This makes theassessment of factors potentially affecting cure and recurrencerates,suchasseverity,treatment,orothervariables, difficult.

Anotherlimitationistheretrospectivematched-cohort meth-odology.Sourcesoferrorduetoconfoundingandbiasaremore commoninretrospective studiesthan inprospectivestudies.In addition,matchinginfectedpatientswithnon-infectedpatientsby propensityscoringmayhaveyieldeddifferentresults.Furthermore, obtaininginformationfrommedicalrecordscouldintroducebias aroundtheassessmentofoutcomes,duetopotentialinaccuracy and alackofinformationregardingtheoutcomecriteria.

Afurtherpotentiallimitationrelatestotheseverityofdiseasein thepatientsstudied.Thehospitalsparticipatingwerealltertiary care institutions, which may have resulted in the inclusion of patientswithmoreseverediseasethanifthestudyhadinvolved otherinstitutions.However,patientAPACHEIIIscores(anestimate ofdiseaseseverity)wereingeneralrelativelylow(mean9.3–34.7; maximumscoreof73ona299-pointscale).Similarly,meanscores basedontheCharlsoncomorbidityindex,usedtoestimatesurvival at10years,rangedfrom2.8–6.3,withanindividualmaximumof 18 on a 45-point scale. These scores are indicative of patient populations with a moderate 10-year survival prognosis. The Charlsoncomorbidityindextakesintoaccountpatientage;asthe meanageofpatientswas>65yearsinMadridandintheinfected patientcohort inRome, the higherCharlson comorbidityindex scores and thus moderate 10-year survival prognosis in these populationsareperhapsnotunexpected.

Finally,thedurationofdatacollectionrangedfrom10months– 7yearsinthedifferentstudycentres,withsomepatientstreatedas earlyas2006beingincluded.Therefore,itispossiblethatchanges inpatientmanagement,aswellastherecenttrendtowardsshorter hospital stays in recent years, could have biased some of the estimatestowardsestimatingalongerattributablestay.

Inconclusion,thesedataaddtotheevidencethattheburdenof CDI,whichisknowntobeincreasing,remainsconsiderable.The causesoftheincreasingburdenaretwo-fold:first,theincidence andseverityareincreasing,andsecond,thepopulationisageing. As this study shows, the impact of CDI in older patients is considerable,eventhoughdifferencesincureandrecurrencerates betweenpatientagegroupswerelesspronouncedinSpainthanin Italy,andinthosewithrecurrentCDI.Inthiscontext,treatments

that can reduce LOS by reducing recurrence rates have the potential toreduce the burden of CDI. Othersolutions include antibioticstewardship,i.e.,promotingtheselectionoftheoptimal antibioticdrugregimen,dose,durationoftherapy, androuteof administration,andinfectioncontrolmeasures,includingcleaning andbarrierprecautions.Jonesetal.estimatedtheannualcostof CDIinEuropeat

s

3billionperyear,36_{furtheremphasizingthat}

approachesthatcanreduceCDI-associatedresourceuseandcosts shouldbeofinterest.Antibioticsareakeycomponentoftherapy for CDI, but currently represent a minimal cost in the overall budgetforCDImanagement.Theintroductionofnewantibiotics will increase drug costs; however, these agents are likely to shortenhospitalstay,reduceCDIrecurrence,andreducethetime toclinicalresponse.37–39_{Therefore,theuseofnewantibioticsmay}

bejustifiedeconomicallyifreductionsinthecostofCDIdueto shorterhospitalLOSand/orfewerrecurrencesaredemonstrated. Furthermore, other strategies for the treatment of CDI are in developmentoravailable:toxin-targetedmonoclonalantibodies areindevelopment,andbacteriotherapywithprobioticsandfecal microbiota transplantation are available forthird-line useafter failure of systemic drug therapy. However, the costs of these approaches differ considerably and they therefore need to be assessedfromapharmaco-economicperspective.

Acknowledgements

ThisstudywassponsoredbyAstellasPharmaEMEA.Astellas Pharma EMEA contracted EcoStat Consulting, which employs WMH, to coordinate data collection and analyse and prepare reports ofthedata.MWandJN, whoareemployedbyAstellas PharmaEMEA,contributedtothedevelopmentofthemanuscript, butthedecisiontosubmittheworkandthechoiceofjournalwas made collectively by all authors. Medical writing support was providedbyAndrewNobleatBioscriptMedical,andwasfundedby AstellasPharmaEMEA.

Ethical approval: The study was approved by the ethics committeeoftheparticipatinginstitutions.

Conflictofinterest:AA,SDB,ALV,SG,BI,RS,andNPhavedeclared no conflicts; WMH is an employee of EcoStat Consulting, contracted by Astellas Pharma EMEA, the manufacturer of fidaxomicin, to collect and analyse the data; MW and JN are employeesofAstellasPharmaEMEA.

AppendixA. Supplementarydata

Supplementarydataassociatedwiththisarticlecanbefound,in theonlineversion,athttp://dx.doi.org/10.1016/j.ijid.2015.05.013. References

1.KhannaS,PardiDS.ThegrowingincidenceandseverityofClostridiumdifficile infectionininpatientandoutpatientsettings.ExpRevGastroenterolHepatol 2010;4:409–16.

2.LoVecchioA,ZacurGM.Clostridiumdifficileinfection:anupdateon epidemiol-ogy,riskfactors,andtherapeuticoptions.CurrOpinGastroenterol2012;28:1–9.

3.RupnikM,WilcoxMH,GerdingDN.Clostridiumdifficileinfection:new devel-opmentsinepidemiologyandpathogenesis.NatRevMicrobiol2009;7:526–36.

4.KhannaS,PardiDS.Clostridiumdifficileinfection:newinsightsinto manage-ment.MayoClinProc2012;87:1106–17.

5.MorilloSG,TimenetskyMdoC.Norovirus:anoverview.RevAssocMedBras (1992)2011;57:453–8.

6.Tschudin-SutterS,TammaPD,NaegeliAN,SpeckKA,MilstoneAM,PerlTM. Distinguishingcommunity-associatedfromhospital-associatedClostridium dif-ficileinfectionsinchildren:implicationsforpublichealthsurveillance.Clin InfectDis2013;57:1665–72.

7.BurckhardtF,FriedrichA,BeierD,EckmannsT.Clostridiumdifficilesurveillance trends,Saxony,Germany.EmergInfectDis2008;14:691–2.

9.PepinJ,ValiquetteL,AlaryME,VillemureP,PelletierA,ForgetK,etal. Clostridi-umdifficile-associateddiarrheainaregionofQuebecfrom1991to2003:a changingpatternofdiseaseseverity.CMAJ2004;171:466–72.

10.BauerMP,NotermansDW,vanBenthemBH,BrazierJS,WilcoxMH,RupnikM, etal.ClostridiumdifficileinfectioninEurope:ahospital-basedsurvey.Lancet 2011;377:63–73.

11.BarbutF,DelmeeM,BrazierJS,PetitJC,PoxtonIR,RupnikM,etal.AEuropean surveyofdiagnosticmethodsandtestingprotocolsforClostridiumdifficile.Clin MicrobiolInfect2003;9:989–96.

12.FreemanJ,BauerMP,BainesSD,CorverJ,FawleyWN,GoorhuisB,etal.The changingepidemiology ofClostridiumdifficileinfections. ClinMicrobiolRev 2010;23:529–49.

13.LongtinY,TrottierS,BrochuG,Paquet-BolducB,GarencC,LoungnarathV,etal. ImpactofthetypeofdiagnosticassayonClostridiumdifficileinfectionand complication rates in a mandatory reporting program. Clin Infect Dis 2013;56:67–73.

14.AsensioA,Vaque-RafartJ,Calbo-TorrecillasF,Gestal-OteroJJ,Lopez-Fernandez F,Trilla-GarciaA,etal.IncreasingratesinClostridiumdifficileinfection(CDI) among hospitalised patients, Spain 1999–2007. EuroSurveill 2008;13(31). pii=18943.

15.AlcalaL,MarinM,MartinA,Sanchez-SomolinosM,CatalanP,PelaezMT,etal. LaboratorydiagnosisofClostridiumdifficileinfectioninSpain:a population-basedsurvey.JHospInfect2011;79:13–7.

16.Rodriguez-PardoD,AlmiranteB,BartolomeRM,PomarV,MirelisB,NavarroF, etal.EpidemiologyofClostridiumdifficileinfectionandriskfactorsfor unfa-vorableclinicaloutcomes:resultsofahospital-basedstudyinBarcelona,Spain. JClinMicrobiol2013;51:1465–73.

17.DiBellaS,MussoM,CataldoMA,MeledandriM,BordiE,CapozziD,etal. ClostridiumdifficileinfectioninItalianurbanhospitals.Datafrom2006through 2011.BMCInfectDis2013;13:146.

18.MongeD,MillanI,Gonzalez-EscaladaA,AsensioA.[TheeffectofClostridium difficileinfectiononlengthofhospitalstay.Acohortstudy].EnfermInfecc MicrobiolClin2013;31:660–4.

19.MagaliniS,PepeG,PanunziS,SpadaPL,DeGaetanoA,GuiD.Aneconomic evaluationofClostridiumdifficileinfectionmanagementinanItalianhospital environment.EurRevMedPharmacolSci2012;16:2136–41.

20.SammonsJS,LocalioR,XiaoR,CoffinSE,ZaoutisT.Clostridiumdifficileinfection isassociatedwithincreasedriskofdeathandprolongedhospitalizationin children.ClinInfectDis2013;57:1–8.

21.SongX,BartlettJG,SpeckK,NaegeliA,CarrollK,PerlTM.Risingeconomic impactofClostridiumdifficile-associateddiseaseinadulthospitalizedpatient population.InfectControlHospEpidemiol2008;29:823–8.

22.WiegandPN,NathwaniD,WilcoxMH,StephensJ,ShelbayaA,HaiderS.Clinical andeconomicburdenofClostridiumdifficileinfectioninEurope:asystematic reviewofhealthcare-facility-acquiredinfection.JHospInfect2012;81:1–14.

23.KnausWA,WagnerDP,DraperEA,ZimmermanJE,BergnerM,BastosPG,etal. TheAPACHEIIIprognosticsystem.Riskpredictionofhospitalmortalityfor criticallyillhospitalizedadults.Chest1991;100:1619–36.

24.CharlsonME,PompeiP,AlesKL,MacKenzieCR.Anewmethodofclassifying prognosticcomorbidityinlongitudinalstudies:developmentandvalidation.J ChronicDis1987;40:373–83.

25.McCabeWR,JacksonGG.Gram-negativebacteremia:I.Etiologyandecology. ArchInternMed1962;110:847–55.

26.CohenSH,GerdingDN,JohnsonS,KellyCP,LooVG,McDonaldLC,etal.Clinical practiceguidelinesforClostridiumdifficileinfectioninadults:2010updateby theSocietyforHealthcareEpidemiologyofAmerica(SHEA)andtheInfectious DiseasesSocietyofAmerica(IDSA).InfectControlHospEpidemiol2010;31:431– 55.

27.Asensio A,Bouza E,Grau S, Rubio-Rodriguez D, Rubio-Terres C. [Cost of Clostridium difficile associated diarrhea in Spain]. Rev Esp Salud Publica 2013;87:25–33.

28.NationalInstituteofStatistics.Consumerprices:dataandinformation.Rome, Italy:Istat;2014.

29.DubberkeER,ButlerAM,ReskeKA,AgnielD,OlsenMA,D’AngeloG,etal. AttributableoutcomesofendemicClostridiumdifficile-associateddiseasein nonsurgicalpatients.EmergInfectDis2008;14:1031–8.

30.TabakYP,ZilberbergMD,JohannesRS,SunX,McDonaldLC.Attributableburden ofhospital-onsetClostridiumdifficileinfection:apropensityscorematching study.InfectControlHospEpidemiol2013;34:588–96.

31.EckmannC,WassermanM,LatifF,RobertsG,Beriot-MathiotA.Increased hospitallengthofstayattributabletoClostridiumdifficileinfectioninpatients withfourco-morbidities:ananalysisofhospitalepisodestatistics infour Europeancountries.EurJHealthEcon2013;14:835–46.

32.Pop-VicasA,ShabanE,LetourneauC,PechieA.Empiricalantimicrobial pre-scriptionsinpatientswithClostridiumdifficileinfectionathospitaladmission andimpactonclinicaloutcome.InfectControlHospEpidemiol2012;33:1101–6.

33.SchutzeGE,WilloughbyRE.Clostridiumdifficileinfectionininfantsandchildren. Pediatrics2013;131:196–200.

34.LessaFC,GouldCV,McDonaldLC.CurrentstatusofClostridiumdifficileinfection epidemiology.ClinInfectDis2012;55(Suppl2):S65–70.

35.ForsterAJ,TaljaardM,OakeN,WilsonK,RothV,vanWalravenC.Theeffectof hospital-acquiredinfectionwithClostridiumdifficileonlengthofstayin hospi-tal.CMAJ2012;184:37–42.

36.JonesAM,KuijperEJ,WilcoxMH.Clostridiumdifficile:aEuropeanperspective.J Infect2013;66:115–28.

37.CornelyOA.CurrentandemergingmanagementoptionsforClostridiumdifficile infection:whatistheroleoffidaxomicin?ClinMicrobiolInfect2012;18(Suppl 6):28–35.

38.CornelyOA, CrookDW,Esposito R,Poirier A,SomeroMS,WeissK,etal. FidaxomicinversusvancomycinforinfectionwithClostridiumdifficilein Eur-ope,Canada,andtheUSA:adouble-blind,non-inferiority,randomised con-trolledtrial.LancetInfectDis2012;12:281–9.