Antimicrobial stewardship in a Gastroenterology Department: Impact on antimicrobial consumption, antimicrobial resistance and clinical outcome

ContentslistsavailableatScienceDirect

Digestive

and

Liver

Disease

j o u r n a l ho me p a g e :w w w . e l s e v i e r . c o m / l o c a t e / d l d

Alimentary

Tract

Antimicrobial

stewardship

in

a

Gastroenterology

Department:

Impact

on

antimicrobial

consumption,

antimicrobial

resistance

and

clinical

outcome

Andrea

Bedini

_,

_Nicola

_De

_Maria

_,

_Mariagrazia

_Del

_Buono

_,

_Marcello

_Bianchini

_,

Mauro

Mancini

_,

_Cecilia

_Binda

_,

_Andrea

_Brasacchio

_,

_Gabriella

_Orlando

_,

Erica

Franceschini

_,

_Marianna

_Meschiari

_,

_Alessandro

_Sartini

_,

_Stefano

_Zona

_,

Serena

Paioli

_,

_Erica

_Villa

_,

_Inge

_C.

_Gyssens

_,

_Cristina

_Mussini

a_{ClinicofInfectiousDiseases,AziendaOspedaliero-Universitaria,PoliclinicodiModena,Italy} b_{GastroenterologyUnit,AziendaOspedaliero-Universitaria,PoliclinicodiModena,Italy} c_{PharmaceuticalDepartment,AziendaOspedaliero-Universitaria,PoliclinicodiModena,Italy} d_{DepartmentofInfectiousDiseases,HasseltUniversity,Belgium}

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received4May2016 Accepted20June2016 Availableonline30June2016 Keywords: Antifungals Antimicrobialstewardship Carbapenems Gastroenterology MDR-microorganisms

a

b

s

t

r

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c

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Background:Amajorcauseoftheincreaseinantimicrobialresistanceistheinappropriateuseof antimi-crobials.

Aims:Toevaluatetheimpactonantimicrobialconsumptionandclinicaloutcomeofanantimicrobial stewardshipprograminanItalianGastroenterologyDepartment.

Methods:BetweenOctober2014andSeptember2015(periodB),aspecialistininfectiousdiseases(ID) controlledallantimicrobialprescriptionsanddecidedaboutthetherapyinagreementwith gastroen-terologists.Thedefineddailydosesofantimicrobials(DDDs),incidenceofMDR-infections,meanlength ofstayandoverallin-hospitalmortalityratewerecomparedwiththoseofthesameperiodintheprevious 12-months(periodA).

Results:DuringperiodB,theIDspecialistperformed304consultations:antimicrobialswerecontinued in44.4%ofthecases,discontinuedin13.8%,notrecommendedin12.1%,de-escalated9.9%,escalatedin 7.9%,andstartedin4.0%.Comparingthe2periods,weobservedadecreasedofantibioticsconsumption (from109.81to78.45DDDs/100patient-days,p=0.0005),antifungals(from41.28to24.75DDDs/100pd, p=0.0004),carbapenems(from15.99to6.80DDDsx100pd,p=0.0032),quinolones(from35.79to17.82 DDDsx100pd,p=0.0079).NodifferenceswereobservedinincidenceofMDR-infections,lengthofhospital stay(LOS),andmortalityrate.

Conclusions:ASPprogramhadapositiveimpactonreducingtheconsumptionofantimicrobials,without anincreaseinLOSandmortality.

©2016EditriceGastroenterologicaItalianaS.r.l.PublishedbyElsevierLtd.Allrightsreserved.

1. Background

Infectionscaused bymultidrug-resistant (MDR) microorgan-isms are difficult to treat, leading to significant mortality and morbidity,prolongedlengthofhospitalstay,andexcessivecosts. Theriseofantimicrobialresistancewithadiminishingantibiotic pipelineposesaseriousthreatworldwide,especiallyconcerning

∗ Correspondingauthorat:InfectiousDiseasesDepartment,Azienda Ospedaliero-Universitaria,Policlinico di Modena, Viadel pozzo 71, 41125 Modena,Italy. Tel.:+390594222717;fax:+390594222604.

E-mailaddress:andreabedini@yahoo.com(A.Bedini).

Gram-negativemicrobes[1].Theoveruseormisuseof antimicro-bialagentsisthevitalcomponentintheemergenceandspread of MDR microorganisms. Unfortunately, Italy has a long tradi-tion of widespread use of antibiotics and a high incidence of MDRmicroorganisms[2,3].Antimicrobialstewardshipprograms (ASP)havebeenadvocatedbymanytoextendthelifeexpectancy of theantimicrobialarmamentarium. Todate, there is growing evidence demonstrating the benefits of stewardship, including reductions of antimicrobial usage and costs [4–6]. During the pastdecades,the useof broad-spectrum antimicrobials in Gas-troenterologyDepartmentsincreased,particularlyamongpatients withcirrhosisandspontaneousbacterialperitonitis(SBP). Bacte-rialinfectionispresent in32–34%ofhospitalizedpatientswith

http://dx.doi.org/10.1016/j.dld.2016.06.023

cirrhosis, which is 4–5 fold higher than hospitalized patients in general, and it accounts for about 30–50% of deaths [7–9]. Common types of infections in patients with cirrhosis include SBP (25–31%), urinary tract infection (UTI) (20–25%), pneumo-nia(15–21%), bacteremia (12%), and soft tissue infection (11%)

[10–12].ThemajorcausativeorganismsareGram-negative bac-teria, e.g., Escherichiacoli, Klebsiella spp. and Enterobacter spp., whereasGram-positivebacteriacompriseabout20%,and anaer-obesonly3%[10].Inalargeprospectivestudyofcirrhoticpatients withinfections,multi-drugresistant(MDR)bacteriawereisolated in4%,14%,and35%ofcommunity-acquired,healthcare-associated, and nosocomial infections, respectively (p<0.001) [13]. The mainresistantorganisms wereextended-spectrum␤-lactamase (ESBL)-producing Enterobacteriaceae, followed by Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA), and Enterococcus faecium [13].There wasa significantly higher incidence of septicshock and deathfrom infections caused by resistantbacteria.Notably,theefficacyofempiricalantibiotic treat-mentwasdecreasedinnosocomialinfections(40%),comparedto community-acquiredandhealthcare-associatedepisodes(83%and 73%, respectively;p<0.0001), especially in SBP, UTI,and pneu-monia(26%,29%and44%,respectively)[13].Infectiousdiseases (ID)consultation hasan importantrole inreducing inappropri-ate antimicrobial use [14–16]. To target this, an antimicrobial stewardshipprogram(ASP)hasbeenimplementedatthe Gastroen-terologyDepartmentoftheUniversityHospitalofModena,Italy. TheASPwasbasedoncase-audits: anIDspecialist,member of theantimicrobialstewardshipgroup,visitedtheGastroenterology Department twicea weekand controlledall antimicrobial pre-scriptions,finallydecidingaboutthetherapyinagreementwith gastroenterologists.Thisdepartmenthadaveryhighconsumption ofcarbapenems(up30DDDsx100pd)intherecentyears.Aimsof thisstudyweretoevaluatetheimpactoftheASPonantimicrobial consumption,incidenceofMDRmicro-organismsinfectionsand clinicaloutcome.

2. Methods

Thiswasanobservationalprospectivestudyevaluating,after 12 months of intervention, the impact of newly implemented procedure(ASP)attheGastroenterologyDepartmentofthe Uni-versity Hospitalof Modena, Italy. Data for comparison withan historic cohort, were collected retrospectively from the hospi-tal’s data warehouse. The antimicrobial stewardship group is multi-disciplinary, consisting of clinical microbiologists, infec-tiousdisease(ID)physicians,andhospitalpharmacists.Thegroup reportstothehospital’sAntimicrobialCommitteeandInfection PreventionCommittee,whichhaveamandatefromtheboardof directorstoimplementandruntheASP.AnIDspecialist,member oftheantimicrobialstewardshipgroup,visitedthewardtwicea week,generallyonTuesdayandonFriday,anddiscussed antimi-crobialtherapybed-sidewiththetreatingphysicians,face-to-face. Duringthecase-audit,thetherapywasdiscussedandtheavailable diagnosticswerereviewed.Usingtheexpertiseandexperienceof boththeIDspecialistandthewardphysician,adecisiononthe antimicrobialtherapywasmade.

Finaldecisionswerealwaysbasedonlocalguidelinesfor antimi-crobial therapy, which in turn arebased on national and IDSA guidelines,andonratesoflocalresistancetoantimicrobials.

InclusionofpatientsintheASPwasdonebyaspecialistinIDwho controlledalltherapiestwiceaweek:allin-patientswhoreceived oneormoreantimicrobialsatthetimeofthevisitwereincluded inthestudy.Patients’antimicrobialconsumptionwasmeasuredin defineddailydoses(DDDs)per100patientdays(DDDs/100pd),as statedbytheWHO[17].

Weevaluatedanddescribedthereasonsforantimicrobial pre-scription.Fordiagnosisofpneumoniaweconsideredthepresence ofrespiratorysymptoms(withorwithoutfever)with≥1opacity onthechestradiographs;thepresenceof>250polymorphonuclear leukocytes(PMN)/mm3_{intheasciticfluidisusedtodefine} spon-taneousbacterialperiotonitis(SBP);cholangitiswassuspectedin anypatientwhoappearsseptic,jaundiced,orwhohave abdomi-nalpain,associatedwithanobstructionofthebiliarytree.Forthe diagnosisofurinarytractinfections(UTIs)andbloodstream infec-tions,weconsideredtheisolationofabacteria/fungusfromurine orbloodcultureinpresenceofsymptomscompatiblewiththe clin-icalsyndrome.Forcirrhoticpatients,thepresenceoffeverwasnot anessentialcriterionforinfection.

We compared theDDDs of antimicrobials, the incidence of infections caused by MDR-microorganisms, themean lengthof stayandtheoverallin-hospitalmortalityratewiththoseofthe patientsadmitted inthesame Departmentduring theprevious 12-months(1October 2013–30September2014,periodA).We consideredthefollowingMDR-microorganisms(usingthecriteria suggestedbyEuropeanCommitteeonAntimicrobial Susceptibil-ity Testing– EUCAST)[18]:E. coliESBL-producing strain(MICs for cefotaxime>2_␮g/ml), MRSA (MICs for oxacillin_≥4_␮g/ml), vancomycin-resistant Enterococcus spp. (VRE; MICs for van-comycin≥4␮g/ml)andcarbapenem-resistantbacteria(CRB;MICs formeropenem>8␮g/ml).

2.1. Statisticalanalysis

AnalysiswasperformedbyusingIBMSPSSStatistics22(IBM, Armonk, NY,USA).The comparisonbetweentheincidence rate of the infections caused by MDR-bacteria was performed by a two-sample test of proportions. For antibiotic consumption of thetotalDepartment,includingpatientswithoutintervention(s), monthlyDDDsweregroupedinpre-interventionandduring inter-ventionperiods.Pooledmedian DDDs werecompared between periodsusingWilcoxon(Mann–Whitney)U-test.Univariatelinear regressionanalyseswereperformedtoassessmeansand slopes ofvariationsofDDDsduringpre-andduringintervention. Signif-icancethresholdwassetforap<0.05.Analysiswasperformedby usingIBMSPSSStatistics22(IBM,Armonk,NY,USA).

3. Results

BetweenOctober2014andSeptember2015,784patientswere admitted totheGastroenterologyDepartment oftheUniversity HospitalofModena,Italy.Duringthisperiod(periodB),176(22.4%) patients received at least one ID consultation and have been enrolledinthestudy.Overall,304IDconsultationswereperformed. Sixty-onepercentofthepatientsweremalesandthemeanage was63years(range:19–95years).Case-auditstookonaverage between 10 and 15min, including administration time. Demo-graphiccharacteristicsofthepatients,underlyingdiseasesandtype ofinfectionareshownin Table1.Themostcommoninfections werepneumonia(24.43%),bloodstreaminfection(BSI;18.75%)and cholangitisorcholecystitis(17.04%).Thirty-two(18.18%)patients receivedantimicrobialswithoutaproveninfection(11patientsfor pancreatitis,8forprophylaxisaftervaricealbleedingand13for encephalopathyincirrhosis).

3.1. IDconsultations

During period B, the ID specialist performed 304 consulta-tionsfor176patients(Fig.1):theantimicrobialprescriptionwas unchangedin135cases(44.4%),interruptedin42(13.8%),not rec-ommendedin37(12.1%),de-escalatedin30(9.9%),escalatedin 24(7.9%),andstartedin12(4.0%).In13cases(4.3%)thedosage

Fig.1. AdviceoftheIDspecialistaboutantimicrobialtreatmentforthe176patientsadmittedtotheGastroenterologydepartmentbetweenOctober2014andSeptember 2015(ABTx:antimicrobialtreatment).

Table1

Demographiccharacteristics,underlyingdiseasesandtypeofinfectionofthe176 patientsadmittedtotheGastroenterologyDepartmentattheUniversity Hospi-talofModenathatreceivedatleast1IDconsultationbetweenOctober2014and September2015. Characteristics N(%) 176(100) Sex Male 108(61.4) Female 68(38.6)

Age(mean;min–max) 63years(19–95)

Underlyingdiseases Cirrhosis 90(51.13) Gallstones 34(19.31) HCC 22(12.50) Pancreatitis 11(6.3) Livertransplant 10(5.68) IBD/diverticulitis? 13(7.38) Neoplasia(differentbyHCC) 13(7.38) Other 8(4.5) Typeofinfection Pneumonia 43(24.43) BSI 33(18.75) Cholangitis/cholecystitis 30(17.04) UTI 28(15.90) Peritonitis 18(10.22) Others 20(11.36) Moreinfections 37(21.02) None 32(18.18) Encephalopathyincirrhosis 13(7.38) Pancreatitis 11(6.25)

Prophylaxisforvaricealbleeding 8(4.54)

ofantimicrobialswascorrectedandinanother11cases(3.6%)the

classofantimicrobialswaschanged.Inthe98.02%ofthecases,the

IDconsultantandthemedicalteamofthedepartmentfoundan

agreementonantimicrobialtherapytobeprescribed.

3.2. Antimicrobialconsumption

During period B, there wasan overall significantly decrease

ofantibiotics from109.81to78.45DDDs per100patient-days,

p=0.0005, and antifungals from 41.28 to 24.75 DDDsx100pd,

p=0.0004.ThegreatestimpactoftheASPwasobservedon

car-bapenems(Fig.2),whichdecreasedfrom15.99to6.80DDDs/100pd

(p=0.0032), and quinolones, which decreased from 35.79 to 17.82DDDs/100pd(p=0.0079).Alsotheoverallconsumption of glycopeptidesandechinocandinsdecreased(Table2),butnot sig-nificantly (p=0.193 and p=0.440, respectively). This reduction in broad-spectrum antibiotic use wasaccompanied by a slight

increasein theconsumptionof penicillins(from 44.29to47.75 DDDs/100pd,p=0.729),butnotofotherantibioticsas aminoglyco-sides,macrolides,linezolid,daptomycineandtigecycline(datanot shown).Thirdandfourthgenerationcephalosporinsmoderately decreasedfrom13.46to12.60DDDs/100pd,p=0.488.

3.3. Infections,LOSandmortalityrate

Table2showstheclinical,microbiologicalandpharmacological dataofthepatientsadmittedtotheGastroenterologyDepartment duringtheperiodA(October2013–September2014)andtheperiod B(October2014–September2015)ofthestudy.Nosignificant dif-ferenceswereevidencedin thenumber ofadmissions,LOSand in-hospitalmortalityrate.Itshouldbenotedthatallpatientswho hadaninfectiouscauseofdeath(12/176,6.81%)wereperforming anantibiotictherapyeffectiveonthebasisofthemicrobiological isolates.Furthermore,weobservedthat,incomparisonwithnon cirrhoticpatients,individualswithlivercirrhosis(90/176,51.13%) had higher mortality rate due to infectious causes (2.32% and 11.11%,respectively;p<0.033),andahigherLOS(16.51and20.88 days,respectively;p:n.s.).Inthe50.0%ofthecases,thedeathfor bacterialinfectionsoccurred,incirrhoticpatients,within15days afterinfection.Itisnoteworthy,however,thattheincidenceofMDR bacteriainfectionsdecreasesaftertheimplementationofASP,but withoutreachingastatisticalsignificance.OnlytheincidenceofK. pneumoniacarbapenem-resistantmoderatelyincreased(p=0.823). 4. Discussion

ID services play an important role in improving antimicro-bial use by providing expert advice on the appropriate use of antimicrobialagents,educationtoprescribers,anddevelopingand implementing evidence-basedguidelines. It wassuggested that consultationwithanIDspecialistisoneofthesixclinicalstrategies toreduceinadequateantimicrobialtreatmentinthehospital set-ting[19].Manystudiesdemonstratedimprovedpatientoutcomes when IDphysicians wereinvolved in thecare of patientswith bacteraemia, with the advantage of reducing morbidity, mor-tality,and cost of care[14].Indeed, a previousstudyfrom our institutionshowedthatIDconsultationledtocostreductionby advisinglessexpensiveantibioticsandreducingthird-and fourth-generation cephalosporins, piperacillin/tazobactam, teicoplanin, and parenteral quinolones [20]. To our knowledge, this is the first study on antimicrobial stewardship in a Gastroenterology Department. Our data demonstrate important results. First,

Fig.2. Antimicrobialstewardshipprogram(ASP)effectsontheantibioticandantifungalconsumptionattheGastroenterologyDepartmentbetweenOctober2014and September2015incomparisonwiththeprevious24months,analyzedusingunivariatelinearregressionmodels(A:Allantibiotics;B:Allantifungals;C:Carbapenems;D: Quinolones).

antimicrobialtherapywaschangedin21.4%,discontinued com-pletelyin13.8%,andnotrecommendedin12.1%ofcases.Similarly, inaUrologyDepartmentinNetherlands,thetherapywaschanged in 37.7% and discontinued in 23.7% of patients [21], and in a Turkishhospitalthetherapywaschangedin57.4%ofpatientsand antibioticswerenotnecessaryfor9.8%[22].Thisfindingis consis-tentwithpreviousstudieswheretheuseofantimicrobialtherapy wasjudgedtobeinappropriateorrequiredchange.Inastudyby Yinnon[23]therewasachangeoftherapyordiscontinuationof antibioticsin46%.Otherstudiesfoundthat41–66%ofantibiotic waschangedafterIDconsultation[24,25].

Second, theASP had a positive impact onthe consumption ofantibioticsandantifungals,especiallyasregardscarbapenems, quinolones,glycopeptidesandechinocandins.Oneofthemain rea-sonswhyweselectedtheGastroenterologyDepartmentfortheASP wasthatithadaveryhighconsumptionofcarbapenems(up30 DDDs/100pd)duringthepastyears.Thiswasmainlyduetothe factthatsince2011anincreaseofinfectionandcolonizationrates ofESBL-positiveEnterobacteriaceaewasobservedinourhospital andthefirst-lineempiricaltreatmentincirrhoticpatientswith sep-sisorPBSwaschangedfromceftriaxonetomeropenem.Therefore,

theASPwasfocusedespeciallyinreducingthecarbapenemsand quinolonesconsumption.Animportantresultofourstudyisthat thereductioninbroad-spectrumantibioticconsumptionwasnot associatedwithanincreaseinLOSand,inmortalityrate. More-over,theincidenceofMDRbacterialinfectionsdecreasedduring theASPimplementationperiod,evenifitdidnotreach statisti-calsignificance.Thiscouldindicatethatareductionintheuseof broad-spectrumantibioticsmayhavecontributedalowerselection ofMDRbacteria.

Objective of the case-audit wasto reacha consensus-based agreementbetweentheIDspecialistandthephysicianattheward, using (local) guidelines,available diagnostics and theexpertise andexperienceofbothphysicians.Thisshouldoptimize antimi-crobialtreatment.Thecase-auditfocusedontheimprovementof patientcarethroughrelativelyeasytoachieveimprovementsafter afew daysoftherapy,suchasearlyde-escalationof antimicro-bial therapy andstop whenthere wasnolongeran indication. Furthermore,theface-to-facecase-auditonthewardprovidedan extraopportunityforquestionsaboutappropriatenessoftherapy andrequestingadditionalconsultationsforotherpatientsonthe ward.

Table2

Clinical,microbiologicalandantimicrobialconsumptiondataofpatientsadmittedtotheGastroenterologyDepartmentinperiodA(October2013–September2014)and periodB(October2014–September2015).

PeriodA Oct2013–Sep2014 PeriodB Oct2014–Sep2015 p Admissions 761 784 – Bed-occupationrate(%) 109% 118%

PatientsevaluatedbyIDspecialistfortheASPa_{(%) 0(0.0) 176(22.44) –}

Daysofhospitalization 5298 5502 –

Lengthofstay(meanindays) 7.11 7.01 –

InfectionsduetoMDR-microorganisms:N;incidence(episodes/100admissions)(95%CI)

MRSAb _{7;0.92(0.37–1.89) 3;0.89(0.36–1.84) 0.204} E.coliESBL+ 20;2.63 (1.60–4.06) 13;1.66 (0.88–2.83) 0.196 CRBc _13;1.71 (0.91–2.92) 9;1.14(0.52–2.17) 0.359 K.pneumoniaeKPC+ 6;0.79(0.29–1.71) 7;0.89(0.36–1.84) 0.823 P.aeruginosaCarba+ 4;0.52(0.14–1.34) 1;0.12 (0.003–0.71) n.a. A.baumanniiCarba+ 3;0.39(0.08–1.15) 1;0.12 (0.003–0.71) n.a. VREd _11;1.44 (0.72–2.58) 9;1.14(0.52–2.17) 0.608

Deaths(mortalityrate%) 23(3.0) 26(3.31) 0.742

DDDs/100pdofantibiotics 109.81 78.45 0.0005 Allpenicillins 44.29 47.75 0.729 3rdto4thGcephalosporin 13.46 12.6 0.488 Carbapenems 15.99 6.80 0.0032 Quinolones 35.79 17.82 0.0079 Glycopeptides 17.15 9.09 0.193 DDDs/100pdofantifungals 41.28 24.75 0.0004 Echinocandins 2.84 1.66 0.440

a_{ASP:antimicrobialstewardshipprogram.} b _{MRSA:methicillin-resistantS.aureus.} c _{CRB:carbapenem-resistantbacteria.} d _{VRE:vancomycin-resistantEnterococcusspp.}

Ourstudyconfirmsthat cirrhosisisoneofthemainreasons foradmissioninGastroenterologyDepartment.Thepatientswith cirrhosisaccounted forthe 51.13% ofthestudy populationand resultedtohaveahigherLOSandin-hospitalmortalityrate. Arvan-iti et al. demonstrated that bacterialinfections in cirrhosis are associatedwithpooreroutcomeandthatmortalityincreasedabout 4fold[26].Bothshort-andlong-termmortalityratesofsepsisin cirrhoticpatientsareveryhigh;26–44%ofpatientsdiewithin1 monthafterinfectionandanother33%diein1year[26,27].Also weobservedapooreroutcomeinthepatientswithcirrhosisand bacterialinfections,anddespiteaneffectiveantimicrobial treat-ment,50.0%ofthesepatientsdiedwithin15daysafterinfection. Factorsthatmusttobetakenintoaccountaspredictorsofdeath duringorfollowinginfectionare:advancedliverdisease, nosoco-mialorigin,gastrointestinalhaemorrhage,encephalopathy,liver cancer,presenceofshockandorganfailure(especiallyrenalfailure)

[26,27].

Ourstudyhassomelimitations.EffectsofASPwereevaluated foraGastroenterologyDepartmentinasingleacademicsettingand itdoesnotallowgeneralconsiderations.Nevertheless,wethink thatintheabsenceofanydataevenastudyconductedonasingle GastroenterologyDepartmentcouldgiveimportantinformation. Moreover,aGastroenterologyDepartmentduetotheseverityofits casemixandthepeculiarityofcirrhoticpatientscouldrepresent agoodexampleofhowASPcouldbeimplementedalsoinsetting treatingmorecomplicatedpatients.

AnotherimportantlimitationwasthatthecomparisonofLOS andthemortalityrateinthe2periodsofthestudyconsideredall thepatientsadmittedtothedepartmentduringtheperiodAand theperiodB, andnotonlythepatientsthatreceivedorneeded antimicrobialtreatment.Finally,wedidnotperformacostbenefit analysis.

Inconclusion,ASPinterventionsarebeneficialwithout show-ing any negative impact on survival by reducing the use of

broad-spectrumantibioticsandforthisreasonitshouldbe pro-motedthroughoutthehospitaldepartments.

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