Ventilator-associated pneumonia: the influence of bacterial resistance, prescription errors, and de-escalation of antimicrobial therapy on mortality rates

w w w . e l s e v i e r . c o m / l o c a t e / b j i d

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

Original

article

Ventilator-associated

pneumonia:

the

influence

of

bacterial

resistance,

prescription

errors,

and

de-escalation

of

antimicrobial

therapy

on

mortality

rates

Ana

Carolina

Souza-Oliveira

,

Thúlio

Marquez

Cunha

,

Liliane

Barbosa

da

Silva

Passos

_,

_Gustavo

_Camargo

_Lopes

_,

_Fabiola

_Alves

_Gomes

_,

Denise

Von

Dolinger

de

Brito

Röder

a_{UniversidadeFederaldeUberlândia(UFU),FaculdadedeMedicina,ProgramadePósGraduac¸ãoemCiênciasdaSaúde,Uberlândia,} MG,Brazil

b_{UniversidadeFederaldeUberlândia(UFU),HospitaldeClínicas,Uberlândia,MG,Brazil} c_{InstitutodeCiênciasBiomédicas,Uberlândia,MG,Brazil}

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o

Articlehistory:

Received13October2015 Accepted20June2016 Availableonline26July2016

Keywords:

Ventilator-associatedpneumonia Bacterialresistance

Prescriptionerrors

De-escalationofantibiotictherapy

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Ventilator-associatedpneumoniaisthemostprevalentnosocomialinfectioninintensive careunitsandisassociatedwithhighmortalityrates(14–70%).

Aim: This study evaluated factors influencing mortality of patients with Ventilator-associated pneumonia (VAP), including bacterial resistance, prescription errors, and de-escalationofantibiotictherapy.

Methods:Thisretrospectivestudyincluded120casesofVentilator-associatedpneumonia admitted totheadultadultintensivecare unitoftheFederalUniversityofUberlândia. Thechi-squaretestwasusedtocomparequalitativevariables.Student’st-testwasused forquantitativevariablesandmultiplelogisticregressionanalysistoidentifyindependent predictorsofmortality.

Findings: De-escalationofantibiotictherapyandresistantbacteriadidnotinfluence mor-tality.Mortalitywas4timesand3timeshigher,respectively,inpatientswhoreceivedan inappropriateantibioticloadingdoseandinpatientswhoseantibioticdosewasnotadjusted forrenalfunction.Multiplelogisticregressionanalysisrevealedtheincorrectadjustment forrenalfunctionwastheonlyindependentfactorassociatedwithincreasedmortality.

Conclusion: PrescriptionerrorsinfluencedmortalityofpatientswithVentilator-associated pneumonia,underscoringthechallengeofproperVentilator-associatedpneumonia treat-ment,whichrequirescontinuousreevaluationtoensurethatclinicalresponsetotherapy meetsexpectations.

©2016PublishedbyElsevierEditoraLtda.onbehalfofSociedadeBrasileirade Infectologia.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http:// creativecommons.org/licenses/by-nc-nd/4.0/).

∗ _{Correspondingauthor.}

E-mailaddress:[email protected](A.C.Souza-Oliveira).

http://dx.doi.org/10.1016/j.bjid.2016.06.006

1413-8670/©2016PublishedbyElsevierEditoraLtda.onbehalfofSociedadeBrasileiradeInfectologia.Thisisanopenaccessarticleunder theCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Althoughtherehavebeenadvancesinpreventing ventilator-associatedpneumonia(VAP),itremainsthemostprevalent nosocomial infection in intensive care units (ICU).1 _VAP

impairspatientrecoverybyincreasinglengthof hospitaliza-tion,durationofmechanicalventilation,andhospitalization costs.2_{Moreover,VAPisassociatedwithhighmortalityrates}

(14–70%),whicharehigherininfectionsduetoresistant bacte-ria, inappropriate antimicrobial therapy use, and incorrect antimicrobialprescriptionorde-escalationtherapy.3,4

VAPisoftencausedbyresistantbacteria,whichmaylimit therapeutic options and compromise patient outcomes in clinicalpractice.5

AsVAPisassociatedwithsignificantmorbidityand mor-tality,thechoiceofinitialempirictreatmentshouldtakeinto accounttheriskofinfectionscausedbyresistantorganisms.In addition,properprescriptionofantimicrobialtherapyshould alsoconsiderthetype,dosage,anddurationofdrug adminis-tration.DespitetheavailabilityofguidelinesforVAPdiagnosis andtreatment,therapystillvariessignificantlybetween insti-tutionsandtheoccurrenceofincorrecttherapyprescription isquitehigh,rangingfrom10%to73%.6,7

Theaimof this study was toevaluatefactors influenc-ingthemortalityofpatientsdiagnosedwithVAP,including bacterialresistance,prescriptionerrors,andde-escalationof antimicrobialtherapy.

Methods

Thisretrospectivestudyreviewedmedicalrecordsofpatients admittedtotheadultICUoftheFederalUniversityof Uber-lândia(Adult ICU/UFU),between January1st and July31st, 2013. Thepatients included inthe study were 18 years or older who were diagnosed with VAP. Diagnosis was based on criteria established bythe AmericanThoracic Society and theInfectiousDiseasesSocietyofAmerica,8 _including:

mechan-icalventilationfor atleast48hand appearance ofnewor progressivepulmonaryinfiltrateonchestradiographs asso-ciated with at least two clinical signs and/or laboratory changes suggesting an ongoing infection, including fever (>38◦_{C)orhypothermia(<35}◦_{C);leukocytosis(>10,000/mm}3₎

orleukopenia(<4000/mm3_{);purulenttrachealsecretions;and}

oxygenationchanges.

Outofthetotalof467medicalrecordsofpatients admit-tedtotheAdultICU/UFUduringthestudyperiodanalyzed, therewere132casesofVAPin120patients,since12patients hadtwoepisodesofinfection.Inpatientswhohadmorethan oneepisodeofVAP diagnosedduring thestudy period, we includedonlythefirstidentifiedcaseofVAP.Thestudywas approvedbytheEthicsCommitteeoftheFederalUniversity ofUberlândia(protocolnumber775.657)andregisteredasa clinicaltrialsserviceoftheU.S.NationalInstitutesofHealth (protocolnumber30121978).

Medicalrecordswereabstractedtoobtaininformationon patientage,gender,primarydiagnosisatadmission, comor-bidities, prognostic indexes (AcutePhysiology and Chronic Health Disease Classification System II [APACHE II] and

Simplified Acute Physiology Score III [SAPS III]); causative bacteria identified and sensitivity profiles, the characteris-ticsofantimicrobialprescriptions,andoutcome(dischargeor death).

Basedondatainthemedicalrecords,specificsabout pre-scription and administrationofantimicrobialtherapy were obtained, including whether treatment was administered afterhavingobtainedtheresultsofsensitivityprofilingusing quantitativeculture,aswellasde-escalation(interruptionof antimicrobialtreatmentorreplacementbyanantimicrobial withlimited-spectrumcoverage);escalation(additionofanew antimicrobialorreplacementbyabroad-spectrum antimicro-bial);ormaintenance(maintenanceofantimicrobialinitially prescribedorreplacementbyanantimicrobialwiththesame coverageprofile).8

Errorsinantimicrobialprescriptionwereclassifiedas fol-lows: inappropriate choice(different choicefrom literature recommendations); errors in loading or maintenance dose (prescriptionofahigherorlowerdosecomparedtothe indi-cated dose); errors in the interval between doses (higher or lowerinterval betweendosescomparedtotheindicated interval);delayinstartingantimicrobialtherapy(morethan one hour between prescription and administration of the first antimicrobialdose);inappropriate adjustmentforbody weight (nodose correctionbasedon patient weight); inap-propriateadjustmentforrenalfunction;errorsintreatment duration (prescription for shorter or longer duration than theindicatedperiod).Toanalyzetreatmentadequacybased on the literature, we used guideline recommendations for management and health care of adults with nosocomial pneumoniaassociatedwithmechanicalventilationfromthe

AmericanThoracicSociety and theInfectious DiseasesSociety of America.8 The Sanford Guide to Antimicrobial Therapy8 were used as standards for decisions about starting time; dose andindicateddosage;andadjustments,whennecessary,for weightandrenalfunction.9_{Errorinstartingofantibiotic}

ther-apywasdefinedbythe SurvivingSepsisCampaign10 _asmore

than one hour between prescription of the first antibiotic dose bythe attendingphysicianand administrationto the patient.

Multidrug-resistantbacteriaweredefinedasbacteria resis-tanttothreeormoreclassesofantimicrobials.Gram-positive bacteria were assessed for oxacillin resistance.9 _According

to local characteristics the resistance profile of the Adult ICU/UFUhasbeendefinedasfollows:Staphylococcusaureusand

Staphylococcusepidermidissensitiveornottooxacillin(MRSA),

PseudomonasaeruginosaandAcinetobacterbaumanniiresistant tocarbapenems(imipenemandmeropenem), enterobacteri-aceae(Escherichiacoli,Enterobacterspp,Klebsiellapneumoniaespp, Serratia spp)fortheproductionofbeta-lactamaseextended spectrum(ESBL)andStenotrophomonasmaltophiliaresistantto trimethoprim/sulfamethoxazole.

Statisticalanalysis

Chi-square testwas usedto compare qualitativevariables. Student’sttestwasusedtocomparemeansbetweengroups ofnormallydistributedquantitativevariables.

Multiplelogisticregressionanalysiswasusedtoevaluate mortalityindependentpredictorsintheICU.SPSSStatisticsfor

Table1–Clinicalcharacteristicsandprognosisbasedonclinicaloutcomesofdischargeordeathamongpatients

diagnosedwithventilator-associatedpneumonia.

Discharge Death p-Value

Age(years) 41±15 61±18 0.000a

Daysofhospitalization(average) 29±19days 47±33days 0.001a

Prognosticindexes

APACHEII(scores) 18.2±7.2 21.7±7.1 0.028a

MortalityAPACHEII(%) 25±18 38±25 0.003a

SAPSIIIAdmission(scores) 57.7±13.3 67.7±15.3 0.001a

MortalitySAPSIIIAdmission(%) 35±20 49±24 0.002a

Diagnosisatadmission n(%) n(%) Neurologic 35(2) 13(11) 0.131 Trauma 26(2) 2(2) 0.001a Respiratory 6(5) 8(7) 0.091 Infectious 5(4) 7(6) 0.101 Cardiovascular 2(1) 10(8) 0.001a Othersb _{2(2) 4(3) 0.260} Comorbidities n(%) n(%) Smoking 12(10) 3(4) 0.513 SAH 12(10) 2(2) 0.001a Alcoholism 12(10) 2(2) 0.130 DM 2(3) 7(8) 0.008a Heartdisease 1(1) 7(9) 0.000a Lungdisease 1(1) 4(3) 0.039a

SAH,systemicarterialhypertension,DM,diabetesmellitus;APACHEII,AcutePhysiologyandChronicHealthDiseaseClassificationSystemII; SAPSIII,SimplifiedAcutePhysiologyScoreII.

a _p<0.05.

b _{Burnedandpancreatitis.}

Windowswasusedforanalysis,andresultswereconsidered statisticallysignificantwhenp<0.05.

Results

Ofpatientsincludedinthisstudy,32%werediagnosedwith VAPintheAdultICU/UFUduringthestudyperiod.An over-allmortalityrateof35%ofpatientswithVAPwasobserved. Thepatientswerepredominantlymale(74%),withanaverage ageof49±19years,averagetimeofhospitalizationof35±26 days,andaverageadmissionAPACHEIIandSAPSIIIprognostic indexscoresof19.5±7.5and61.9±15,respectively.

Patient clinical characteristics, prognostic index scores, and dischargeor deathoutcomes inthe ICU are shown in

Table 1. The mortality rate was higher in older patients andthosewithhigherprognosticindexscores. Cardiovascu-larfailurewasthemostfrequentreasonforhospitalization (p=0.000).Analysisofcomorbiditiesrevealedasignificant cor-relationbetweendeathanddiabetes(p=0.008),heartdisease (p=0.000),andlungdisease(p=0.039).Theaveragedurationof hospitalizationwas38%higherinthegroupofpatientswho died(p=0.001)(Table1).

Multi-drug resistant microorganisms were detected in 45.6%ofinfections,69.2%ofwhichwerecaused byA. bau-mannii,47.6%byP.aeruginosa,36.7%byS.aureus,and42.3% byextended spectrum ␤-lactamase producing bacteria. No carbapenemase-producingbacteria wereobserved(Table2). Therewasnoobserveddifferenceinmortalityratesamong

Table2–Bacteriologicalprofileofpatientsdiagnosed

withventilator-associatedpneumoniawhowere

admittedtotheadultintensivecareunitoftheHospital

deClinicasoftheFederalUniversityofUberlândia.

Bacteria General Resistant

n % n % Pseudomonasaeruginosaa _{42 30.8 20 47.6} Staphylococcusaureusb _{30 23.8 11 36.7} Acinetobacterbaumanniia _{26 19.0 18 69.2} Serratiasppd _{10 7.4 4 40.0} Stenotrophomonasmaltophiliac _{10 7.4 0 0.0} Klebsiellapneumoniaesppd _{8 5.9 5 62.5} Enterobactersppd _{6 4.4 1 15.0} Escherichiacolid _{2 1.5 1 50.0} Staphylococcusepidermidisa _{2 1.5 1 50.0} Allbacteria 136 100 62 45.6

a _{Resistanttocarbapenems(imipenemandmeropenem).} b _{Resistanttooxacillin(multidrugresistantStaphylococcusaureus).} c _{Resistanttotrimethoprim/sulfamethoxazole.}

d _{Producersofextended-spectrumbeta-lactamase.In16patients}

wereidentifiedmorethanonemicroorganisms.

infectionscausedbyresistantorsusceptibleorganisms(27% vs.46%,p=0.104).

Initialantimicrobialtherapywasmaintained,escalation, andde-escalationin57%,33%,and10%ofcases,respectively. Therewerenodifferencesinmortalityratesamongcasesin

Table3–Evaluationoffactorsaffectingoutcomesofpatientsdiagnosedwithventilator-associatedpneumonia.

Discharge Death p-Value

n(%) n(%)

Age>60years 11(13.4) 32(13.4) 0.000a

ICUadmission>21days 48(58.5) 33(58.5) 0.106

Prescriptionerrors n(%) n(%) p-Value

Errorinloadingdose 1(1) 4(8) 0.031a

Errorinmaintenancedose 12(15) 11(22) 0.304

Errorintheintervalbetweendoses 18(22) 10(20) 0.964

Delayinstartingantimicrobialtherapy 57(70) 28(56) 0.223

Inappropriateadjustmentforrenalfunction 5(6) 15(30) 0.000a

Errorintreatmentduration 9(89) 4(8) 0.299

Conduct n(%) n(%) p-Value De-escalation 10(12) 2(4) 0.160 Continuation 30(37) 12(24) 0.685 Maintenance 42(51) 32(72) 0.419 Bacteria n(%) n(%) p-Value PseudomonasaeruginosaMRa _{9(41) 11(55) 0.087} AcinetobacterbaumanniiMRa _{9(64) 9(75) 0.254} StaphylococcusaureusMRb _{10(30) 1(20) 0.914}

a _{Resistanttocarbapenems(imipenemandmeropenem).}

b _{Resistanttooxacillin(multidrugresistantStaphylococcusaureus);MR=multidrugresistant;ICU=intensivecareunit.}

whichtreatmentwasde-escalatedcomparedtocasesinwhich itwasmaintainedorescalated(16.6%vs.33.3%,p=0.160).

Themostcommonerrorinantimicrobialprescriptionswas delayinstartingtreatment,followedbytheintervalbetween doses.Analysisoftheinfluenceofprescriptionerrorson mor-talityraterevealeda4-foldincreaseinmortalityinpatients whoreceivedaninappropriateloadingdose(p=0.031),anda 3-foldincreasewhenthedosagewasnotadjustedforrenal function(p=0.000)(Table3).

Multiplelogisticregressionanalysisrevealedtheincorrect adjustmentforrenalfunctionwastheonlyindependentfactor associatedwithincreasedmortality(Table4).

Discussion

Although guidelines for VAP treatment are available, it remainsthemostprevalentinfectionintheICUandis asso-ciatedwithhighmortalityrates.3_{Thehighmortalityratein}

patientswith VAPinthis study (35%)is similartorates of 32.1%1_and44.3%11_{reportedinotherBrazilianinvestigations,}

aswellasareviewstudyinwhichtheratevariedfrom14%to 70%.12–15

Thehighermortalityratesinolderpatientswerelikelydue toimpairedfunctionalstatuswithadvancingage.This obser-vationwassupportedbyastudyinwhichageover55years wasanindependentpredictor ofmortalityinpatientswith VAP(p=0.005).11 _{Chronicdiseasessuchasdiabetesmellitus}

aswellasheartandlungdiseasewereassociatedwithpoor prognosisofpatientswithVAP.Thisfindingalsoreportedby Resendeet al.,inwhichthepresenceofcomorbiditieswas significantlyassociatedwithmortality(p=0.029).16

ThepredominanceinthisstudyofGram-negativebacteria, includingP.aeruginosaandA.baumannii,issimilartoreports fromothercountriesinSouthAmerica,17_{theUnitedStates,}18

and Turkey.19 _{VAPisoftenrelatedtohighratesofresistant}

bacteria.20_{Theincidenceofmulti-drugresistantAcinetobacter}

andPseudomonasisincreasingandhadbeenassociatedwith increased ICU stays, mechanical ventilation, and possibil-ityofinappropriatetreatmentinpatientsreceivingstandard therapy.5,18,19,21

The lack of association between bacterial resistance and mortality has also been described in the literature22

and can beexplained by differences between study popu-lations, preexisting comorbidities, infection severity, and rate of inappropriate empirical treatment. Several studies have demonstrated that the association betweenmortality and antimicrobialresistancedifferedfrom oursamplewith respecttoage,asweincludedolderpatients,comparedtoan averageageof63.4years23_{and62.3years,}24_{andwithhigher}

rateofcomorbidities.Heartdiseaseand lungdiseases were reportedin25%and20%ofpatients,respectively.24_These

find-ingsreinforcetheassociationbetweenincreasingimpairment offunctionalstatuswithage,andthepresenceofchronic dis-eases.

TheSurvivingSepsisCampaignemphasizestheimportance ofdailyreevaluationofantimicrobialtherapybasedon the results ofculture proliferation assays withthe aim of dis-continuingtreatment,whenpossible,toreduceantimicrobial resistance,toxicity,andcosts.10_{Highrateofantibiotic}

mainte-nance(57%ofmaintenancevs43%de-escalationorescalation) has been described in the literature.6 _{Rello et al.}4

consid-eredthelowpercentageoftherapyde-escalationtobedue tothehigh rateofinfection causedbymulti-drugresistant

Table4–Multiplelogisticregressionanalysisofdeathpredictorsinventilator-associatedpneumoniaintheadult

intensivecareunitoftheHospitaldeClinicasoftheFederalUniversityofUberlândia.

Death CI(95%)

Frequency OR Lowerlimit Upperlimit

Discontinued 02 3.439 0.436 27.100

Errorinloadingdose 04 6.254 0.456 85.725

Errorinmaintenancedose 09 1.232 0.248 6.116

Erroroftheintervalbetweendoses 09 0.391 0.082 1.865

Delayinstartingantimicrobialtherapy 25 0.877 0.284 2.710

Inappropriateadjustmentforrenalfunction 15 8.756 1.803 42.531

Errorinthedurationtreatment 02 0.178 0.023 1.409

Age>60yearsold 29 0.137 0.047 1.398

ICUadmission>21days 18 1.034 0.374 2.883

Pseudomonasaeruginosa 20 0.297 0.082 1.075

Acinetobacterbaumannii 12 0.318 0.079 1.279

Staphylococcusaureus 5 1.367 0.326 5.742

Multi-drugresistantbacteria 20 0.848 0.326 5.742

R2_{of0.674;OR=oddsratio;CI=confidenceinterval.}

bacteriaincludingnon-glucosefermentingstrains(P. aerugin-osaandA.baumannii)thatwerealsoprevalentinoursample population.Althoughintendedtoreducepossible antimicro-bialresistance,toxicity,andcosts,treatmentde-escalationis lesslikelyforinfectionscausedbydrug-resistantinfections, asalsodescribedbyAlvarez-Lermaetal.25_{Theyreportedthat}

reductionoftheinitialspectrumofantibioticsoccurredonly in23%ofpatientsinfectedwithresistantpathogenscompared to 68% ofpatients infectedwith sensitive microorganisms (p<0.001).

AmulticenterstudyconductedintheUnitedStates,6 _as

well as investigations carried out in Spain4 _{and Greece,}26

foundthat mortality rates were significantly reduced after de-escalationofantibiotic treatment. However,subsequent investigations,includingourstudy,didnotfindany correla-tionbetweentreatmentde-escalationandpatientmortality.25

Thedifferentresultsafterevaluatingtheinfluenceoftherapy de-escalationonmortalitywerepossiblyduetoconfounding factors.Amongtheseis thedifficulty indistinguishing the influenceonmortalityratesduetotreatmentde-escalation itself or administration an appropriate therapy, since a correlation between appropriate therapy and higher de-escalationrateshasbeenobserved.27_{Inonestudy,Giantsou}

etal.26 _{includedonlypatientsreceivingappropriatetherapy}

and observedsignificantly lower mortalityrates after ther-apyde-escalationcomparedtomaintenance.Differencesin antimicrobialsusceptibility mayalsoexplaindifferent mor-talityrates, as observedina multicenter study that found significantlylowermortalityrateswhentherapywas discon-tinued(p=0.001).However,therateofinfectionbyresistant bacteriawasmuchlowerthaninourstudy,whichmighthave influencedthedifferencesinobservedresults.6

Errorinstartingantibioticadministration, themost fre-quentlydetectederror inourstudy,probably occurreddue toalackofcommunicationbetweenmultidisciplinaryteams to immediately initiate the antibiotic as soon as VAP was diagnosed. The complex system of drug prescription also includedothercircumstancesthatcontributetoerrors,such aslackofattention,excessive workload,lackof communi-cationbetweenteams, andlackofknowledgeand training

ofprescribingphysicians.Errorsinprescribingantimicrobial agents cause short- and long-term consequences that are notjustrestricted toindividuals:theycan leadnotonlyto inadequate clinical response and increased morbidity and mortality,butalsoinvolvethecommunitybycontributingto increasedbacterialresistance.28_{Thelackofincreased}

mortal-ityinpatientswithdelayedstartofantibiotictreatmentinthis studydisagreedwithotherreportsemphasizingthe relation-shipbetweenearlyadministrationofantibioticsandreduced mortality,asreportedbyLevyetal.,29 _inwhichthe

admin-istrationofantibioticswithinthefirsthourafterdiagnosisof severesepsisandsepticshockreducedthemortalityratefrom 37%to30.8%(p=0.001).

Inthis study,prescriptionofinappropriateantimicrobial loadingdosesandnotadjustingdosageforrenalfunctionwere determinantfactorsrelatedtoincreasedmortality.The4-fold increasedmortality(p=0.031)observedinpatientswith inap-propriate loadingdose was probably dueto aninability to reachproperantimicrobialconcentrationsatthetargetsite. Thelackofknowledgeandattentionintheinitial administra-tionofhigherdosesoratshorterintervalsweredeterminant forthedevelopmentofunfavorableoutcomesamongthese patients.

Althoughrenalfunctionwasevaluateddailyintheadult ICUoftheFederalUniversityofUberlândia,asignificant num-beroferrorsinadjustingforrenalfunctioncauseda3-fold increase in mortality rate (p=0.000). In addition, incorrect adjustmentforrenalfunctionwastheonlyindependentfactor associatedwithmortalityinthemultiplelogisticregression analysis.Thiserrorwasprobablyduetoalackofattentionto adjustforcurrentcreatinineclearance,easeofcopying elec-tronic prescriptions from the previous day, and negligence in prescribinganextra dose afterhemodialysis. The nega-tiveinfluenceontheoutcome ofthesepatientswasdueto thedeleteriouseffectsinducedbytoxiclevelsofantimicrobial agentswhentheindicateddosewasnotreduced,ornotto reachtheappropriatetherapeuticlevelwhentheextradose afterhemodialysiswasnotrecommended.Thesefactorswere describedbyCarneiroetal.,30_{whoreportedaveryhighrate}

Prescription errors influenced the mortality rates of patientswithVAP,underscoringthechallengeofproperVAP treatment,whichrequirescontinuousreevaluationtoensure thatclinicalresponsetotherapymeetsexpectations.

Thelimitationofthisstudyisduetoretrospectivedesign, sincethe data were obtained from informationabstracted frommedicalrecords.

Conclusions

Inconclusion,thisstudyobservedthatde-escalationof antibi-otictherapyandVAPduetoresistantbacteriadidnotinfluence mortalityrates.Inappropriateloadingdoseandlackof adjust-mentforrenalfunctionweremorefrequentinpatientswho died.Multiplelogisticregressionanalysisrevealedthe incor-rectadjustmentforrenalfunctionwastheonlyindependent factorassociatedwithincreasedmortality.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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e

s

1. RochaLdeA,VilelaCA,CezárioRC,AlmeidaAB,GontijoFilho P.Ventilator-associatedpneumoniainanadult

clinical–surgicalintensivecareunitofBrazilianuniversity hospital:incidence,riskfactors,etiology,andantibiotic resistance.BrazJInfectDis.2008;12:80–5.

2. HayashiY,MorisawaK,KlompasM,etal.Towardimproved surveillance:theimpactofventilatorassociated

complicationsonlengthofstayandantibioticuseinpatients inintensivecareunits.ClinInfectDis.2013;56:471–7.

3. TeixeiraPJZ,HertzFTP,CruzDB,CaraverF,HallalRC,Moreira JS.Pneumoniaassociadaàventilac¸ãomecânica:impactoda multirresistênciabacteriananamorbidadeemortalidade.J BrasPneumol.2004;30:540–8.

4. RelloJ,VidaurL,SandiumengeA,etal.De-escalationtherapy inventilatorassociatedpneumonia.CritCareMed.

2004;32:2183–90.

5. ChungDR,SongJH,KimSH,etal.Highprevalenceof multidrug-resistantnonfermentersinhospital-acquired pneumoniainAsia.AmJRespirCritCareMed.

2011;184:1409–17.

6. KollefMH,MorrowLE,NiedermanMS,etal.Clinical characteristicsandtreatmentpatternsamongpatientswith ventilator-associatedpneumonia.Chest.2006;5:1210–8.

7. RelloJ,OllendorfDA,OsterG,etal.Epidemiologyand outcomesofventilator-associatedpneumoniainalargeUS database.Chest.2002;122:2115–21.

8. AmericanThoracicSociety/InfectiousDiseasesSocietyof America.Guidelinesforthemanagementofadultswith hospital-acquired,ventilator-associated,and

healthcare-associatedpneumonia.AmJRespirCritCareMed. 2005;171:388–416.

9. GilbertDN,ChambersHF,EliopoulosGM,MichaelSS.The Sanfordguidetoantimicrobialtherapy.Sperryville: Copyright;2014.

10.DellingerRP,LevyMM,RhodesA,etal.Survivingsepsis campaign:internationalguidelinesformanagementofsevere sepsisandsepticshock:2012.CritCareMed.2012;41:582–637.

11.GuimarãesMM,RoccoJR.Prevalenceofventilator-associated pneumoniainauniversityhospitalandprognosisforthe patientsaffected.JBrasPneumol.2006;32:339–46.

12.HeylandDK,CookDJ,GriffithL,KeenanSP,Brun-BuissonC. Theattributablemorbidityandmortalityof

ventilator-associatedpneumoniainthecriticallyillpatient. AmJRespirCritCareMed.1999;159:1249–56.

13.JosephNM,SistlaS,DuttaTK,BadheAS,ParijaSC. Ventilator-associatedpneumonia:areview.EurJIntMed. 2010;21:360–8.

14.MelsenWG,RoversMM,BontenMJ.Ventilator-associated pneumoniaandmortality:asystematicreviewof observationalstudies.CritCareMed.2009;37:2709–18.

15.Gvozdenovi´cL,Kolarovi´cJ,Sarkanovi´c-Luki´cM,Popovi´cM, Trivi´cS.Incidenceandoutcomeofventilator-associated pneumonia(ourexperience).BrazJInfectDis.

2012;16:599–600.

16.ResendeMM,MonteiroSG,CallegariB,FigueiredoPM, MonteiroCR,Monteiro-NetoV.Epidemiologyandoutcomes ofventilator-associatedpneumoniainnorthernBrazil:an analyticaldescriptiveprospectivecohortstudy.BMCInfect Dis.2013;13:1–6.

17.MedellM,HartM,MarreroO,EspinosaF,MontesdeOcaZ, ValdésR.Clinicalandmicrobiologicalcharacterizationof pneumoniainmechanicallyventilatedpatients.BrazJInfect Dis.2012;16:442–7.

18.RestrepoMI,PetersonJ,FernandezJF,QinZ,FisherAC, NicholsonSC.Comparisonofthebacterialetiologyof early-onsetandlate-onsetventilator-associatedpneumonia insubjectsenrolledin2largeclinicalstudies.RespirCare. 2013;58:1220–5.

19.PiskinN,AydemirH,OztoprakN,etal.Inadequatetreatment ofventilator-associatedandhospital-acquiredpneumonia: riskfactorsandimpactonoutcomes.BMCInfectDis. 2012;12:2–9.

20.MedellM,MedellM,MartínezA,ValdésR.Characterization andsensitivitytoantibioticsofbacteriaisolatedfromthe lowerrespiratorytractofventilatedpatientshospitalizedin intensivecareunits.BrazJInfectDis.2012;16:

45–51.

21.RoyerS,FariaAL,SekiLM,etal.Spreadofmultidrug-resistant AcinetobacterbaumanniiandPseudomonasaeruginosaclonesin patientswithventilator-associatedpneumoniainanadult intensivecareunitatauniversityhospital.BrazJInfectDis. 2015;1,9-350-7.

22.CombesA,LuytCE,FagonJY,WolffM,TrouilletJL,ChastreJ. Impactofpiperacillinresistanceontheoutcomeof pseudomonasventilator-associatedpneumonia.Intensive CareMed.2006;32:1970–8.

23.KollefMH,SilverP,MurphyDM,TrovillionE.Theeffectof late-onsetventilator-associatedpneumoniaindetermining patientmortality.Chest.1995;108:1655–62.

24.ParkerCM,KutsogiannisJ,MuscedereJ,etal. Ventilator-associatedpneumoniacausedby

multidrug-resistantorganismsorPseudomonasaeruginosa: prevalence,incidence,riskfactors,andoutcomes.JCritCare. 2008;23:18–26.

25.Alvarez-LermaF,AlvarezB,LuqueP,etal.Empiric

broad-spectrumantibiotictherapyofnosocomialpneumonia intheintensivecareunit:aprospectiveobservationalstudy. CritCare.2006;10:1–11.

26.GiantsouE,LiratzopoulosN,EfraimidouE,etal.Deescalation therapyratesaresignificantlyhigherbybronchoalveolar lavagethanbytrachealaspirate.IntensiveCareMed. 2007;33:1533–40.

27.NiedermanMS,SoulountsiV.De-escalationtherapyisit valuableforthemanagementofventilator-associated pneumonia.ClinChestMed.2011;32:517–34.

28.MarquesTC,ReisAMM,SilvaAEBC,etal.Errosde

administrac¸ãodeantimicrobianosidentificadosemestudo multicêntricobrasileiro.RevFarmBioquimUnivSaoPaulo. 2008;44:305–14.

29.LevyMM,DellingerRP,TownsendSR,etal.TheSurviving SepsisCampaign:resultsofaninternationalguidelinebased

performanceimprovementprogramtargetingseveresepsis. IntensiveCareMed.2008;38:367–74.

30.CarneiroM,FerrazT,BuenoM,etal.Ousode

antimicrobianosemumhospitaldeensino:umabreve avaliac¸ão.RevAssocMedBras.2011;57:421–4.