Efficacy of β-lactam/β-lactamase inhibitors to treat extended-spectrum beta-lactamase-producing Enterobacterales bacteremia secondary to urinary tract infection in kidney transplant recipients

Transpl Infect Dis. 2021;23:e13520. wileyonlinelibrary.com/journal/tid  | 1 of 16 https://doi.org/10.1111/tid.13520 © 2020 Wiley Periodicals LLC Received:1September2020 | Revised:23October2020 | Accepted:7November2020 DOI:10.1111/tid.13520 ORIGINAL ARTICLE Efficacy of β-lactam/β-lactamase inhibitors to treat extendedspectrum beta-lactamase-producing Enterobacterales bacteremia secondary to urinary tract infection in kidney transplant recipients (INCREMENT-SOT Project) Ligia C. Pierrotti1 | Elena Pérez-Nadales2,3 | Mario Fernández-Ruiz2,4 | Belén Gutiérrez-Gutiérrez2,5 | Ban Hock Tan6 | Jordi Carratalà2,7 | Isabel Oriol2,7 | Mical Paul8 | Noa Cohen-Sinai9 | Francisco López-Medrano2,4 | Rafael San-Juan2,4 | Miguel Montejo10 | Maristela P. Freire11 | Elisa Cordero2,12 | Miruna D. David13 | Esperanza Merino14 | Seema Mehta Steinke15 | Paolo A. Grossi16 | Ángela Cano2,5 | Elena M. Seminari17 | Maricela Valerio18 | Filiz Gunseren19 | Meenakshi Rana20 | Alessandra Mularoni21 | Pilar Martín-Dávila2,22 | Christian van Delden23 | Melike Hamiyet Demirkaya24 | Zeliha Koçak Tufan25 | Belén Loeches26 | Ranganathan N. Iyer27 | Fabio Soldani28 | Britt-Marie Eriksson29 | Benoît Pilmis30 | Marco Rizzi31 | Julien Coussement32 | Wanessa T. Clemente33 | Emmanuel Roilides34 | Álvaro Pascual2,5 | Luis Martínez-Martínez2,35 | Jesús Rodríguez-Baño2,5 | Julian Torre-Cisneros2,36 | José María Aguado2,4 | Investigators from the REIPI/INCREMENT-SOT Group† 1InfectiousDiseasesDivision,HospitaldasClínicas,UniversityofSãoPauloMedicalSchool,SãoPaulo,Brazil 2SpanishNetworkforResearchinInfectiousDiseases(REIPI),ISCIII,Madrid,Spain 3InfectiousDiseasesGroup,MaimonidesBiomedicalResearchInstituteofCordoba(IMIBIC),ReinaSofíaUniversityHospital,UniversityofCordoba,Cordoba, Spain 4UnitofInfectiousDiseases,“12deOctubre”UniversityHospital,InstitutodeInvestigaciónSanitariaHospital“12deOctubre”(imas12),Universidad Complutense,Madrid,Spain 5ClinicalUnitofInfectiousDiseases,MicrobiologyandPreventiveMedicine,VirgenMacarenaUniversityHospital,InstituteofBiomedicineofSeville, UniversityofSeville,Seville,Spain 6DepartmentofInfectiousDiseases,SingaporeGeneralHospital,Singapore 7DepartmentofInfectiousDiseases,BellvitgeUniversityHospital-IDIBELL,UniversityofBarcelona,L´HospitaletdeLlobregat,Barcelona,Spain 8InfectiousDiseasesInstitute,RambamHealthCareCampus,Haifa,Israel 9Technion-IsraelInstituteofTechnology,Haifa,Israel LigiaCameraPierrottiandElenaPérez-Nadaleshavecontributedequally. †InvestigatorsfromtheREIPI/INCREMENT-SOTGrouparelistedinAcknowledgements. Abbreviations:auROC,areaunderthereceivingoperatorcharacteristicscurve;BC,bloodculture;BLBLI,β-lactam/β-lactamaseinhibitors;BSI,bloodstreaminfection;CCI,age-adjusted Charlsoncomorbidityindex;CI,confidenceinterval;CLSI,ClinicalandLaboratoryStandardsInstitute;CMV,cytomegalovirus;CRE,carbapenem-resistantEnterobacterales;ESBL, extended-spectrumβ-lactamase;ESBL-E,extended-spectrumβ-lactamase-producingEnterobacterales;EUCAST,EuropeanCommitteeonAntimicrobialSusceptibilityTesting;IQR, interquartilerange;KTRs,kidneytransplantrecipients;MDR,multidrug-resistant;MIC,minimuminhibitoryconcentrations;OR,oddsratio;PCR,polymerasechainreaction;PS, propensityscore;SD,standarddeviation;UTI,urinarytractinfection;VIF,varianceinflationfactor. 2 of 16 | PIERROTTI ET al 10InfectiousDiseasesUnit,CrucesUniversityHospital,Bilbao,Spain 11WorkingCommitteeforHospitalEpidemiologyandInfectionControl,HospitaldasClínicas,UniversityofSãoPauloMedicalSchool,SãoPaulo,Brazil 12ClinicalUnitofInfectiousDiseases,MicrobiologyandPreventiveMedicine,InstituteofBiomedicineofSeville,UniversityHospitalsVirgendelRocío/CSIC/ UniversityofSeville,Seville,Spain 13UniversityHospitalsBirminghamNHSFoundationTrust,Birmingham,UnitedKingdom 14UnitofInfectiousDiseases,GeneralUniversityHospitalofAlicante,ISABIAL,Alicante,Spain 15SchoolofMedicine,JohnsHopkinsUniversity,Baltimore,USA 16DepartmentofMedicineandSurgery,UniversityofInsubria,Varese,Italy 17InfectiousDiseasesClinic,FondazioneIRCCSPoliclinicoSanMatteo,Pavia,Italy 18ClinicalMicrobiologyandInfectiousDiseaseDepartment,HospitalGeneralUniversitarioGregorioMarañón,Madrid,Spain 19DepartmentofInfectiousDiseasesandClinicalMicrobiology,AkdenizUniversityFacultyofMedicine,Antalya,Turkey 20IcahnSchoolofMedicineatMountSinai,NewYork,USA 21IRCCS-ISMETT(IstitutoMediterraneoperiTrapiantieTerapieadaltaspecializzazione),Palermo,Italy 22InfectiousDiseasesDepartment,RamónyCajalUniversityHospital,Madrid,Spain 23UnitforTransplantInfectiousDiseases,UniversityHospitalsofGeneva,Geneva,Switzerland 24BaşkentUniversitySchoolofMedicine,Ankara,Turkey 25InfectiousDiseasesandClinicalMicrobiologyDepartment,MedicalSchoolofAnkaraYildirimBeyazitUniversity,Ankara,Turkey 26InfectiousDiseasesUnit,HospitalUniversitarioLaPaz,IdiPAZ,Madrid,Spain 27ClinicalMicrobiologyID&Infectioncontrol,GlobalHospitals,Hyderabad,India 28DivisionofInfectiousDiseases,DepartmentofMedicine,AziendaOspedalieraUniversitariaIntegratadiVerona,Verona,Italy 29DepartmentofMedicalSciences,SectionofInfectiousDiseases,UppsalaUniversity,Uppsala,Sweden 30DepartmentofInfectiousDiseasesandTropicalMedicine,ParisDescartesUniversity,Necker-EnfantsMaladesUniversityHospital,Centred’Infectiologie Necker-Pasteur,InstitutImagine,AP-HP,Paris,France 31InfectiousDiseasesUnit,ASSTPapaGiovanniXXIII,Bergamo,Italy 32DivisionofInfectiousDiseases,CUB-HôpitalErasme,UniversitéLibredeBruxelles,Brussels,Belgium 33FaculdadedeMedicinadaUniversidadeFederaldeMinasGerais(UFMG),TransplantInfectiousDisease,LiverTransplantProgram,HospitaldasClínicasda UFMG,BeloHorizonte,Brazil 34InfectiousDiseasesUnitand3rdDepartmentofPediatrics,AristotleUniversitySchoolofHealthSciences,HippokrationHospital,Thessaloniki,Greece 35ClinicalUnitofMicrobiology,DepartmentofMicrobiology,ReinaSofíaUniversityHospital,MaimonidesBiomedicalResearchInstituteofCordoba(IMIBIC), UniversityofCordoba,Córdoba,Spain 36ClinicalUnitofInfectiousDiseases,ReinaSofíaUniversityHospital,MaimonidesBiomedicalResearchInstituteofCordoba(IMIBIC),UniversityofCordoba, Córdoba,Spain Correspondence JulianTorre-Cisneros,ClinicalUnitof InfectiousDiseases,ReinaSofíaUniversity Hospital,MaimonidesBiomedicalResearch InstituteofCordoba(IMIBIC),Universityof Cordoba,Córdoba,Spain. Email:[email protected]. Funding informationThisworkwas supportedby:(1)PlanNacionalde I+D+i2013-2016andInstitutode SaludCarlosIII(ISCIII),Subdirección GeneraldeRedesyCentrosde InvestigaciónCooperativa,Ministerio deCiencia,InnovaciónyUniversidades, SpanishNetworkforResearchin InfectiousDiseases[RD16/0016/0001, RD16/0016/0002,REIPIRD16/0016/0008; RD16/0016/00010],co-financedby EuropeanDevelopmentRegionalFund “AwaytoachieveEurope”,Operative ProgramIntelligentGrowth2014-2020;(2) EuropeanSocietyofClinicalMicrobiology andInfectiousdiseasesStudyGroupfor InfectionsinCompromisedHosts(ESGICH, granttoJ.M.A.);(3)SociedadAndaluza Abstract Background: Whether active therapy with β-lactam/β-lactamaseinhibitors(BLBLI) is as affective as carbapenems for extended-spectrum β-lactamase-producing Enterobacterales(ESBL-E)bloodstreaminfection(BSI)secondarytourinarytractinfection(UTI)inkidneytransplantrecipients(KTRs)remainsunclear. Methods: We retrospectively evaluated 306 KTR admitted to 30 centers from January2014toOctober2016.Therapeuticfailure(lackofcureorclinicalimprovementand/ordeathfromanycause)atdays7and30fromESBL-EBSIonsetwasthe primaryandsecondarystudyoutcomes,respectively. Results: Therapeuticfailureatdays7and30occurredin8.2%(25/306)and13.4% (41/306)ofpatients.Hospital-acquiredBSI(adjustedOR[aOR]:4.10;95%confidence interval[CI]:1.50-11.20)andPittscore(aOR:1.47;95%CI:1.21-1.77)wereindependentlyassociatedwiththerapeuticfailureatday7.Age-adjustedCharlsonIndex (aOR:1.25;95%CI:1.05-1.48),Pittscore(aOR:1.72;95%CI:1.35-2.17),andlymphocytecount≤500cells/μLatpresentation(aOR:3.16;95%CI:1.42-7.06)predicted therapeuticfailureatday30.Carbapenemmonotherapy(68.6%,primarilymeropenem)wasthemostfrequentactivetherapy,followedbyBLBLImonotherapy(10.8%, | 3 of 16 PIERROTTI ET al 1 | INTRODUCTION Bloodstreaminfections(BSI)representacommoncomplicationafter solidorgantransplant(SOT),withanincidencehigherthanthatexpected in the general population.1Urinarytractinfection(UTI)isthe mostcommonsourceofBSIinkidneytransplantrecipients(KTRs),2- 4mainlyasaresultofthecombinedimpactofinvasiveprocedureson the urinary tract and underlying immunosuppression.2,5 The increasing prevalence of infections caused by multidrug-resistant (MDR) gram-negative bacilli, such as extended-spectrum β-lactamase (ESBL)-producingEnterobacterales(ESBL-E),isofparticularconcern intheSOTsetting.6-9Approximately10%ofKTRwilldevelopanUTI causedbyESBL-Ewithinthefirstyear,10andthesepatientsfacea threetimes higherrisk ofrecurrence comparedtothose infected withnon-MDRbacteria.10,11 ThemanagementofinfectionscausedbyESBL-Eremainschallenging,withlimitedantimicrobialsavailableandscarcesupportingevidence.Carbapenemshavebeenconsideredasthefront-line therapy both in the general population12 and in immunocompromisedpatients,includingKTR.13Observationalstudiesconducted inthegeneralpopulation—suchasthemultinationalINCREMENT cohort(ClinicalTrials.govidentifier:NCT01764490)—haveshown that,fororganismsshowinginvitrosusceptibility,β-lactam/β-lac- tamase inhibitors (BLBLI) may be a good alternative to carbapenems for the treatment of BSI caused by ESBL-E, particularly among non-critically ill patients with UTI.14-17Onthecontrary, other studies, including a recently published randomized trial, havereportedadifferenceinmortalityfavoringcarbapenems.18-20 Interpretationofpreviousstudiesisfurther complicatedbythe lowerreliabilityandreproducibilityofinvitrosusceptibilitytestingtopiperacillin-tazobactamascomparedtocarbapenemswhen gradientmethods,suchasE-test,areused.21WhetherthesefindingscanbeextrapolatedtotheSOTpopulationremainstobeassessed.Theaimofthepresentstudywastocomparetheimpact oftherapeuticregimensbasedoncarbapenemsversusBLBLIon theclinicaloutcomeinalargemultinationalcohortofKTRwith ESBL-EBSIsecondarytoUTI. 2 | MATERIALS AND METHODS 2.1 | Study population and setting The INCREMENT-SOT project (ClinicalTrials.gov identifier NCT02852902) comprised a retrospective international cohort of SOTrecipientsdiagnosedwithclinicallysignificant(ie,meetingcriteriaforsystemicinflammatoryresponsesyndrome)BSIcausedby ESBL-Eorcarbapenemase-producingEnterobacterales admitted to 40tertiaryhospitalsin16countriesfromJanuary2004toOctober 2016. For the present analysis,KTRs with monomicrobial ESBL-E BSIsecondarytoUTIwereeligible.Patientdatawerecollectedat eachsitebyreviewofmicrobiologyreportsandpatients’chartsuntil day30afterincidentbloodcultures(BCs)weretaken.Exclusioncriteriawerekeymissingdataregardingtherapeuticregimensand/or outcomes,deathearlierthan24hoursaftertheindexdate(ie,that ofBSIonset),andtheadministrationofactivetherapyforatleast 2dayspriortoBCsampling.Thestudyprotocolwasapprovedby theSpanishAgencyofMedicines(codeFIB-COL-2015-01)andby theEthicsCommitteeoftheHospitalUniversitarioReinaSofía(Act 243,code2907),whichwaivedtheneedtoobtainwritteninformed consent.Approvalwasalsogainedatparticipatingcentersaccording tolocalrequirements. 2.2 | Study outcomes and definitions The primary study outcomewastherapeuticfailure,definedasthe lackofcureorclinicalimprovement(ie,persistenceorworsening mostlypiperacillin-tazobactam).Propensityscore(PS)-adjustedmodelsrevealedno significant impact of the choice of active therapy (carbapenem-containing vs any otherregimen,BLBLI-vscarbapenem-basedmonotherapy)withinthefirst72hours onanyofthestudyoutcomes. Conclusions: OurdatasuggestthatactivetherapybasedonBLBLImaybeaseffectiveascarbapenem-containingregimensforESBL-EBSIsecondarytoUTIinthespecificpopulationofKTR.Potentialresidualconfoundingandunpoweredsamplesize cannotbeexcluded(ClinicalTrials.govidentifier:NCT02852902). KEYWORDS bloodstreaminfection,carbapenem-sparingregimen,extended-spectrumβ-lactamase- producing Enterobacterales,kidneytransplantation,outcomes,urinarytractinfection deTrasplantedeÓrganoSólido(SATOT, granttoL.M.M.);(4)Researchproject PI16/01631integratedintothePlanEstatal deI+D+I2013-2016andco-financedbythe ISCIII-SubdirecciónGeneraldeEvaluación yFomentodelaInvestigaciónandthe FondoEuropeodeDesarrolloRegional (FEDER);(5)M.F.R.holdsaresearch contract“MiguelServet”(CP18/00073) fromISCIII,MinisteriodeCiencia, InnovaciónyUniversidades.Theworkwas alsosupportedbythefollowingEuropean SocietyofClinicalMicrobiologyand Infectiousdiseases(ESCMID)studygroups: InfectionsinCompromisedHosts(ESGICH), BloodstreamInfectionsandSepsis(ESGBIS) andAntimicrobialResistanceSurveillance (ESGARS). 4 of 16 | PIERROTTI ET al offever,leukocytosisorothersignsofinfection,and/orpersistentlypositiveBCforthesamemicroorganism),and/ordeathfrom anycauseatday7fromtheonsetofBSI.Therapeuticfailureat day 30 was considered as secondary outcome. The main explanatory variablewasthetypeofactivetherapy(accordingtothecategoriesdefinedbelow)administeredwithinthefirst72hoursfrom BSIonset.Sensitivityanalyseswerealsoperformedbasedonthe regimen used during the first 24 hours and 7 days. The tested hypothesis(BLBLIarenotassociatedwithworseoutcomesthan carbapenem-containing regimens after controlling for potential confounders)wasspecifiedaprioriinthestudyprotocol.Because oftheexploratorynatureofthestudyandtheexpectedlowproportionofpatientstreatedwithBLBLIacrossparticipatinginstitutions, nosamplesizeestimationonthebasisof theanticipated incidence of study outcomes was performed. In addition, the statisticalanalysiswasnotformallymodeledonanon-inferiority assumption. EpisodesofESBL-EBSIwereconsideredhospital-acquiredifsymptomsstartedbeyondthefirst48hoursfromhospitaladmissionor within48hoursfromaprevioushospitaldischarge.Enterobacterales wereidentifiedusingstandardmicrobiologicaltechniquesateach center.ESBLproductionwasscreenedinallisolateswithdiminished susceptibilitytothird-generationcephalosporins—akeyphenotypic propertyofESBLenzymes—andconfirmedbystandardmethods.22 Susceptibilitywasstudiedusingautomatedsystemsordiskdiffusion andinterpretedaccordingtotheguidelines(ClinicalandLaboratory StandardsInstitute[CLSI]orEuropeanCommitteeonAntimicrobial SusceptibilityTesting[EUCAST])appliedateachcenter.23,24Isolates wereconsideredtobeESBLproducersifatleastonephenotypic confirmatorytestwaspositiveaccordingtothecorrespondingCLSI orEUCASTcriteriaapplicableatthetimeoftesting,oriftheyhad beencharacterizedbyPCRandDNAsequencingusingestablished methods. Active therapywasdefinedasadministrationofatleastone antimicrobial agent to which the isolate showed susceptibility in vitro, at the standard dose and frequency.12 Specifically, standardintravenousdosingregimensforthemostcommonantimicrobials administered were as follows: piperacillin-tazobactam, 3/0.375gto4/0.5g every6-8hours;meropenem,1-2gevery 8hours;ertapenem,1gevery24hours;andimipenem-cilastatin, 500/500mgto1/1gevery6-8hours.Alldoseswereadjustedto renalfunction.Thetherapywasconsideredtobeinactiveifthe isolate was non-susceptible to the agent(s) administered or the dosing was inappropriate. Monotherapywasdefinedastheadministrationofasingleactivedrugforatleast48hours(exceptfor patientswhodiedinlessthan48hours,andwhowereincluded iftheyreceivedatleastonecompletedayoftherapy).Thedefinitioncriteriaforcombination antibiotic therapy(ie,simultaneous administrationoftwoormoreactivedrugs)variedaccordingto thetimeelapsedsincetheinitiationoftreatment,inordertoaccountforchangesinantimicrobialtherapyduringthecourseofBSI (fromempiricaltotargetedtherapy).Forthefirst24or72hours from the onsetofBSI,combinationtherapywasdefined asthe administrationoftwoormoreactiveantimicrobialagentsforat least24hours.Fortherapyadministeredwithinthefirst7days, thedefinitionrequiredtheuseoftwoormoreactiveagentsfor atleast72hours.Source controlincludedatleastoneofthefollowingmeasures:surgicaldebridement(eg,laparotomyfororgan/ space surgical site infection), non-surgical debridement (eg, imaging-guideddrainageofperinephricabscessorinfectedkidney cyst),and/orremovalorreplacementofurinarycatheter.Toavoid confoundingbyindicationbias,onlythosesourcecontrolproceduresperformedbeforethetimeofoutcomeassessment(ie,days 7and30fortheprimaryandsecondaryoutcomes,respectively) were taken into account. Severity of infection and comorbidity burdenwereassessedbymeansofthePittbacteremiascore,25 the age-adjustedCharlsoncomorbidityindex(CCI),26andtheMcCabe score.27Thediagnosisofcytomegalovirus (CMV) infectionrequired thepresenceoflaboratory-confirmedCMVreplicationbyeither pp65antigenemiaassayorPCR-basednucleicacidamplification testing. CMV diseasewasdefinedasevidenceofCMVreplication with attributable symptoms.28 2.3 | Statistical analysis Continuousvariableswerepresentedasthemean± standard deviation(SD)orthemedianwithinterquartilerange(IQR).Categorical datawere expressed asabsolute andrelativefrequencies.The χ2 testorFisher'sexacttestwereusedtocomparecategoricalvariables,asappropriate.TheStudent'st-testorMann-WhitneyU test wereappliedforcontinuousvariables.Univariateandmultivariable logisticregressionmodelswereappliedtoidentifyfactorspredictingtherapeuticfailure.Foranalysisoftherapeuticfailureatdays7 and30(primaryandsecondaryoutcomes),weexploredtheimpact oftheantibioticregimenadministeredwithinthefirst72hoursfrom theonsetofBSI.Furthersensitivityanalyseswereperformedaccordingtotheregimenusedduringthefirst24hours(forprimary andsecondaryoutcomes)and7days(forthesecondaryoutcome only).Ateachofthesewindows,therapeuticregimenswereclassifiedintooneofthefollowingmutuallyexclusivecategories:active versus inactive therapy; combination therapy versus monotherapy; carbapenem-containingversusotheractiveregimens;andcarbapenemversusBLBLImonotherapy.Absoluteriskdifferenceswith95% confidenceintervals(CIs)weredeterminedwiththeallegedlymore effectiveregimen(ie,combinationtherapy,carbapenem-containing regimen,andcarbapenemmonotherapy)asthereference. Associations were given as odds ratios (ORs) and 95% CIs. Multicollinearityamongexplanatoryvariableswasanalyzedusingthe varianceinflationfactor(VIF).TheHosmer-Lemeshowtestwasused toassessthegoodness-of-fitofthemodels.Thirty-daysurvivalcurves wereplottedbytheKaplan-Meiermethodanddifferencesrelatedto therapeuticregimenswerecomparedwiththelog-ranktest. Topartiallyovercomethelimitationposedbythenon-random- izeddesignofthestudy,wecalculatedthepropensityscores(PS)for receivingeitherthecarbapenem-containingtherapy(vsanyother | 5 of 16 PIERROTTI ET al activeregimen)ortheBLBLI-based(vscarbapenem-based)monotherapy,withinthefirst72hoursandgiventhepatient'sbaseline characteristics and the clinical features at BSI presentation. Both scoreswereestimatedbymeansofbackwardstepwiselogisticregression models including variables with P-values< 0.1 in the univariateanalysis(TablesS1andS2),andthefitoftheresultingmodels was assessed by means of the area under the receiving operator characteristics curve (auROC). PS were entered as a covariate in multivariablemodelstoadjustforpotentialconfoundingbyfactors influencingthechoiceoftherapy. StatisticalanalysiswasperformedwithSPSSversion20.0(IBM Corp.)andgraphsweregeneratedwithPrismversion6.0(GraphPad SoftwareInc). 3 | RESULTS 3.1 | Characteristics of the study population Overall,306episodesofESBL-EBSIoccurringin306KTRswere included from 30 centers in14 countries.The clinical and microbiologicalfeaturesareshowninTable1.Themedianintervalfrom transplantationtoBSIonsetwas119days,and23.2%oftheepisodesoccurredwithinthefirstmonth.Themedianlengthofstay was16days(9-33.5).Mostpatientswerereceiving triplemaintenanceimmunosuppressionconsistingofcorticosteroids,tacrolimus, and mycophenolic acid or mycophenolate mofetil. Regarding the ESBL-Eidentified,Escherichia coli(62.1%)andKlebsiellaspp.(35.0%) accountedforthemajorityofcases. Therapeutic failure at days 7 and 30 (primary and secondary outcomes) occurred in 8.2% (25/306) and 13.4% (41/306) of patients.All-causemortalityratesatdays7and30were1.0%(3/306) and2.9%(9/306),respectively.Allbutonedeathwereconsidered attributabletoESBL-EBSI.Theratesofcureandclinicalimprovementwere2.6%(8/206)and89.2%(273/306)byday7,and77.5% (237/306)and9.2%(28/306)byday30,respectively. Thetherapeuticregimensgivenatdifferenttimeintervalsare detailed in Table 2. Most patients received active therapy with carbapenemmonotherapy(144[47.1%]forthefirst24hours,210 [68.6%]forthefirst72hours,and237[77.5%]forthefirst7days fromBSIonset),whereasBLBLImonotherapy(mostlypiperacillin-tazobactam)waschosen inabout 10% of cases.Piperacillintazobactamwasmostcommonlyadministeredatdosesof4/0.5g every8hours(46.7%[14/30])and2/0.25gevery8hours(20.0% [6/30]).Theuseofcombinationantibiotictherapywasanecdotal. Twenty-onepatients(6.8%)receivedduringthefirst72hoursan antibioticthatlackedinvitroactivityagainsttheisolate,which mainly included second- or third-generation cephalosporins (10 patients[47.6%]),piperacillin-tazobactam(eightpatients[38.1%]), orquinolones(twopatients[9.5%]).Withinthesubgroupofpatientswhoreceivedmonotherapyduringthefirst72hoursfrom BSIonset,5.0%(13/261)weresubsequentlytransitionedtoasecond active antibiotic. 3.2 | Risk factors for therapeutic failure Univariateandmultivariableanalysesoffactorspredictingtherapeuticfailureatday7(primaryoutcome)areshowninTable3. Attheunivariatelevel,recipientgender,timeintervalfromtransplantation to BSI onset, use of trimethoprim-sulfamethoxazole prophylaxis, presence of urinary stenosis, hospital-acquired infection, acuterejectionwithin theprior month, Pitt bacteremia score,andthedegreeofsepsisseveritywereassociatedwiththis outcome.SincethePittscoreandthepresenceofsepticshock exhibitedsignificantmulticollinearity(VIFvalues>1.5),onlythe formervariablewasincludedintothelogisticregressionmodel. Thepresence ofhospital-acquired BSI(OR:4.10;95%CI:1.50- 11.20; P-value =0.006)andthePittbacteremiascoreatBSI onset(OR[perone-pointincrease]:aOR:1.47;95%CI:1.21-1.77; P-value<0.0001)remainedasindependentpredictorsfortherapeuticfailureatday7. Age-adjusted CCI (OR [per one-point increase]: 1.25; 95% CI: 1.05-1.48;P-value=0.010),Pittscore(OR[perone-pointincrease]: 1.72; 95% CI: 1.35-2.17; P-value <0.0001), and an absolute lymphocytecount≤500cells/μLatBSIonset(OR:3.16;95%CI:1.42- 7.06;P-value=0.005)wereindependentpredictorsfortherapeutic failureatday30(Table4).Therewerenosignificantdifferencesin 30-daysurvivalbetweenpatientsreceivingornotreceivingactive therapywithinthefirst24(98.3%vs95.3%,respectively;log-rank test P-value=0.365)or72hours(100.0%vs95.9%;log-ranktest P-value=0.293)fromtheonsetofBSI. 3.3 | Impact of different therapeutic regimes on study outcomes Theimpactonstudyoutcomesofdifferentregimenswasnextinvestigatedwithinthesubgroupofparticipantswhoreceivedactivetherapy.First,wecomparedtheincidenceoftherapeuticfailureatday7 (primaryoutcome)inpatientsreceivingcombinationtherapyversus monotherapy during thefirst 72 hours from the onset ofBSI, with no significant differences found between both groups (8.3% [1/12] vs8.4%[22/261],respectively;riskdifference:0.06%;95%CI:−0.15- 0.16;unadjustedOR[uOR]:0.99;95%CI:0.12-8.01;P-value=0.991) (Figure1A).Therewerenosignificantdifferencesintheoccurrenceof therapeuticfailureatday30(secondaryoutcome)either(16.7%[2/12] vs13.0%[34/261];riskdifference:−3.63%;95%CI:−0.23-0.16;uOR: 1.34;95%CI:0.28-6.36;P-value=0.717)(Figure1B).Next,weevaluatedtheimpactofusingacarbapenem-containingregimenversusany otheractiveregimenduringthefirst72hours.Nosignificantdifferenceswereobserved,eitheratday7(8.7%[19/219]vs7.4%[4/54]; riskdifference:−1.27%;95%CI:−0.09-0.07;uOR:1.18;95%CI:0.39- 3.65; P-value=0.764)(Figure2A)orday30(13.7%[30/219]vs11.1% [6/54]; risk difference: −2.59; 95% CI: −0.13-0.07; uOR: 1.27; 95% CI:0.50-3.23;P-value=0.615)(Figure2B).Finally,wecomparedthe riskoftherapeuticfailurebetweenpatientstreatedwithcarbapenem monotherapyversusBLBLImonotherapy.Onceagain,weobservedno 6 of 16 | PIERROTTI ET al significantdifferencesatday7(9.0%[19/210]vs3.0%[1/33];riskdifference:−6.01%;95%CI:−0.16-0.04;uOR:3.18;95%CI:0.41-24.62; P-value=0.267)(Figure2A)orday30(13.8%[29/210]vs9.1%[3/33]; riskdifference:−4.72%;95%CI:−0.17-0.08;uOR:1.60;95%CI:0.46- 5.59; P-value=0.459)(Figure2B)betweenboththerapeuticmodalities.Inaddition,therewerenosignificantdifferencesinhospitalstay betweenanyofthesetherapeuticregimens(TableS3). TABLE 1 Clinicalcharacteristicsofthestudycohort Variable (n = 306) Patient-relatedvariables Age,years[mean± SD] 56.6 ± 13.9 Malegender[n(%)] 163(53.3) Geographicarea[n(%)] Europe 190(62.1) Asia 56(18.3) SouthAmerica 18(5.9) NorthAmerica 17(5.6) Israel 25(8.2) McCabescore[n(%)] Non-fatal 230(75.2) Ultimatelyfatal 61(19.9) Rapidlyfatal 15(4.9) Age-adjustedCCI[median(IQR)] 4(3-6) Majorpre-transplantcomorbidities[n(%)] Diabetes 152(49.7) Coronaryheartdisease 45(14.7) Congestiveheartfailure 37(12.1) Liverdisease 31(10.1) Chronicpulmonarydisease 25(8.2) Transplant-relatedvariables TimefromtransplantationtoBSIonset,days [median(IQR)] 119(35.3-1.378) BSIwithinthefirstpost-transplantmonth [n(%)] 71(23.2) Simultaneouskidney-pancreas transplantation[n(%)] 5(1.6) Inductiontherapy[n(%)] Basiliximab 110(35.9) Anti-thymocyteglobulin 82(26.8) MaintenanceimmunosuppressionatBSIonset[n(%)] Corticosteroids 275(89.9) Tacrolimus 242(79.1) Cyclosporine 51(16.7) Mycophenolicacid/mycophenolatemofetil 244(79.7) Azathioprine 22(7.2) mTORinhibitor 26(8.5) TMP/SMXprophylaxiswithintheprior month[n(%)] 163(53.3) UrinarystenosisatBSIonset[n(%)] 55(18.0) ICUadmissionwithinthepriormonth[n(%)] 37(12.1) Dialysiswithinthepriormonth[n(%)] 65(21.2) CMVinfectionwithinthepriormonth[n(%)] 31(10.1) CMVdiseasewithinthepriormonth[n(%)] 15(4.9) Acutegraftrejectionwithinthepriormonth [n(%)] 30(9.8) (Continues) Variable (n = 306) BSIepisode-relatedvariables Hospital-acquiredBSI[n(%)] 127(41.5) Pittbacteremiascore[median(IQR)] 0(0-2) Hemodynamicseverity[n(%)]a Severe sepsis 36(12.6) Septicshock 13(4.5) Lymphocytecountatpresentation≤500 cells/μL[n(%)]b 117(39.9) Microbiologicalresults[n(%)] Escherichia coli 190(62.1) Klebsiella spp. 107(35.0) Enterobacter spp. 4(1.3) Other 5(1.6) Treatment-relatedvariablesandoutcomes BSIsourcecontrol[n(%)] 113(36.9) Surgical debridement 26(8.5) Non-surgicaldebridement 44(14.4) Removal/replacementofurinarycatheter 67(21.9) TimetoBSIsourcecontrol,days[median (IQR)]c 3(0-9) Overalldurationoftherapy,days[median (IQR)]d 14(12-21) Durationofactivetherapy,days[median (IQR)]d 14(11-20) Timetoactivetherapy,days[median(IQR)] 0(0-1) Lengthofstay,days[median(IQR)] 16(9-33.5) Therapeuticfailure[n(%)] Atday7(primaryoutcome) 25(8.2) Atday30(secondaryoutcome) 41(13.4) All-causemortality[n(%)] Atday7(primaryoutcome) 3(1.0) Atday30(secondaryoutcome) 9(2.9) Note: BSI,bloodstreaminfection;CCI,age-adjustedCharlson comorbidityindex;CI,confidenceinterval;CMV,cytomegalovirus; ICU,intensivecareunit;IQR,interquartilerange;mTOR; mammaliantargetofrapamycin;SD,standarddeviation;TMP/SMX, trimethoprim-sulfamethoxazole. aDatanotavailablefor20patients. bDatanotavailablefor13patients. cDatanotavailablefor36patients. dDatanotavailablefor3patients. TABLE 1 (Continued) | 7 of 16 PIERROTTI ET al 3.4 | Propensity score-adjusted analysis Next,weappliedaPS-basedapproachtoinvestigatewhetherthe therapeuticregimenadministeredwithinthefirst72hoursfromBSI onsetinfluencedstudyoutcomes.ThefollowingvariableswereincludedinthePSfortheuseofacarbapenem-containingregimen: geographicalarea(EuropeorNorthAmericavsothersites),simultaneous kidney-pancreas transplantation, certain pre-transplant chronic conditions (diabetes, liver disease, congestive heart failure,andchronicpulmonarydisease),CMVdiseasewithintheprior month,andpresenceofarapidlyorultimatelyfataldiseaseaccordingtotheMcCabescore(TableS1).TheauROCoftheresultingPS was0.738(95%CI:0.664-0.812).Theriskoftherapeuticfailureat day7(PS-adjustedOR:4.66;95%CI:0.58-37.28;P-value=0.147)or atday30(PS-adjustedOR:2.13;95%CI:0.55-8.20;P-value=0.274) wasnotfoundtobesignificantlyaffectedbytheuseofacarbapenem-containingregimenversusanyotheractiveregimen.Inaddition,wefurtheradjustedbythedegreeofsepsisseverity(Pittscore andpresenceofsepticshock)andcomorbidityburdenindifferent regressionmodels,sincetherelativelylownumberofpatientssuffering from therapeutic failure at either point was insufficient to performasinglemultivariableanalysiswithoutincurringinmodel overfitting.Noneoftheseadjustmentssuggestedariskdifference accordingtotheuseofacarbapenem-containingtherapyoranalternativeregimen(FigureS1). This methodological approach was also applied to compare theuseofBLBLIversuscarbapenemwithinthesubgroupofpatientstreatedwithmonotherapyinthefirst72hoursfromBSI onset.ThevariablesincludedinthePSfortheuseofcarbapenem-basedmonotherapyascomparedtoBLBLI-basedmonotherapywere:geographicalarea(EuropeorNorthAmericavsother studysites),pre-transplantchronicconditions(congestiveheart failureandchronicpulmonarydisease),presenceofarapidlyor ultimatelyfataldiseaseaccordingtotheMcCabescore,andreceiptofactivetherapywithinthefirst24hours(TableS2).The auROCofthescorewas0.794(95%CI:0.719-0.869).Again,neithertheriskoftherapeuticfailureatday7(PS-adjustedOR:4.36; 95%CI:0.51-37.38;P-value=0.179)orday30(PS-adjustedOR: 2.59;95%CI:0.66-10.21;P-value=0.175)appearedtobeinfluencedbythechoiceofcarbapenem-basedversusBLBLI-based monotherapy(FigureS2). 3.5 | Sensitivity analysis Finally, to evaluate the consistency of these findings, we investigatedtheimpactoftherapyadministeredduringtimeperiodsother thanthe72-hourwindow.Therewerenosignificantdifferencesin the incidence of7-day and 30-day therapeuticfailure amongdifferenttherapeuticregimensadministeredwithinthefirst24hours fromBSI(FiguresS3andS4,TableS4).Nosignificantdifferences werefoundin30-daytherapeuticfailureaccordingtothetypeof therapyusedwithinthefirst7dayseither(FigureS5,TableS4). 4 | DISCUSSION Inthepresentstudy,wewerenotabletodetectsignificantdifferencesintheriskoftherapeuticfailure(lackofcureorclinical improvement and/or death from any cause) among KTRs with ESBL-EBSIsecondarytoUTIthatweretreatedwithcarbapenem- or BLBLI-based regimens. Absolute risk differences observed weresmall(rangingfrom−6.01%to0.06%)andofquestionable relevance froma clinicalperspective.AlthoughcurrentconsensusstatementsfavorBLBLI-basedregimensfornon-severeESBL infections,29,30 such recommendations are supported by limited data.Ourresearchwouldreinforcepreviousstudiessuggesting thatBLBLImonotherapymaybeaseffectiveasacarbapenemto treatESBL-EBSI,particularlyforlow-inoculuminfectionsinnoncritically ill patients.14-17 The very low number of KTRs within the BLBLI group that receivedamoxicillin-clavulanicacid(n=2)implythatourresults aremostlyapplicabletopiperacillin-tazobactam,inlinewithother studiesperformedinthenon-transplantpopulation.16,17 Whether bothBLBLIsareequallyeffectivefortreatingESBL-Eremainsdebatable,althoughapotential“inoculumeffect”hasbeenproposed for piperacillin-tazobactam but not for amoxicillin-clavulanic acid.31Inaddition,variationshavebeenreportedintheratesof susceptibilitytopiperacillin-tazobactamaccordingtothespecific ESBLenzymeinvolved,withhigheractivityforCTX-M-14-likeenzymesascomparedtootherβ-lactamases(suchasCTX-M-15-like, CMY-like,OXA-1,orSHVenzymes).32Itshouldbenotedthatthe CLSIandEUCASTguidelinesdifferintheinterpretativecriteriafor categorizinganisolateassusceptibletopiperacillin-tazobactam, withminimuminhibitoryconcentration(MIC)breakpointssetat ≤16mg/Land≤8mg/L,respectively.Giventheretrospectivedesignofthestudy,suchadiscrepancycomplicatesdataaggregation acrosscenters.Indeed,ifwefocusedonepisodestreatedwithpiperacillin-tazobactammonotherapyduringthefirst72hours,67.7% (21/31)and32.3%(10/31)oftheisolateshadbeentestedbythe CLSIandEUCASTmethods. Toourknowledge,thisis thefirst studytocomparetheefficacyofcarbapenemsandBLBLIforESBL-EBSIinthespecific settingofSOT.Immunocompromisedindividualswereincludedin asystematicreviewandmeta-analysisthatdemonstratedcomparablemortalityratesforpatientswithESBL-EBSItreatedwithcarbapenems or other regimens.14Nonetheless,mostofthemwere diagnosedwithmalignancyandneutropenia,withonlyalownumberofSOTrecipients.33Inlinewiththesefindings,arecentinternationalstudyinneutropenichematologicalpatientswithESBL-E BSIalsofailedtodemonstratedifferencesbetweencarbapenems andBLBLI.34 In contrast with our results and most of the previously reportedstudies,resultsfromamulticenter,open-label,randomized non-inferiority trial of piperacillin-tazobactam versus meropenem forthedefinitivetreatmentofBSIcausedbyceftriaxone-resistant E. coli or K. pneumoniaedidnotsupporttheuseofBLBLIasacarbapenem-sparingoption.20Incontrasttothepresentstudy,about 8 of 16 | PIERROTTI ET al onethirdoftheparticipantsintheMERINOtrialhadnon-urinary sources,andtheriskdifferencefor30-daymortalityinthissubgroup was sensibly higher than that observed among patients with BSI fromurinarysource(14.1%vs3.7%,respectively).Previousstudies havedemonstratedpooreroutcomesininfectionsfromnon-urinary sourcestreatedwithpiperacillin-tazobactam-basedregimens.35,36 Theabsenceofdemonstrabledifferencesintheratesoftherapeuticfailureatdays7and30amongpatientsreceivingBLIBLversuscarbapenemsmustbeinterpretedwithparticularcaution,given thelownumberofpatientstreatedwithBLBLIandthesubsequent riskofinadequatepowertorejectthenullhypothesis.Alternative carbapenem-sparingactiveregimensotherthanBLBLIwereusedin asmallproportionofpatients,whichprecludesconclusionsabout theirpotentialefficacyforthetreatmentofpost-transplantESBL-E BSI of urinary origin. In addition, we found no differences in the ratesoftherapeuticfailurebetweenpatientstreatedwithcombinationtherapyormonotherapy,regardlessofthetimeelapsedfrom theonsetofBSItotheinitiationofaninvitroactiveagent. Thelowmortalityratesobserved(1.0%atday7and2.9%atday 30)wereconsistentwiththosepreviouslypublishedamongKTRs, whichrangedfrom2.5%to11%,36,37 and would have contributed tothequiteunexpectedlackofapparentimpactintermsofworse outcomesofnotreceivingactivetherapy.Theimprovedoutcomes reportedforBSIfromurinarysourcemaybeexplainedbythepresence of a lower inflammatory response and the higher antibiotic concentrationtypicallyreachedintheurinarytract.Althoughthe developmentofsepticshockrepresentsamajorpredictorofmortality,36KaliletalshowedthatmortalitywasactuallylowerinSOT recipients with bacteremic sepsis compared with non-transplant patients, suggesting that post-transplant immunosuppression may provideasurvivaladvantagethroughmodulationoftheinflammatory response.38Ontheotherhand,theoverallfavorableoutcomes foundinourstudymayreflecttheoccurrenceofalesssevereinfection,consistentwiththelowage-adjustedCCI(medianof4)andPitt bacteremia(medianof0)scorevalues,andthesmallproportionof patientswithrapidlyfataldisease(4.9%). Inthemultivariableanalysis,hospital-acquiredinfectionand Pittscorewereassociatedwithanincreasedoddsoftherapeutic failureatday7.Ontheotherhand,age-adjustedCCI,Pittscore,and thepresenceoflymphopenia(≤500cells/μL)atpresentationwere associatedwiththerapeuticfailureatday30.Surprisingly,despite thehighrateofinadequate(non-active)initialempiricantimicrobialtherapywithinthefirst24and72hours(37.9%and10.8%,respectively),thisvariablewasnotassociatedwithaworseoutcome ineitherunivariateormultivariablemodels.Previousstudieshave alsoreportedhighratesofinadequateinitialantimicrobialtherapy totreatESBL-EBSIintheoverallpopulation,39-41 which may reach upto60%instudiestargetingtheSOTpopulation.6 Some previousstudiesreportedthat,followingmultivariateadjustment,inappropriate initial empiric therapy was not associated with increased mortalityafterSOT,6althoughinadequatelytreatedUTIepisodes exertedadeleteriousimpactongraftfunctionandpatientsurvival amongKTRs.3,5Again,suchalowmortalityratemayberelated tothelowerinflammatoryresponseinthesepatientscompared to non-transplant patients. Unfortunately, we lack data on the medium-andlong-termevolutionofrenalgraftfunctionbetween patientsreceivingandnotreceivingadequatetherapy,although nosignificantdifferenceswerefoundintheoveralllengthofstay (whichmayserveasaproxyforthedevelopmentofacutekidney injuryortherequirementofrenalreplacementtherapyduringthe incidenthospitalization). Carbapenemmonotherapy(primarilymeropenem)wasthemost frequentactivetherapyused,followedbyBLBLI(mostlypiperacillin-tazobactam).Toovercomethelimitationposedbythenon-ran- domizedretrospectivedesign,PS-adjustedanalysesforreceivingthe front-lineandintuitively“morepotent”therapy(carbapenem-con- tainingorcarbapenem-basedregimens)versusthe“alternative”less TABLE 2 Descriptionoftherapeuticregimensadministered Therapeutic regimen [n (%)] Time interval from BSI onset 24 hours 72 hours 7 days Activetherapy 190(62.1) 273(89.2) 298(97.4) Monotherapy 179(58.5) 261(85.3) 287(93.8) Carbapenem 144(47.1) 210(68.6) 237(77.5) Meropenem 76(24.8) 105(34.3) 109(35.6) Ertapenem 46(15.0) 72(23.5) 94(30.7) Imipenemcilastatin 22(7.2) 33(10.8) 32(10.5) BLBLI 22(7.2) 33(10.8) 32(10.5) Piperacillintazobactama 20(6.5) 31(10.1) 30(9.8) Amoxicillinclavulanic acid 2(0.7) 2(0.7) 2(0.7) Quinolone 5(1.6) 9(2.9) 10(3.3) Aminoglycoside 3(1.0) 3(1.0) 1(0.3) Otherb 5(1.6) 6(2.0) 6(2.0) Combinedtherapy 10(3.3) 12(3.9) 11(3.6) Carbapenemcontaining 7(2.3) 9(2.9) 9(2.9) Othercombinationsc 3(1.0) 3(1.0) 2(0.7) Inactivetherapy 116(37.9) 33(10.8) 8(2.6) Inactiveagentin vitro 59(19.3) 21(6.8) 3(1.0) Noantibiotic administered 57(18.6) 12(3.9) 5(1.6) Note: BLBLI,β-lactam/β-lactamaseinhibitor;BSI,bloodstreaminfection. aPiperacillin-tazobactamwasadministeredatthefollowingdoses: 4/0.5gevery8hours(n=14),2/0.25gevery8hours(n=6),2/0.5g every6hours(n=3),4/0.5gevery12hours(n=2),3/0.375gevery 6hours(n=2),4/0.5gevery24hours(n=1),unknown(n=2). bOthermonotherapyregimensusedwithinthefirst24hoursincluded cefepime(n=3),trimethoprim-sulfamethoxazole(n=2),andtigecycline (n=1). cOthercombinationregimensusedwithinthefirst24hoursincluded BLBLIplusaminoglycoside(n=1)orquinolone(n=1),andceftazidime plusquinolone(n=1). | 9 of 16 PIERROTTI ET al TABLE 3 Univariateandmultivariableanalysesoffactorsfortherapeuticfailureatday7(primaryoutcome) Therapeutic failure at day 7 (n = 25) No therapeutic failure at day 7 (n = 281) Univariatef Multivariableg OR 95% CI P-value OR 95% CI P-value Age,years[mean± SD] 57.2±17.3 56.6 ±13.7 Malegender[n(%)] 18(72.0) 145(51.6) 2.41 0.98-5.96 0.056 Timeintervalfrom transplantation,days[median (IQR)] 68(23-194) 133(36-1,543) 1.00 0.99-1.00 0.073 BSIwithinthefirstposttransplantmonth[n(%)] 7(28.0) 64(22.8) Inductiontherapywithantithymocyteglobulin[n(%)] 9(36.0) 73(26.0) TMP/SMXprophylaxiswithinthe priormonth[n(%)] 18(72.0) 145(51.6) 2.41 0.98-5.96 0.056 Urinarystenosis[n(%)] 9(36.0) 46(16.4) 2.87 1.19-6.89 0.018 - - - ICUadmissionwithintheprior month[n(%)] 6(24.0) 31(11.0) Dialysis within the prior month [n(%)] 9(36.0) 56(19.9) CMVinfectionwithintheprior month[n(%)] 5(20.0) 26(9.3) CMVdiseasewithintheprior month[n(%)] 3(12.0) 12(4.3) Hospital-acquiredBSI[n(%)] 19(76.0) 108(38.4) 5.07 1.96-13.10 0.001 4.10 1.50-11.20 0.006 Acutegraftrejectionwithinthe priormonth[n(%)] 6(24.0) 24(8.5) 3.38 1.23-9.27 0.018 - - - Age-adjustedCCI[median(IQR)] 5(3-6) 4(2-6) Rapidlyorultimatelyfatal McCabescores[n(%)] 10(40.0) 66(23.5) PittbacteremiascoreatBSIonset [median(IQR)] 2(0-4.5) 0(0-1) 1.50d 1.24-1.82 <0.0001 1.47d 1.21-1.77 <0.0001 SepticshockatBSIonset[n(%)]a 6(24.0) 7(2.6) 11.82e 3.61-38.69 <0.0001 Lymphocytecount≤500cells/μL atBSIonset[n(%)]b 14(56.0) 103(38.4) Surgical debridement within the first7days[n(%)] 2(8.0) 11(3.9) Non-surgicaldebridement[n(%)] 6(24.0) 38(13.5) (Continues) 16 of 16 | PIERROTTI ET al Enterobacteriaceae. 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