Predictors of 7- and 30-day mortality in pediatric intensive care unit patients with cancer and hematologic malignancy infected with Gram-negative bacteria

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

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

Original

article

Predictors

of

7-

and

30-day

mortality

in

pediatric

intensive

care

unit

patients

with

cancer

and

hematologic

malignancy

infected

with

Gram-negative

bacteria

Patrícia

de

Oliveira

Costa

_,

_Elias

_Hallack

_Atta

_,

_André

_Ricardo

_Araujo

_da

_Silva

a_{CenterofHaematopoieticStemCellTransplantation,InstitutoNacionaldoCâncer(INCA),RiodeJaneiro,RJ,Brazil}

b_{UniversidadeFederalFluminense(UFF),Niteroi,RJ,Brazil}

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received11April2014 Accepted19May2014 Availableonline19July2014

Keywords:

Cancer

Pediatricintensivecareunit InfectionwithGram-negative bacteria

Mortality

a

b

s

t

r

a

c

t

Background:InfectionwithGram-negativebacteriaisassociatedwithincreasedmorbidity

andmortality.Theaimofthisstudywastoevaluatethepredictorsof7-and30-daymortality inpediatricpatientsinanintensivecareunitwithcancerand/orhematologicdiseasesand Gram-negativebacteriainfection.

Methods:DatawerecollectedrelatingtoallepisodesofGram-negativebacteriainfection

thatoccurredinapediatricintensivecareunitbetweenJanuary2009andDecember2012, andthesecasesweredividedintotwogroups:thosewhoweredeceasedsevenand30days afterthedateofapositivecultureandthosewhosurvivedthesametimeframes.Variables ofinterestincludedage,gender,presenceofsolidtumororhematologicdisease,cancer status,centralvenouscatheteruse,previousPseudomonasaeruginosainfection,infection bymultidrugresistant-Gram-negativebacteria,colonizationbymultidrug resistant-Gram-negativebacteria,neutropeniaintheprecedingsevendays,neutropeniaduration≥3days, healthcare-associatedinfection,lengthofstaybeforeintensivecareunitadmission,length ofintensivecareunitstay>3days,appropriateempiricalantimicrobialtreatment,definitive inadequateantimicrobialtreatment,timetoinitiateadequateantibiotictherapy, appro-priate antibiotic duration≤3days, andshock.In addition,useofantimicrobialagents, corticosteroids,chemotherapy,orradiationtherapyintheprevious30dayswasnoted.

Results:Multivariatelogisticregressionanalysisresultedinsignificantrelationshipbetween

shockandboth7-daymortality(oddsratio12.397;95%confidenceinterval1.291–119.016;

p=0.029) and30-day mortality (odds ratio6.174; 95% confidenceinterval 1.760–21.664;

p=0.004), betweenantibiotic duration ≤3days and 7-day mortality (odds ratio 21.328; 95%confidenceinterval2.834-160.536;p=0.003),andbetweencolonizationbymultidrug resistant-Gram-negativebacteriaand30-daymortality(oddsratio12.002;95%confidence interval1.578–91.286;p=0.016).

Conclusions: Shockwasapredictorof7-and30-daymortality,andcolonizationbymultidrug

resistant-Gram-negativebacteriawasanimportantriskfactorfor30-daymortality. ©2014ElsevierEditoraLtda.Allrightsreserved.

∗ _{Correspondingauthor.}

E-mailaddress:[email protected](P.deOliveiraCosta). http://dx.doi.org/10.1016/j.bjid.2014.05.012

Introduction

Children undergoing treatment for malignancy have an excellent chance of survival, with an overall survival rate approaching75%.1_{Inmostcases,childrenwhodiefollowing}

treatmentforcancerdosoasaresultoftheirdisease.However, despitesignificantimprovementsinsupportivecare, approxi-mately16%ofthedeathswithinfiveyearsfollowingdiagnosis areduetocomplicationsoftherapy.1_{Infectioncontinuesto}

beonesuchlife-threateningcomplicationin immunocompro-misedchildren.1

Withrecentadvancesincancertreatmentsand improve-mentsincriticalcare,anincreasingnumberofpatientswith hematologic malignancies are being admittedto intensive careunits(ICU).2_{Despitetheassociatedimprovementsin}

out-comes,mortalityremainshighincriticallyill patientswith hematologicmalignancies,particularlyinthepresenceof ICU-acquirednosocomialinfections.2_{Inaddition,infectionresults}

inICUadmissionincancerpatients.

Oncologicpatientsareatagreaterriskofdeveloping sep-sisandnosocomialinfectionsasaconsequenceofanumber ofmechanisms,includingimmunosuppressionrelatedtothe diseaseitselfandtoaggressivetreatments,suchascombined regimensofchemotherapyandradiationtherapy,highdose steroids,andhematopoieticstemcelltransplantation.3

More-over,despiterecentimprovementsinsurvivalrates,sepsisin patientswithcancerremainsassociatedwithhighmorbidity, mortality,costs,anduseofICUresources,andinformationon thistopicislimited.3

Researchhas previouslyfocused on adultpatients with cancer. Little is known regarding the predictors of 7- and 30-day mortality related to Gram-negative bacterial (GNB) infectioninchildrenwithcancerwhoarehospitalizedinthe ICU.Therefore,thisstudyaimedatevaluatingthepredictors of7-and30-daymortalityriskinchildrenwithcancerand/or hematologicdiseaseswhowerealsoinfectedwithGNB.

Patients

and

methods

Studydesign

Weperformeda case–control study inthe pediatricICU of the NationalCancer Institute(INCA), Riode Janeiro,Brazil, whichisanexemplarytertiaryoncologypublichospital.The 6-bedpediatricICUadmitsonlypatientswithsolidtumorsand hematologicmalignancies.AdmissiontotheICUisnot gen-erallypermittedforpalliativecare.However,somepatients maybeadmittedwhileafullassessmentoftheextentoftheir cancerandtherapeuticoptionsisstillongoing.

WecollecteddatarelatedtoallGNBepisodesthatoccurred betweenJanuary2009andDecember2012inpatientsagedless than18years,whowerehospitalizedfor>24hinthepediatric ICU.Thestudywasapprovedbytheethicscommitteeofthe FluminenseFederalUniversity.

GNBinfectionsweredividedintotwogroupsbytimeand survivalstatus:patientswhoweredeceasedandthosewho survivedsevenand30daysafterthedateofapositiveculture. Ateach timeperiod,thepatientswere fromthe sameunit

andhadinfectionsthatoccurredatthesametimeandatthe samesites.

Thefollowingdatawerecollected:age,gender,presence ofsolidtumororhematologicdisease,cancerstatus,central venouscatheteruse,previousPseudomonasaeruginosa infec-tion,healthcare-associatedinfection,infectionbymulti-drug resistant (MDR)-GNB, colonization by MDR-GNB (assessed usingarectalswaborstoolculture),neutropeniainthe preced-ingsevendays,neutropeniaduration≥3days,lengthofstay beforeICUadmission,lengthofICUstay>3days, appropri-ateempiricalantimicrobialtreatment,definitiveinadequate antimicrobialtreatment, appropriateantibioticduration ≤3 days, the time to initiate adequate antibiotic therapy, and shock (within two days before or afterthe date ofa posi-tiveculture).Inaddition, theuseofanyofthefollowingin theprevious30dayswasnoted:antimicrobialagents, corti-costeroids,chemotherapy,orradiationtherapy.Colonization withantibiotic-resistantGNBwasdetectedviaweeklyroutine surveillance(nasalandrectalswabs).

Definitionofterms

Deathwithinsevendaysor30daysafterthedateofapositive culture wasconsidered as7-and 30-day mortality, respec-tively.Anepisodeofinfectionwasdefinedastheisolationof GNBfromthreedaysbeforethedateofpediatricICU admis-sion tothelast dayofhospitalization inthe pediatricICU, fromculturesofblood,urine,stools,broncho-alveolarlavage, trachealaspirate,cerebrospinal fluid,orcathetertip,inthe presenceofassociated,compatibleclinicalsignsorsymptoms. Thetrachealaspiratewascollectedfromendotrachealtubes and tracheostomiesofpatientswhounderwentmechanical ventilation. Thediagnosticcriteriaforpneumoniaincluded purulent tracheobronchial secretion and new pathogenic bacteria isolatedfromtrachealaspirateorbroncho-alveolar lavage inadditiontotwo ormoreofthe followingcriteria: fever>38◦C;leukocytes>12,000cells/mLor<4000cells/mL;a newandpersistent(>48h)infiltrateonchestradiograph;new onsetorworseningcough,dyspnea,ortachypnea;and declin-inggasexchange.Cathetercultureswereperformedwhena catheterwasremoved forsuspectedintravascular catheter-related infection, if the patient had unexplained sepsis or erythemaoverlyingthecatheterinsertionsite,oriftherewas purulenceatthecatheterinsertionsite.Theendofthe infec-tionepisodewasthedatewhentheinfectionwasconsidered toberesolvedbythemedicalteam.

Thepresenceofextendedspectrumbeta-lactamase (ESBL)-producing Enterobacteriaceae; microorganisms with intrinsic resistance mechanisms such as S. maltophilia and

Eliz-abethkingia meningoseptica; carbapenem-resistant GNB; or

strainsofA.baumanniiwereconsideredasMDR-GNB infec-tion. Polymicrobialinfection involvedthe isolationofmore thanonepathogenfromaculturesample.

Neutropeniawasdefinedasanabsoluteneutrophilcount <500neutrophils/mm3_{inbloodsamples.Shockwasdefinedas} arterialhypotensionrequiringvasoactivedrugs.

Initial antimicrobial treatment was considered inappro-priateifthetreatmentregimendidnotincludeatleastone antibioticactiveinvitroagainstthemicroorganism.Itwasalso consideredinappropriatewhentheantibiotictreatmentwas

Table1–CharacteristicsofpediatricpatientswithGram-negativebacterialinfectionbasedonrectalswaborstoolculture.

Withswaborculture

n=83 n(%) Withoutswabor culture n=18 n(%) pvalue Gender(boys) 42(50.6) 10(55.6) 0.792 Age(years)a _{5(0.2–18) 12(1–17) 0.023} MDR-GNB 42(50.6) 6(33.3) 0.298

Cancerstatus(controlled) 15(18.1) 5(27.8) 0.262

Hematologicdiseases 21(25.3) 3(16.7) 0.551

Previousantibiotictherapyb _{75(90.4) 14(77.8) 0.219}

Centralvenouscatheter 76(91.6) 17(94.4) 1.000

Useofcorticosteroidsb _{75(90.4) 17(94.4) 1.000}

Neutropeniac _{23(27.7) 4(22.2) 0.774}

Neutropeniaduration≥3days 14(16.9) 4(22.2) 0.590

Healthcare-associatedinfection(fromwardandpediatricICU) 68(82.0) 14(77.8) 0.683

LengthofstaybeforeICUadmissiona _{2(0–89) 2.5(0–14) 0.844}

LengthofICUstay>3days 42(50.6) 8(44.4) 0.636

Chemotherapy/radiationtherapyb _{61(73.5) 11(61.1) 0.389}

PreviousepisodeofPseudomonasaeruginosainfectionb _{13(15.7) 4(22.2) 0.497}

Inappropriateinitialantimicrobialtreatment 37(44.6) 9(50) 0.795

Definitiveinadequateantimicrobialtreatment 3(3.6) 2(11.1) 0.216

Timetoinitiateadequateantibiotictherapy(days)a _{1(0–10) 0(0–7) 0.908}

Shock 30(36.1) 5(27.8) 0.592

7-daymortality 6(7.2) 2(11.1) 0.630

30-daymortality 19(22.9) 2(11.1) 0.348

ICU,intensivecareunit;MDR-GNB,multi-drugresistant-gram-negativebacteria. a _{Reportedasmedian(range).}

b _{Inthe30dayspriortothepositivecultureforgram-negativebacteria.} c _{Inthe7dayspriortothepositivecultureforgram-negativebacteria.}

notstartedonthedateofthepositiveculture.Furthermore, inpatientsfrom whomESBL-producingbacteriahad grown incultures,treatmentwithpenicillinandcephalosporinswas consideredinappropriate.Definitiveinadequateantimicrobial treatmentwasdefinedwhenthepatientdidnotreceiveany antibioticactiveinvitroagainstthemicroorganismduringthe periodofinfection.

Microbiologicalstudies

Bacterial identification was performed by the INCA micro-biology laboratory using the Vitek automated method (Bio-Merieux,Inc.,France)withmanualconfirmationof bacte-rialisolatesandantimicrobialresistance,asperthestandards recommendedbytheClinicalLaboratoryStandardInstitute (CLSI).

Statisticalanalysis

StatisticalanalysiswasconductedusingSPSSv17(SPSSInc; Chicago,Illinois,USA).Continuousvariableswerecompared using Mann–Whitney Utest and Student’s t-test. Categori-calvariableswereanalyzedusingtwo-tailedChi-squaretest. Oddsratios(OR)and95%confidenceintervals(CI)were cal-culated. Separate multivariate logistic regression analyses includedthefactorspotentiallyassociatedwith7-or30-day mortalitybasedonstatisticallysignificantvariablesin univari-ateanalyses.Avalueofp<0.05wasconsideredstatistically significant.

Results

In the period from January 1, 2009 to December 31, 2012, therewere101episodesofGNBinfectionin76patientsoutof 765totaladmissionstothepediatricICU.Oftheseepisodes, 47(46.5%)wererelatedtoMDR-GNBinfection.Eight(10.5%) patientspresentedwith>1episodeofnon-MDR-GNB infec-tion,4(5.3%)patientspresentedwith>1episodeofMDR-GNB infection, and 8 (10.5%) patients presented with separate episodesofMDR-GNBandnon-MDR-GNBinfections.Asingle GNBwasisolatedin98(97.0%)episodes,andinthree(3.0%) episodes,twoisolateswererecovered.All-causemortalityrate was7.9%(8/101)onday7and20.8%(21/101)onday30.

Duringthestudyperiod,18episodesdidnothavearelated rectalswaborstoolculture(twodeceasedand16survivors); however, the characteristics, except for age, were similar between these patients and those with a swab or culture (Table1).

Fig. 1 provides the frequency of each pathogen in the patientswith7-daymortality.Themostfrequentlyoccurring pathogensinthesepatientswereA.baumanii(37.5%)and

Pseu-domonas(25.0%).Inthisgroup,thebacteriawereisolatedfrom

thesitesasfollows:3(37.5%)fromacombinationoftracheal aspirate and blood cultures,3 (37.5%)from blood cultures, 1(12.5%)fromtrachealaspirateculture,and1(12.5%)from a combination ofcatheter tip,trachealaspirate, and blood cultures.Therewasconcordancebetweentheisolate microor-ganismswhentheGNBwereisolatedfromacombinationof differentculturesites.

Enterobacter sp 1 13% Acinetobacter sp 3 37% Escherichia coli 1 13% Pseudomonas sp 2 25% Klebsiella pneumoniae 1 12%

Fig.1–Gram-negativebacterialisolatesdetectedinthepatientswithGram-negativebacterialinfectionsand7-day mortality(deathwithinsevendaysofthepositiveculture)inapediatricintensivecareunit(n=8).

Escherichia coli 9 10% Klebisiella pneumoniae 14 15% Citrobacter sp. 1 1% Elizabethkingia meningoseptica 4 4% Proteus mirabilis 2 2% Acinetobacter sp. 19 20% Enterobacter sp 7 8% Morganella morganii 2 2% Stenotrophomonas maltophilia 7 8% Klebsiella oxytoca and Escherichia coli

1 1% Pseudomonas sp

25 27% Stenotrophomonas maltophilia and

Pseudomonas sp 1 1%

Klebsiella pneumoniae and Escherichia coli

1 1%

Fig.2–Gram-negativebacterialisolatesdetectedinthepatientswithGram-negativebacterialinfectionswhosurvivedat sevendaysafterthepositivecultureinapediatricintensivecareunit(n=93).

Table2–Demographicandclinicalvariablesrelatedto7-daymortalityinpatientswithGram-negativebacterial infectionsinapediatricintensivecareunit(ICU),analyzedusingunivariateandmultivariatelogisticregression.

Univariatelogisticregressionanalysis Multivariatelogistic regressionanalysis Survivors n=93 n(%) Non-survivors n=8 n(%) OR 95%CI pvalue OR 95%CI pvalue Gender(boys) 46(49.5) 6(75) 3.065 0.588–15.979 0.184 – – – Age(years)a _{6(0.2–17) 13(1–18) 1.149 0.994–1.328 0.060 – – –} Hematologicdiseases 21(22.6) 3(37.5) 2.057 0.454–9.327 0.350 – – –

Cancerstatus(controlled) 19(20.4) 1(12.5) 0.556 0.064–4.801 0.594 – – –

Previousantibiotictherapyb _{82(88.2) 7(87.5) 0.939 0.105–8.372 0.955 – – –}

Centralvenouscatheter 86(92.5) 7(87.5) 0.570 0.061–5.312 0.621 – – –

Useofcorticosteroidsb _{84(90.3) 8(100) 1.539 0.000 0.999 – – –}

Neutropeniac _{22(23.7) 5(62.5) 5.379 1.189–24.327 0.029 – – 0.500}

Neutropeniaduration≥3days 15(16.1) 3(37.5) 3.120 0.673–14.471 0.146 – – –

Healthcare-associatedinfection (fromwardandpediatricICU)

76(81.7) 6(75.0) 0.671 0.125–3.617 0.643 – – –

LengthofstaybeforeICU admissiona

2(0–89) 1(0–7) 0.926 0.795–1.078 0.320 – – –

LengthofICUstay>3days 47(50.5) 3(37.5) 1.703 0.385–7.541 0.492 – – –

Chemotherapy/radiationtherapyb _{65(69.9) 7(87.5) 3.015 0.354–25.671 0.312 – – –}

PreviousepisodeofPseudomonas aeruginosainfectionb

16(17.2) 1(12.5) 0.688 0.79–5.982 0.734 – – –

ColonizationbyMDR-GNB 22/77(28.6) 3/6(50) 1.091 0.163–7.305 0.929 – – –

Inappropriateinitialantimicrobial treatment

52(55.9) 3(37.5) 0.473 0.107–2.096 0.324 – – –

Timetoinitiateadequate antibiotictherapy(days)a

1(0–10) 0(0–4) 0.704 0.347–1.431 0.333 – – –

Definitiveinappropriateantibiotic treatment

3(3.2) 2(25) 10.000 1.393–71.766 0.022 – – 0.457

Antibioticduration≤3days 3(3.2) 4(50) 30 4.954–181.686 <0.001 21.328 2.834–160.536 0.003

Shock 28(30.1) 7(87.5) 16.250 1.909–138.340 0.011 12.397 1.291–119.016 0.029

InfectionbyMDR-GNB 42(45.2) 5(62.5) 2.024 0.457–8.966 0.353 – – –

CI,confidenceinterval;ICU,intensivecareunit;MDR-GNB,multidrug-resistantgram-negativebacteria;OR,oddsratio. a _{Reportedasmedian(range).}

b _{Inthe30dayspriortothepositivecultureforgram-negativebacteria.} c _{Inthe7dayspriortothepositivecultureforgram-negativebacteria.}

Fig. 2 provides the frequency of each pathogen in the patientswho survivedforatleast7days.Inthesepatients, themostfrequentsites ofbacterial isolationwere tracheal aspirate(n=38,40.9%),bloodculture(n=15,16.1%),andurine culture(n=14,15.1%).

The most frequently occurring underlying diseases in thepatients with7-day mortalitywere rhabdomyosarcoma (25%),acutelymphoblastic leukemia (12.5%),acutemyeloid leukemia(12.5%),osteosarcoma(12.5%),centralnervous sys-temtumor(12.5%),retinoblastoma(12.5%),andnon-Hodgkin’s lymphoma(12.5%).Onlyonepatientinthisgrouphad under-gonebonemarrowtransplantation.Regardingcancerstatus, 50.0% of the patients were recently diagnosed, 37.5% had experienceddisease progressionor relapse, and 12.5% had controlleddisease.

AmongpatientswhosurvivedsevendaysafterGNB infec-tion, the most frequently occurring diseases were central nervoussystemtumor(38.7%),neuroblastoma(14%),and non-Hodgkin’slymphoma(9.7%).Regardingcancerstatus,50.5%of thepatientswererecentlydiagnosed,29.0%hadexperienced diseaseprogressionorrelapse,and20.4%hadcontrolled dis-ease.Noneofthepatientsinthisgrouphadundergonebone marrowtransplantation.

Among patients with 7-day mortality, there were two (25.0%)episodesofinfectionatadmission(acquiredathome), three (37.5%) episodes of healthcare-associated infections acquiredattheward,andthree(37.5%)episodesof healthcare-associatedinfectionacquiredatthepediatricICU.Ofpatients who survived seven days after GNB infection, there were 17 (18.3%) episodes of infection at admission (acquired at home),19(20.4%)episodesofhealthcare-associatedinfection acquiredattheward,and57(61.3%)episodesof healthcare-associatedinfectionacquiredatthepediatricICU.

Table 2 provides the univariate and multivariate logis-tic regression risk factor analyses for the 7-day mortality. Shock,neutropenia,antibioticduration≤3days,anddefinitive inappropriateantibioticusewereassociatedwith7-day mor-talityinunivariateanalyses.Shock(p=0.029)andantibiotic duration≤3days(p=0.003)werevariablesthatremained sig-nificantlyassociatedwith7-daymortalityinthemultivariate logisticregressionanalysis.

Fig. 3 provides the frequency of each pathogen in patientswith30-daymortality.Themostfrequentlyoccurring pathogensinthesepatientswerePseudomonas(28.6%),E.coli

(23.8%),andAcinetobacter(23.8%).Inthisgroup,themost fre-quentsitesofbacterialisolationweretrachealaspirate(n=5,

Proteus mirabilis 1 5% Escherichia coli 5 24% Pseudomonas sp. 6 28% Klebsiella pneumoniae 2 9% Enterobacter sp. 1 5% Acinetobacter 5 24%

Klebsiella pneumoniae and Escherichia coli

1 5%

Fig.3–Gram-negativebacterialisolatesdetectedinthepatientswithGram-negativebacterialinfectionsand30-day mortality(deathwithin30daysofthepositiveculture)inapediatricintensivecareunit(n=21).

23.8%), blood culture(n=5,23.8%), combination oftracheal aspirateandbloodculture(n=3,14.3%)andurineculture(n=3, 14.3%).

Themostfrequentlyoccurringunderlyingdiseasesinthe patientswith30-daymortalitywerecentralnervoussystem tumor(28.6%),acute lymphoblasticleukemia (14.3%),acute myeloid leukemia (9.5%), rhabdomyosarcoma (9.5%), prim-itive neuroectodermal tumor (9.5%), retinoblastoma (9.5%), non-Hodgkin’slymphoma(9.5%),neuroblastoma(4.8%),and osteosarcoma(4.5%).Onlyonepatientinthisgrouphad under-gonebonemarrowtransplantation.Regardingcancerstatus, 47.6% of the patients were recently diagnosed, 47.6% had experienceddiseaseprogressionorrelapse,and4.8%had con-trolleddisease.

Inthepatientswhosurvived30daysafterGNBinfection, themostfrequentlyoccurringunderlyingdiseaseswere cen-tral nervous system tumor (38.7%), neuroblastoma(15.0%), andnon-Hodgkin’slymphoma(10.0%).Regardingcancer sta-tus,51.3%ofthepatientswererecentlydiagnosed,25.0%had experienceddisease progressionor relapse, and 23.8% had controlleddisease. None ofthe patients inthis group had undergonebonemarrowtransplantation.

In the patients with 30-day mortality, there were five (23.8%)episodesofinfectionatadmission(acquiredathome), 6(28.6%)episodesofhealthcare-associatedinfectionacquired attheward,and10(47.6%)episodesofhealthcare-associated infectionacquiredatthe pediatricICU.Inthepatientswho survived30daysafterGNBinfection,therewere14 (17.5%) episodes of infection at admission (acquired at home), 16 (20.0%)episodesofhealthcare-associatedinfectionacquired attheward,and50(62.5%)episodesofhealthcare-associated infectionacquiredatthepediatricICU.

Fig.4providesthefrequencyofeachunderlyingdiseases amongpatientswhosurvived30days.Inthesepatients,the mostfrequentsitesofbacterialisolationweretracheal aspi-rate (n=34, 42.5%), blood culture (n=13,16.3%), and urine culture(n=11,13.8%).

The results of the univariate and multivariate logistic regression analyses are provided in Table 3. Only shock (p=0.004)andcolonizationbyMDR-GNB(p=0.016)were sig-nificantlyassociatedwith30-daymortalityinthemultivariate logisticregression.

Discussion

Researchhaspreviouslyfocusedonadultpatients,whilethe sampleofthe present study includedcriticallyill pediatric patientswithcancerandGNBinfection,aspecificand vulnera-blepopulationofwhichthereislittleinformationavailable,in apediatricICUthatspecializesinthemanagementofpatients withcancerandseverecomplications.Shockemergedasan importantpredictorofboth7-and30-daymortality. Further-more,appropriateantibioticduration≤3dayswasassociated with7-daymortality,whereascolonizationbyMDR-GNBwas associatedwith30-daymortality.Atthesame time,cancer statuswas notassociatedwithmortality,potentiallyowing totheexclusionofpalliativecarepatientsfromICU admis-sion.Theidentificationofriskfactorsformortalityinthese patientswithGNBinfectionmayassistwiththeprevention offutureinfectionsandplanningofappropriatemanagement strategies.

Thisisparticularlyimportantgiventhatsepsiscontinues tobeacommoncomplicationinpatientswithcancerandis

Pseudomonas sp. 21 26% Stenotrophomonas maltophilia and Pseudomonas sp. 1 1% Klebsiella pneumoniae 13 16% Escherichia coli 5 6% Morganella morganii 2 3% Acinetobacter sp. 17 21% Proteus mirabilis 1 1% Enterobacter sp 7 9% Citrobacter sp. 1 2% Elizabethkingia meningoseptica 4 5% Stenotrophomonas maltophilia 7 9%

Klebsiella oxytoca and Escherichia coli

1 1%

Fig.4–Gram-negativebacterialisolatesdetectedinthepatientswithGram-negativebacterialinfectionswhosurvived30 daysafterthepositivecultureinapediatricintensivecareunit(n=80).

responsibleforalmosthalfofICUadmissionsinnonscheduled surgicalpatients.3Oncologicpatientsrepresentaconsiderable proportionofsepticpatientswithuptooneinsixseverely sep-ticpatientshavingmalignancies;thesepatientshavea30% higherriskofdeathwhencomparedwithgeneralpatients.3

Childrenwithmultipleorgandysfunctionsyndromeand sep-sisarealsoatagreaterriskofmortalitythanthosewithout sepsis.4

Theimpact ofappropriateempiricalantimicrobial ther-apyhas notbeen clearly established.In the current study, a significant association was not found between mortality andinitialappropriateantimicrobialtreatmentor thetime toinitiateadequateantibiotictherapy.Theseresultssupport thosereportedinpreviousstudiesindicatingthatantibiotic resistance5,6_{andinitialappropriateantimicrobialtreatment}7

mayhavelimitedimpactonmortality.

Therelationshipbetweenthetimelinessofadequate ther-apyandprognosisiscomplex.Physiciansoftenprescribeearly extended-spectrum antimicrobial therapy to patients that presentwithsevereclinicalconditions;5_{theclinicaloutcome}

isinfluencedbydiseaseseverityanddegreeofvirulence,3_and

patientswithseriousunderlyingdiseaseandsepticshockare lesslikelytotolerate delaysinthe administrationof effec-tive antibiotics. In contrast, antimicrobial therapy is often delayed inpatients who donothave organ dysfunctionor forwhom there isa delay ina positive blood culture.5 _In

adultswithcancerandStenotrophomonasmaltophiliainfection, everyadditionaldayofadequateantibiotictherapyhasbeen

demonstratedtodecreasetheriskofmortalityby1.36,7_whilea

retrospectivecohortstudysuggestedthateveryhourofdelay ineffectiveantibioticadministrationfrom thesecond hour aftertheonsetofpersistentorrecurrenthypotension(septic shock)significantlyincreases hospitalmortality.8 _Moreover,

shock has been associated with mortality in a number of studies.3,5,9,10 _{Therefore,thedelayofappropriateantibiotics}

confersagreaterriskofmortalityinpatientswithshockand influencesprognosis.Theresultsofthecurrentstudy,in addi-tion to those of other studies, support the significanceof diseaseseverityonpatientoutcomes.Theimpactofresistant GNBinfectiononmortalityalsodependsontheseverityofthe underlyingdisease,andthenatureandseverityoforgan fail-urearemajordeterminantsofoutcomeincriticallyillpatients withcancer.5_{Inthepresentstudy,theseverityofthe}

under-lyingdiseasemayexplaintheobservedassociationbetweena shortduration(≤3days)ofantibioticadministrationand7-day mortality.Finally,patientswithearlymortalityneverreceive antimicrobialtherapy.5

However, it has also been shown that a 2–3-day delay in adequate antibiotic therapy has little effect on patient mortality, potentially related to the original focus of the infection.11_{Forexample,pooreroutcomeshavebeenobserved}

inpatientswithnon-urinarytractinfections,primarily pneu-monia and abdominal infections.3 _{In the present study,}

pneumonia (38.6%, n=39/101) and bloodstream infections (17.8%, n=18/101) accounted for over half of the infec-tions (56.4%),and theseinfections areassociatedwithpoor

Table3–Demographicandclinicalvariablesrelatedto30-daymortalityinpatientswithGram-negativebacterial infectionsinapediatricintensivecareunit(ICU)analyzedusingunivariateandmultivariatelogisticregression.

Univariatelogisticregressionanalysis Multivariatelogistic regressionanalysis Survivors n=80 n(%) Non-survivors n=21 n(%) OR 95%CI pvalue OR 95%CI pvalue Gender(boys) 43(53.8) 9(42.9) 0.645 0.245–1.702 0.376 – – – Age(years)a _{6(0.2–17) 11(0.5–18) 1.039 0.954–1.131 0.377 – – –} Hematologicdiseases 17(21.3) 7(33.3) 1.853 0.646–5.314 0.251 – – –

Cancerstatus(controlled) 19(23.8) 1(4.8) 0.161 0.020–1.276 0.084 – – –

Previousantibiotictherapyb _{71(88.8) 18(85.7) 0.761 0.187–3.101 0.703 – – –}

Centralvenouscatheter 73(91.3) 20(95.2) 1.918 0.223–16.512 0.553 – – –

Useofcorticosteroidsb _{71(88.8) 21(100) 4.778 0.000 0.999 – – –}

Neutropeniac _{20(25) 7(33.3) 1.5 0.531–4.239 0.444 – – –}

Neutropeniaduration≥3days 13(16.3) 5(23.8) 1.611 0.502–5.172 0.423 – – –

Healthcare-associatedinfection (fromthewardandpediatricICU)

66(82.5) 16(76.2) 0.679 0.213–2.161 0.512 – – –

LengthofstaybeforeICU admissiona

1.5(0–89) 2(0–36) 0.983 0.941–1.027 0.456 – – –

LengthofICUstay>3days 43(53.8) 7(33.3) 2.324 0.848–6.370 0.101 – – –

Chemotherapy/radiationtherapyb _{54(67.5) 18(85.7) 2.889 0.780–10.693 0.112 – – –}

PreviousepisodeofPseudomonas aeruginosainfectionb

15(18.8) 2(9.5) 0.456 0.096–2.174 0.324 – – –

ColonizationbyMDR-GNB 14/64(21.8) 11/19(57.9) 6.286 1.185–33.346 0.031 12.002 1.578–91.286 0.016

Inappropriateinitialantibiotic 43(53.8) 12(57.1) 1.147 0.435–3.025 0.781 – – –

Timetoinitiateadequateantibiotic therapy(days)a

1(0–10) 1(0–4) 0.955 0.735–1.242 0.733 – – –

Definitiveinappropriateantibiotic treatment

3(3.8) 2(9.5) 2.702 0.421–17.326 0.295 – – –

Antibioticduration≤3days 3(3.8) 4(19) 6.039 1.236–29.509 0.026 4.758 0.764–29.645 0.095

Shock 22(27.5) 13(61.9) 4.284 1.563–11.742 0.005 6.174 1.760–21.664 0.004

InfectionbyMDR-GNB 35(43.8) 12(57.1) 1.714 0.649–4.525 0.276 – – –

CI,confidenceinterval;ICU,intensivecareunit;MDR-GNB,multidrug-resistantgram-negativebacteria;OR,oddsratio. a _{Reportedasmedian(range).}

b _{Inthe30dayspriortothepositivecultureforgram-negativebacteria.} c _{Inthe7dayspriortothepositivecultureforgram-negativebacteria.}

prognoses.However,inthecurrentstudy,thedelayof appro-priateantibioticshadalimitedimpactonmortality,regardless ofthefocusofinfection.

The relationship between inappropriate initial empiric antibiotic therapy and mortality may also be affected by severaldifferentfactors.First,inappropriateantibioticsmay havesomeactivityinvivo.Cephalosporinhasbeenassociated withtreatmentfailure,but canbeeffective forGram nega-tiveproducingESBLinfectionswithlowminimuminhibitory concentrations,12 withmortalityoccurringinonly16.6% of patients with serious ESBL-producing GNB infections with cephalosporinsusceptibilityataminimuminhibitory concen-trationof2–8mcg/mLthatweretreatedwithcephalosporin.13

Piperacillinandtazobactamwerenomoreeffectivethan car-bapeneminarecent analysisofsixprospectivecohorts of patientswithbacteremiacausedbyESBL-producing E.coli.9

Therefore,theuseofinappropriateantibioticsmayhavesome effect, even when followed by appropriate antibiotic ther-apy,andashortdelay(e.g.,uptotwodays)inadjustingthe definitiveantibiotictherapymaynotimpactmortalityifthe antibiotictherapyisadjustedaccordingtotheresultsof sus-ceptibilitytesting.10,11

Furthermore,many issues may influencethe efficacyof antibiotics.Forexample,invitrosuccessmaynottranslatetoin vivoeffectivenessduetoinadequatedosing,variable pharma-cokinetics,orvariablepenetrationintoaffectedtissues,such asthelungsorabscesses.Non-removalofasepticfocus,such asaninfectedintravascularcatheteroranintra-abdominal abscess,maycompromisecurerates.Inaddition,an increas-inglyrecognizedvariablethataffectsantibioticefficacyisthe modeofadministration.Theinappropriateuseofantibiotics mayrenderatheoreticallyeffectiveantibioticineffective.14

TheincreasingprevalenceofESBLcarriageonICU admis-sionraisesimportantquestionsaboutempirictherapypolicies inpatientspresentingwithinfection,whichmayincludethe useofacarbapenemasfirst-linetherapy.15 _Sincethe

emer-genceofantibioticresistanceisassociatedwithwidespread broad-spectrum antibiotic use, the availability of effective treatments becomes limited without the cautious use of carbapenems.15_{Owingtotheincreasingdifficultyinchoosing}

initialempiricalantibioticsagainstpossibleMDR-GNB, clini-calinterventionsforinfectioncontrolmayplayanimportant role indecreasingtheprevalenceofMDR-GNB,and thereby breaktheviciouscycle.16_{ReducingtheincidenceofMDR-GNB}

withmultifacetedinterventionsmaybecrucialinimproving theoutcomesrelatedtoICU-acquiredinfectionsindeveloping countries.16

Inseverely ill hospitalized patients, the normalflora of thebowelcanbeaffected.Undertheseconditions,patients are predisposed to persistent colonization by exogenous pathogensthatcausenosocomialepidemics,17 _andamajor

riskfactorfornosocomialinfectionispriorcolonization.18,19

Theproportionofpositivesurveillanceculturesincreaseswith alongerhospitalstay;therefore,itcouldbeexpectedthatovert colonizationwouldprecedebacteremiathatoccursfollowing aprolongedICUstay.20_{Ithasbeenpreviouslydemonstrated}

thatcolonizationbyMDR-GNB isassociatedwithpoor clin-icaloutcomes inadults,21 _{and the current study indicates}

thatMDR-GNBmightbeassociatedwithlonger-term(30-day) mortality.Itisunknownwhetherhighermortalityamong col-onizedpatientswithaprolongedICUstayisrelatedtomore severeinjuries,a greaternumber ofinterventions,or more severeunderlyingillnesses.Infact,itispossiblethatisolation itselfcontributestopoorclinicalperformance.21_However,the

awarenessofMDR-GNBcolonizationcanleadtomore appro-priateantimicrobialdruguse,improvepatientoutcomes,and decreasetheemergenceofantimicrobialdrugresistance.21

Limitationsofthecurrentstudyincludeitsretrospective designandsmallsamplesize.Despitethese,significant dif-ferenceswereobserved.

Inconclusion,amajorriskfactorformortalityinpediatric oncologicpatientswithGNBinfectionisshock.Consequently, itisimportanttoprovideaggressivetherapy.

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1. PhillipsRS,SuttonAJ,RileyRD,etal.Predictinginfectious complicationsinneutropenicandyoungpeoplewithcancer (IPDprotocol).SystRev.2012;1:8.

2. TurkogluM,MirzaE,Tunc¸canOG,etal.Acientobacter baumanniiinfectioninpatientswithhematologic

malignanciesinintensivecareunit:riskfactorsandimpact onmortality.JCritCare.2011;26:460–7.

3. RosolemMM,RabelloLS,LisboaT,etal.Criticallyillpatients withcancerandsepsis:clinicalcourseandprognosticfactors. JCritCare.2012;27:301–7.

4. TantaleánJA,LeónRJ,SantosAA,SanchezE.Multipleorgan dysfunctionsyndromeinchildren.PediatrCritCareMed. 2003;4:181–5.

5. TabahA,KoulentiD,LauplandK,etal.Characteristicsand determinantsofoutcomeofhospital-acquiredbloodstream infectionsinintensivecareunits:theEUROBACT

InternationalCohortStudy.IntensiveCareMed. 2012;38:1930–45.

6. HaeuslerGM,MechinaudF,DaleyA,etal.Antibioticresistant gram-negativebacteremiainpediatriconcologypatients– riskfactorsandoutcome.PediatrInfectDisJ.2013;32:723–6.

7.DemiraslanH,SevimM,PalaC¸,etal.Riskfactorsinfluencing mortalityrelatedtoStenotrophomonasmaltophiliainfectionin hematology-oncologypatients.IntJHematol.2013;97:414–20. 8.KumarA,RobertsD,WoodKE,etal.Durationofhypotension

beforeinitiationofeffectiveantimicrobialtherapyisthe criticaldeterminantofsurvivalinhumansepticshock.Crit CareMed.2006;34:1589–96.

9.Rodrígues-Ba ˜noJ,PicónE,GijónP,etal.Riskfactorsforand prognosisofnosocomialbloodstreaminfectionscausedby extended-spectrum-beta-lactamase-producingEscherichiacoli. JClinMicrobiol.2010;48:1726–31.

10.KangCI,KimSH,KimDM,etal.Riskfactorsforandclinical outcomesofbloodstreaminfectionscausedby

extended-spectrumbeta-lactamase-producingKlebsiella pneumoniae.InfectControlHospEpidemiol.2004;25:860–7. 11.ToKK,LoWU,ChanJF,etal.Clinicaloutcomeof

extended-spectrumbeta-lactamase-producingEscherichiacoli bacteremiainanareawithhighendemicity.IntJInfectDis. 2013;17:e120–4.

12.KahlmeterG.Breakpointsforintravenouslyused cephalosporinsinEnterobacteriacea—EUCASTandCLSI breakpoints.ClinMicrobiolInfect.2008;14:169–74. 13.PatersonDL,KoWC,VonGottbergA,etal.Outcomeof

cephalosporintreatmentforseriousinfectionsdueto apparentlysusceptibleorganismsproducing

extended-spectrumbeta-lactamases:implicationsforthe clinicalmicrobiologylaboratory.JClinMicrobiol.

2001;39:2206–12.

14.CoronaA,BertoliniG,LipmanJ,WilsonAP,SingerM. Antibioticuseandimpactonoutcomefrombacteremia criticalillness:theBActeraemiaStudyinIntensiveCare (BASIC).JAntimicrobChemother.2010;65:1276–85. 15.RazaziK,DerdeLP,VerachtenM,LegrandP,LespritP,

Brun-BuissonC.Clinicalimpactandriskfactorsfor

colonizationwithextended-spectrum␤-lactamase-producing bacteriaintheintensivecareunit.IntensiveCareMed. 2012;38:1769–78.

16.TanR,LiuJ,LiM,etal.Epidemiologyandantimicrobial resistanceamongcommonlyencounteredbacteriaassociated withinfectionsandcolonizationinintensivecareunitsina university-affiliatedhospitalinShanghai.JMicrobiol ImmunolInfect.2014;47:87–94.

17.CorbellaX,PujolM,AyatsJ,etal.Relevanceofdigestivetract colonizationintheepidemiologyofnosocomialinfections duetomultiresistantAcinetobacterbaumannii.ClinInfectDis. 1996;23:329–34.

18.HarrisAD,McGregorJC,JohnsonJA,etal.Riskfactorsfor colonizationwithextended-spectrum

beta-lactamase-producingbacteriaandintensivecareunit admission.EmergInfectDis.2007;13:1144–9.

19.BalkhyHH,BawazeerMS,KattanRF,etal.Epidemiologyof Acinetobacterspp.-associatedhealthcareinfectionsand colonizationamongchildrenatatertiary-carehospitalin SaudiArabia:a6-yearretrospectivecohortstudy.EurJClin MicrobiolInfectDis.2012;31:2645–51.

20.BlotS,DepuydtP,VogelaersD,etal.Colonizationstatusand appropriateantibiotictherapyfornosocomialbacteremia causedbyantibiotic-resistantgram-negativebacteriainan intensivecareunit.InfectControlHospEpidemiol. 2005;26:575–9.

21.NemethJ,LedergerberB,PreiswerkB,etal.

Multidrug-resistantbacteriaintravellershospitalizedabroad: prevalence,characteristics,andinfluenceonclinical outcome.JHospInfect.2012;82:254–9.