Role of procalcitonin in predicting etiology in bacteremic patients: Report from a large single-center experience

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Contents lists available atScienceDirect

Journal

of

Infection

and

Public

Health

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

Role

of

procalcitonin

in

predicting

etiology

in

bacteremic

patients:

Report

from

a

large

single-center

experience

Matteo

Bassetti

∗

,

Alessandro

Russo,

Elda

Righi,

Elisabetta

Dolso,

Maria

Merelli,

Federica

D’Aurizio,

Assunta

Sartor,

Francesco

Curcio

DepartmentofMedicine,UniversityofUdineandAziendaSanitariaUniversitariaIntegrata,Udine,Italy

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received11February2019

Receivedinrevisedform29April2019 Accepted8June2019 Keywords: Procalcitonin C-reactiveprotein Bacteremia Gram-negative Enterobacteriaceae

a

b

s

t

r

a

c

t

Background:Procalcitonin(PCT)isroutinelyusedforanearlyrecognitionofsevereinfectionsandfor promotingappropriateuseofantibiotics.However,limiteddatacorrelatingvaluesofPCTwithetiology ofinfectionhasbeenreported.

Methods:During2016,allpositivebloodcultures(BC)wereretrospectivelyextractedina1100-beds Italiantertiary-carehospital.PCTandC-reactiveprotein(CRP)valueswererecordedwithin24hfromBC collection.PrimaryendpointofthestudywastoinvestigatethecorrelationbetweenPCTandCRPvalues andtheoccurrenceofbloodstreaminfections(BSI)causedbybacteriaorfungi.

Results:Duringthestudyperiod,1296positiveBCwereincluded:712(54.9%)duetoGram-positive (GP),525(40.5%)duetoGram-negative(GN)strains,and59(4.6%)causedbyfungi.AmongGNisolates, enterobacteriaceaewerereportedin453(86.3%)cases.PCTvalueswerehigherinpatientswithGN etiology(26.1±14.2ng/mL)comparedtoGP(6.9±4.5)andfungi(3.3±2.4).MeanvaluesforCRPinGN, GP,andfungiwerenotdifferent.ReceiverOperatingCharacteristic(ROC)curvesshowedanareaunder curve(AUC)of0.71forPCTand0.51forCRPamongGNisolates;anAUCof0.7forPCTand0.52forCRP amongenterobacteriaceae.LowerAUCforPCTwerereportedforGPandfungi.

Conclusions:PCTshowedmoderateperformanceinearlydetection(within24h)ofGram-negative infec-tions,especiallythose causedbyenterobacteriaceae.Furtherprospective studiesaremandatoryto conﬁrmtheseobservations.

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

Introduction

Rapid identification of bacterial infections and early initia-tionofantibioticregimensarerecognizedasindependentfactors associated withfavorable outcome [1–3];therefore, immediate recognition of sepsis may be essential to start an appropriate antibioticregimen[4,5].However,inclinicalpracticearapid iden-tificationofpathogensisoftendelayedduetoavailablestandard microbiologicaltests.Theearlyidentificationofetiologiesiscrucial toovercometreatmentdelaysandinappropriatetherapies[6].

Procalcitonin(PCT)isabiomarkerwithapotentialrolein diag-nosisandprognosisofbacterialinfections,sinceitsvaluesappeared

∗ Correspondingauthorat:ClinicaMalattieInfettive,AziendaSanitaria Univer-sitariaIntegratadiUdine,PresidioOspedalieroUniversitarioSantaMariadella Misericordia,PiazzaleSantaMariadellaMisericordia15,33100Udine,Italy.

E-mailaddresses:matteo.bassetti@asuiud.sanita.fvg.it,

matteo.bassetti@uniud.it(M.Bassetti).

strictlycorrelatedwiththedevelopmentofseverebacterial infec-tions[7–9].SystematicuseofPCThasbeenproposedaspartofthe initialdiagnosticpathwayandformonitoringantibiotictreatment responseandduration,especiallyincriticallyillpatients[10,11].

RecentstudiesshowedthepotentialroleofPCTfor discriminat-ingbetweensevereinfectionscausedbyGram-negative(GN)and Gram-positive(GP)bacteriaandfungi[12,13].

Aim ofthis studywasevaluation ofPCT levelsin predicting occurrenceofBSIduetoGN,especiallyenterobacteriaceae,GP,and fungiinalargepopulationofpatientswithpositivebloodcultures (BC).

Materialsandmethods

Designofthestudy

Allpositive BC were retrospectivelyextracted, from January 1sttoDecember31st2016,ata 1100-bedsteachinghospitalin Udine,Italy.MicroorganismsdetectedinBCwereconsideredas

https://doi.org/10.1016/j.jiph.2019.06.003

1876-0341/©2019TheAuthors.PublishedbyElsevierLimitedonbehalfofKingSaudBinAbdulazizUniversityforHealthSciences.Thisisanopenaccessarticleunderthe CCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

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clinicallyrelevantpathogensinfollowingconditions:(1)isolation ofa pathogenin≥2BC,consideredasetiology ofinfection; (2) detectionof pathogeninonesetofBC,butconsistentwith cul-turesfromothersuspectedfociofinfectionatthesametimeofBC collection;and(3)detectioninonesetofBC,reportedbyclinician ascauseofinfectionbasedonclinical,radiological,andlaboratory data.Coagulase-negativestaphylococci(CoNS)andotherskin com-mensalswerenotconsideredasetiologyofinfectionwhenisolated fromoneBCsetalone,andinabsenceofclinicaldatasupportinga pathogenicrole.ForeverypositiveBCsampleincludedinthestudy wereextractedPCTandC-reactiveprotein(CRP)valuesrecorded ±24hfromBCcollection.

Allmethodswerecarriedoutinaccordancewithlocaland inter-nationalguidelinesand regulations.Thestudywasapprovedby localethicalcommittee (Departmentof Medicine,University of Udine,PiazzaleSantaMariadellaMisericordia15,33100,Udine, Italy).AttimeofBCacquisition,aninformedconsentwasobtained fromallsubjects;ifsubjectswereunder18yearsfromaparent and/orlegalguardian.

Variablesanalyzed

Patient data were collected from medical charts and from hospitalcomputerized databases orclinical charts accordingto apre-establishedquestionnaire.Thefollowinginformationwere reviewed:demographics;clinicalandlaboratoryﬁndings; comor-bidconditions;microbiologicaldata;sourceofinfection;PCTand CRPvalues(±24hfromBCcollection);durationofintensivecare unit(ICU)andhospitalstay;thesimpliﬁedacutephysiologyscore (SAPSII);developmentofsepticshock;30-daymortality.

CRP,PCTandBCanalysis

PCT concentration was measured by using ADVIA Centaur® BRAHMS Procalcitonin assay on Advia Centaur XP instrument (SiemensHealthineers),withfunctionalsensitivityof0.02ng/mL; CRPconcentrationbyusingC-ReactiveProteingen.3(CRPL3)assay onCobasc702®instrument(Roche),withfunctionalsensitivityof 1mg/L.BCwereprocessedusingtheautomatedBDBACTECTMFX system(Becton-DickinsonMicrobiologySystems).

Primaryendpointandstatisticalanalysis

Primaryendpointofthestudywastoinvestigatethe correla-tionbetweenPCTandCRPvalues(±24hfromBCcollection)with pathogenscausingBSI.

Continuous variables are presented as mean±SD, and dif-ferences were evaluated by t-test. Categorical variables were expressedascountandpercentagesandcomparedbychi-square testorFisher’sexacttest,asappropriate.Weevaluated discrim-inationusingreceiveroperatingcharacteristiccurves(ROC).We comparedROCcurvesforCRPandPCTvalues.Thecalibrationofthe modelwasevaluatedbythegoodness-of-fitHosmer-Lemeshow ␹2_statistic._The_suggested_cut-off_values_were_determined_by_the Youdenindex;then,wecalculatedsensitivity,specificity,negative (NPV)andpositivepredictivevalues(PPV)forthecut-offpointof PCTandCRPinpredictingetiologyofinfection.Tocalculatethese valueswererandomlyextractedpatients,hospitalizedinthesame wardsduringthestudyperiod,withnegativeBCinwhichwere reportedCRPandPCTvalues±24hfromBCcollection.Finally,we performedlogisticregressionanalysisonCRPandPCTcut-off val-uespredictingetiologyofinfection.Alltestsweretwo-tailed,and aPvalue<0.05wasconsideredsignificant.Allcomputationswere carriedoutwithSPSS20.0forWindows(SPSSInc.,Chicago,IL).

Fig.1. Studyﬂowdiagram.

BC:bloodcultures;CoNS:coagulase-negativestaﬁlococci.

Fig.2.WardsofhospitalizationattimeofBCpositivity. BC:bloodcultures.

Results

Duringthestudyperiod4715BCresultedpositive.PositiveBC insameBCset(n=2926),patientswithonly1BCpositiveforCoNS (n=140),andpolymicrobialBC(n=353)wereexcluded(seeFig.1). Atotalof1296positiveBCwereretrieved:ofthese,695(53.6%) episodeswererecordedinmedicalwards,343(26.5%)insurgical wards,and258(19.9%)inICU,asreportedinFig.2.Finally,BCwere positivein712(54.9%)casesforGPstrains,in525(40.5%)forGN strains,andin59(4.6%)forfungi.

InTable1arereportedpathogensisolatedfromBCduringthe studyperiod:themostfrequentisolatewasEscherichiacoli(19.9%), followedbyStaphylococcusaureus(19.2%),andCoNS(16.9%); Can-didaalbicanswasisolatedin40(3.2%)samples.AmongGNisolates, enterobacteriaceaewerereportedin453(86.3%)cases.

AccordingwithetiologyofinfectioninTable2arereportedage, sex,comorbidities,sourceofinfection,lengthofhospitalandICU stay,severityofclinicalcondition,incidenceofsepticshock,and 30-daymortalityinthethreestudygroups.Differenceswereobserved aboutPCT concentrations,thatwerehigherin patientswithGN etiology(26.1±14.2ng/mL),ifcomparedtoGP(6.9±4.5ng/mL) andtofungal(3.3±2.4ng/mL)isolates.Conversely,similarmean valueswerereportedforCRPinGN,GP,andfungaletiology.

AsreportedinFig.3,ROCcurvesshowedanareaundercurve (AUC)of0.71(CI95%0.65–0.75,p<0.001)forPCTand0.51(CI95% 0.45–0.56,p=0.71)forCRPamongGNisolates(Fig.3-A);anAUCof 0.7(CI95%0.64–0.75,p<0.001)forPCTand0.52(CI95%0.46–0.58, p=0.4)forCRPamongenterobacteriaceae(Fig.3-B);anAUCof0.31 (CI95%0.26–0.36,p<0.001)forPCTand0.48(CI95%0.42–0.53,

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Table1

PathogensisolatedfromBCduringstudyperiod.

Etiologies N=1296(%) Escherichiacoli 258(19.9) Staphylococci -CoNS 218(16.9) -Staphylococcusaureus 247(19.2) Klebsiellaspp. 86(6.7) Enterococci -E.faecalis 58(4.5) -E.faecium 28(2.1) Candidaspp. -albicans 40(3.2) -non-albicans 16(1.2) Pseudomonasaeruginosa 42(3.2) Enterobacterspp. 42(3.2) Streptococcuspneumoniae 18(1.3)

Streptococcusgallolyticus(bovis) 14(1.1)

Proteusspp. 12(0.9) Corynebacteriumspp. 12(0.9) Serratiamarcescens 9(0.7) Streptococcuspyogenes 7(0.5) Stenotrophomonasmaltophilia 4(0.3) Acinetobacterbaumannii 2(0.1) Otheretiologies 183(14.1)

BC:bloodcultures;MDR:multidrug-resistant;MSSA:methicillin-sensitive Staphy-lococcusaureus;MRSA:methicillin-resistantStaphylococcusaureus.

p=0.53)forCRPamongGPisolates(Fig.3-C);anAUCof0.44(CI95% 0.33–0.55,p=0.39)forPCTand0.53(CI95%0.42–0.65,p=0.54)for CRPamongfungi(Fig.3-D).

Sensitivity,specificity,NPVandPPVofCRPandPCTinpredicting BCpositiveforGNstrainsandenterobacteriaceaearesummarized inTable 3.AmongGram-negativeisolates, a CRPvalue>5mg/L showedasensitivityof96.2%,aspecificityof6.2%,aNPVof7.6%, andaPPVof95.3%;aPCTvalue>0.5ng/mLshowedasensitivity of93.3%,aspecificityof29.8%,aNPVof79.5%,andaPPVof60.2%. Amongenterobacteriaceae,aCRPvalue>5mg/Lshoweda sensitiv-ityof95.4%,aspecificityof5.6%,aNPVof5.5%,andaPPVof95.4%; aPCTvalue>0.5ng/mLshowedasensitivityof97.9%,aspecificity

Table3

Sensitivity,speciﬁcity,NPVandPPVofCRPandPCTinBCpositiveforGram-negative strainsandenterobacteriaceae.

Sensitivity(%) Speciﬁcity(%) NPV(%) PPV(%) Gram-negative(n=525) CRP>5mg/L 96.2 6.2 7.6 95.3 PCT>0.5ng/mL 93.3 29.8 79.5 60.2 PCT>2ng/mL 76.7 50 73.4 54.5 PCT>10ng/mL 55 70.2 80.1 41.6 Enterobacteriaceae(n=453) CRP>5mg/L 95.4 5.6 5.5 95.4 PCT>0.5ng/mL 97.9 29.2 92.2 61.9 PCT>2ng/mL 81.2 49 76.2 56.4 PCT>10ng/mL 64.6 71.9 73.4 63

CRP:C-reactiveprotein;PCT:procalcitonin;NPV:negativepredictivevalue;PPV: positivepredictivevalue;BC:bloodcultures.

of29.2%,aNPVof92.2%,andaPPVof61.9%;aPCTconcentration >10ng/mLshowedasensitivityof64.6%,aspeciﬁcityof71.9%,a NPVof73.4%,andaPPVof63%.

Finally, logistic regression analysis performed on CRP and PCT values predictingpositivityof BCshowedthat a PCTvalue >10ng/mL(OR3.84,CI95%2.18–6.75,p<0.001)wasindependently associated withGNisolation, whilea PCTvalue >0.5ng/mL(OR 6.01,CI95%1.16–31.72,p=0.03),aPCTvalue>2ng/mL(OR2.52, CI95%1.28–3.96,p=0.03),andaPCTvalue>10ng/mL(OR3.88,CI 95%2.15–7.03,p<0.001)wereindependentlyassociatedwithBC positiveforenterobacteriaceae(seeTable4).

Discussion

Themainfindingsofthisanalysisconfirmrecentdataon bac-teremicpatientswithproven GNbacteremia,where higherPCT concentrations havea significantrole topredict GNetiology, if comparedwithpatientswithGPbacteremiaorfungalinfection.

TheassociationofGNbacteremiawithhighPCTconcentrations, reportedinouranalysis,isinlinewithotherstudiesperformed among different patient populations [12,14–23]. As previously

Table2

Clinicalcharacteristicsandoutcomeofpatientsaccordingwithetiologyofinfection.

Variables Gram-positive bacterialetiology n=712(%) Gram-negative bacterialetiology n=525(%) Fungaletiology n=59(%) Age,mean±SD 58.1±22.8 58.9±24.2 61.1±27.1 Malesex 350(49.1) 259(49.3) 28(47.4) Comorbidities

Chronicliverdisease 20(2.8) 16(3) 6(10.1)

Neoplasm 71(9.9) 68(12.9) 9(15.2)

Diabetes 163(22.8) 142(27.1) 22(37.2)

Heartfailure 247(34.7) 212(40.4) 15(25.4)

Coronaryarterydisease 101(14.2) 56(10.6) 6(10.1)

Chronicrenaldisease 86(12.1) 62(11.8) 8(13.5)

COPD 187(26.2) 141(26.8) 17(28.8)

Sourceofinfection

Primarybacteremia 268(37.6) 207(39.4) 22(37.2)

CVC-relatedbacteremia 110(15.4) 82(15.6) 10(16.9)

Pneumonia 302(42.4) 218(41.5) 0

Catheter-relatedurinarytract 103(14.4) 144(27.4) 16(27.1)

SSTI 101(14.2) 55(10.4) 0

Intra-abdominal 68(9.5) 66(12.5) 12(20.3)

Lengthofhospitalstay 31.2±27.1 33.6±24.2 29.3±26.5

LengthofICUstay,mean±SD 27.7±22.8 30.2±20.2 18.9±16.5

PCTconcentration(ng/mL),mean±SD 6.9±4.5 26.1±14.2 3.3±2.4

CRPconcentration(mg/L),mean±SD 127.1±113.1 126.9±99.4 122±98.9

SAPSIIattimeofinfectiononset,mean±SD 25.1±22.1 24.6±21.4 24.3±22.1

Sepsisorsepticshock 121(16.9) 92(17.5) 11(18.6)

30-daymortality 101(14.2) 102(19.4) 11(18.6)

SD:standarddeviation;ns:notsigniﬁcant;ICU:intensivecareunit;COPD:chronicobstructivepulmonarydisease;CVC:centralvenouscatheter;SSTI:skinandsoft-tissue infection;PCT:procalcitonin;CRP:c-reactiveprotein;SAPS:simpliﬁedacutephysiologyscore.

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Fig.3.ROCcurvesaboutPCTandCRPtopredictBCpositiveforGram-negative(A),enterobacteriaceae(B),Gram-positive(C),andfungi(D). ROC:ReceiverOperatingCharacteristic;CRP:C-reactiveprotein;PCT:procalcitonin;BC:bloodcultures.

Table4

LogisticregressionanalysisaboutCRPandPCTvaluesinpredictingpositivityofBC forGram-negativestrainsandenterobacteriaceae.

Gram-negative OR CI95% p CRP>5mg/L 1.89 0.53–6.73 0.32 PCT>0.5ng/mL 3.12 0.62–15.71 0.16 PCT>2ng/mL 0.73 0.41–1.29 0.28 PCT>10ng/mL 3.84 2.18–6.75 <0.001 Enterobacteriaceae CRP>5mg/L 1.65 0.41–6.69 0.48 PCT>0.5ng/mL 6.01 1.16–31.72 0.03 PCT>2ng/mL 2.52 1.28–3.96 0.03 PCT>10ng/mL 3.88 2.15–7.03 <0.001

CRP:C-reactiveprotein;PCT:procalcitonin;BC:bloodcultures. Inboldarereportedp-valuestatisticallysigniﬁcant.

reported,PCTproduction canbedirectlyinduced by inﬂamma-torycytokines[24]andlipopolysaccharide,thatisoneofthemost importantcellwallcomponentofGNbacteria,isprecociously rec-ognizedbyinnateimmunesystemviatoll-likereceptor4(TLR4), whilelipoteichoic acid(LTA), a cellwallcomponent ofGP bac-teria,is recognizedbytoll-likereceptor 2 (TLR2)[25,26]. These

differencesinactivationofTLR4,forGNbacteria,andTLR2,forGP bacteria,resultindifferentproductionofinﬂammatorycytokines, witha differentgeneexpression alsoin leukocytes[27]. More-over,higherlevelsofIL-6andIL-8havebeenreportedinpatients withGNbacteremiaprobablycontributingtotheseobserved dif-ferencesinPCTresponseduringGNorGPbacteremia[28].These mechanismsaredirectlyrelatedtoPCTvaluesreportedinpositive BCforenterobacteriaceaehavebeenexploredonlyinfewstudies [13]. Previousstudies reportedobservationsthat enterobacteri-aceae,suchasE.coliand K.pneumoniae,athighconcentrations (104_cells/mL) _induce _a _greater _IL-6 _production _compared _to _P. aeruginosa(106_cells/mL),_in_which_production_of_IL-6_is_lower_[₂₉_]. Moreover,datareportedinliteratureshowasPCTvaluesinGPare similartothose observedinfungalinfectioninalmostall stud-iesanalyzingtheroleofPCTtopredictBCresultsinbacteremic patients.

Asmatteroffact,collectionofBCsamplesisuniversallyreported asgoldstandard foretiologicaldiagnosisofBSI,consideringthe highsensitivityandspeciﬁcitytoidentifyetiologyofinfectionand thentotestantimicrobialsensitivity;forthesereasons,thedelayed acquisitionofBCcanstopprocessforanearlydiagnosisofsepsis

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[30].PCTcanbeausefulbiomarkertodetectbacterialetiologyat initialstagesofinfection,butamajorlimitationisrepresentedby thelackofidentiﬁcationofcausativebacteria.Astudyconducted inacutelyfebrilepatientsrevealsthatPCTlevelscouldbehelpful alsoindifferentiatingbacterialfromnon-bacterialinfections[24], andotherstudieshavereportedassociationbetweenhigherPCT levelsandGNbacteremia,ifcomparedtoGPbacteremia[31–33]. Ofinterest,Thomas-Rüddeletal.recentlyassessedthecorrelation betweenPCTconcentrations,inICUpatients,withdifferentfociof infectionduringsepsis:inmultivariateanalysisfocusofinfection andetiologywereindependentlyassociatedwithPCT concentra-tion;therefore,variationsinhostresponseduringbacteremiacould dependfromsiteofinfection,givinganotherpossibleexplanation fordifferencesinPCTconcentrationsduringdifferenttypesof infec-tion[19].

FormostpatientswithpositiveBCthemicrobiologicaltestsand thenewmicrobiologicaltechniques,likeMALDI-TOF,are gener-allyavailableduringthefirst24–48h,butdataaboutsusceptibility usuallyrequireanother1–2days.Duringthistime,decisionsabout choiceofantimicrobialregimensandsourcecontrolofinfection areonlybasedonclinicaljudgment.Consideringavailabledata,no definitiveconclusionssupportuseofPCT,comparedtoCRPorother markers,inmanagementofearly-stagesepsis[34,35];moreover, thehighercost ofPCT can drivephysicians touseother mark-erslikeCRP,resultinginaprolongeddurationofhospitalization anddifficultiestodecidetheappropriateapproachtocritically-ill patients.ForallthesereasonstheclinicaluseofPCT,alsoin pre-dictingBCresults,islimitedbyseveralfactors:firstofall,patients withsevereinfectionsandlowPCTconcentrationshasalow prob-abilityofGNbacteremia,butmightstillhaveasevereGNinfection withoutblooddissemination;then,thereisalargeheterogeneity inPCTlevelsduringGN,GPbacteremiaandcandidemia.Although observedAUCsforGNandGPbacteremiawereverydifferentalso inouranalysis,itisnotsufficientforaclinicalapplication;finally, adiagnostictestguidingdecisionsincriticalsettingsneedstohave abetterdiagnosticaccuracyandhighersensitivityandspecificity, thanvaluesreportedinliterature.Furtherstudiesaremandatory toconfirmtheseobservations;however,arecentimportant meta-analysisshowedthatPCTguidancewasassociatedwitha2–4days reductioninantibioticexposure(5.7vs8.1days,p<0.0001)and areductioninantibiotic-relatedside-effects(16%vs22%,adjusted OR0.68,p<0.0001)[36].

Onthisbasis,thedebateabouttheuseofPCTinclinicalpractice isaboutwhentouseit,inwhichpatients,andhowmanytimes.Data reportedinliteraturesupportapossibleuseofPCT,ifcompared toCRPorothertests,inthediagnosisandprognosisofinfection, butPCTcannotbeusedasastand-alonetool.However,aspartof aclinicalalgorithm,PCTwasassociatedwithreductionof antibi-oticsoveruse,especiallyinICUpatients.Inouranalysis,aCRPvalue >5mg/LshowedahighPPVbutalowNPVcomparedtodifferent cut-offofPCTthatwereindependentlyassociatedwithetiologyof infection.So,inourinterpretationCRPvaluecouldbenot associ-atedwithetiologyofinfectionbutonlywiththepresenceofan infection.

Inconclusions,ourdataconfirmedpreviousobservationsabout theroleofPCTinpredictingBCresultsinalargepopulationof bac-teremicpatients[37].Ofinterest,CRPwasnotabletosignificantly predictBCresults,whilePCTvaluescorrelatedwithGNbacteremia and,amongGNisolates,specificallyidentifiedenterobacteriaceae. High PCT values (>10ng/mL)resulted independently associated withGNisolation;moreover,increasedPCTvalueswerenotstrictly relatedwithisolationofGPstrainsorfungiinBC.Evenwiththe lim-itationofasinglecentreexperienceandtheretrospectivedesign ofthestudy,theseresultsmaybeimportanttodefineanotherrole ofPCT,helpingphysiciansinarapididentificationofbacteremic patientsatriskofGNinfection(especiallyenterobacteriaceae)and

drivingchoiceforamoreappropriateempiricalantibiotictherapy, whileawaitingfordeﬁnitivemicrobiologicalresults[38].

Financialsupportandsponsorship

None.

Conﬂictofinterest

InthepastfiveyearsMBhasparticipatedinadvisoryboards and/orreceivedspeakerhonorariafromAchaogen,Angelini, Astel-las,AstraZeneca,Bayer,Basilea,Cidara,Gilead,Melinta,Menarini, MSD, Nabriva, Paratek, Pfizer, Roche, The Medicine Company, Shionogi,Tetraphase,VenatoRX,andVifor.Theremainingauthors havenoconflictsofinterest.

Authorcontribution

MB,ARandERwrotethemainmanuscripttext;AR,EDand MMcollectedclinicaldata;FDperformedCRPandPCTanalysis;AS andFCperformedBCanalysis.ARperformedstatisticalanalysis.All authorsreviewedthemanuscript.

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