Retrospective evaluation of the clinical characteristics associated with Corynebacterium species bacteremia

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

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

Original

article

Retrospective

evaluation

of

the

clinical

characteristics

associated

with

Corynebacterium

species

bacteremia

Mitsuru

Yanai

_,

_Maiko

_Ogasawasa

_,

_Yuta

_Hayashi

_,

_Kiyozumi

_Suzuki

_,

Hiromichi

Takahashi

_,

_Atsushi

_Satomura

a_{NihonUniversitySchoolofMedicine,DepartmentofInternalMedicine,DivisionofGeneralMedicine,Tokyo,Japan}

b_{NihonUniversitySchoolofMedicine,DepartmentofPathologyandMircobiology,DivisionofLaboratoryMedicine,Tokyo,Japan}

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Articlehistory:

Received15September2017

Accepted21December2017

Availableonline19January2018

Keywords: Corynebacteriumspecies Bloodculture Bloodstreaminfection Contamination

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Objectives:Corynebacterium spp.are becomingrecognized as pathogens that potentially

causevariousinfections.Weaimedtoevaluatetheclinicalcharacteristicsassociatedwith

Corynebacteriumspp.bacteremia.

Patientsandmethods: Weretrospectivelyreviewedthemedicalrecordsofalladultpatients

whohadpositivebloodculturesforCorynebacteriumspp.inasingleuniversityhospital

betweenJanuary2014andDecember2016.Patientsweredividedintoabacteremiagroup

andacontaminationgroupbasedonmicrobiologicaltestresultsandclinical

characteris-tics.Patients’characteristics,antimicrobialsusceptibilityofisolatedspecies,antimicrobials

administered,andpatientoutcomeswereevaluated.

Results:Corynebacteriumspp.wereisolatedfrombloodsamplesof63patients; Corynebac-teriumstriatumwasthepredominantisolate.Twenty-eightpatientsweredeterminedtohave

bacteremia.Youngerage(p=0.023),shortertimetopositivity(p=0.006),longerhospitalstay

(p=0.009),andpresenceofanindwellingvascularcatheter(p=0.002)wereobservedmore

ofteninthebacteremiagroupcomparedtothecontaminationgroup.Thesourceofinfection

inmostpatientswithbacteremiawasanintravenouscatheter.Alltestedstrainswere

sus-ceptibletovancomycin.Fourofthe27patientswithbacteremiadied,despiteadministration

ofappropriateantimicrobialtherapy.

Conclusions:We foundthatyounger age,shortertime to positivity,and presence ofan

indwellingcatheterwererelatedtobacteremiacausedbyCorynebacteriumspp.

Appropri-ateantimicrobialsshouldbeadministeredonceCorynebacteriumspp.areisolatedfromthe

bloodandbacteremiaissuspected.

©2018SociedadeBrasileiradeInfectologia.PublishedbyElsevierEditoraLtda.Thisisan

openaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/

by-nc-nd/4.0/).

∗ _{Correspondingauthor.}

E-mailaddress:yanai.mitsuru@nihon-u.ac.jp(M.Yanai).

https://doi.org/10.1016/j.bjid.2017.12.002

1413-8670/©2018SociedadeBrasileiradeInfectologia.PublishedbyElsevierEditoraLtda.ThisisanopenaccessarticleundertheCC

Introduction

ExceptforCorynebacteriumdiphtheriae,allCorynebacteriumspp.

are ubiquitous skin commensals and are usually

consid-ered to be blood culture contaminants.1 However, some

reportshavehighlighted the importanceofC.striatum and

C.jeikeium ascauses ofcatheter-related bloodstream

infec-tions in immunocompromised patients, and as causes of

various infections in immunocompetent patients, such as

arthritis and endocarditis.2–5 _{It is difficult to distinguish}

contamination from bacteremia whenCorynebacterium spp.

orcoagulase-negativestaphylococciare isolatedfromblood

samples.6–9_{Inclinicalpractice,itisimportanttodistinguish}

contaminationfrombacteremiatopreventunnecessary

pre-scriptionofantimicrobialagents,whichcanleadtoselection

ofantimicrobial-resistantorganisms,longerdurationof

hos-pitalization,andincreasedcosts.10

TherearefewstudiesonCorynebacteriumspp.infection,and

theclinicalsignificanceoftheseorganismsremainsunclear.

Thus,inthisstudy,weaimedtoevaluatetheclinical

charac-teristicsofbloodstreaminfectionscausedbyCorynebacterium

spp.byanalyzingclinicalcasesofbloodculturespositivefor

Corynebacteriumspp.

Patients

and

methods

Patientselectionandstudyperiod

ThisretrospectivecohortstudywasconductedattheNihon

UniversityItabashiHospital(NUIH),a1037-bedteaching

hos-pital.Thecatchmentarea ofNUIH encompassesthe north

partofTokyo,Japan.Wereviewedthemedicalrecordsofall

patientsaged>18yearswhohadpositivebloodcultureresults

forCorynebacteriumspp.betweenJanuary2014andDecember

2016.Onlythefirstepisodewasconsideredincaseofmultiple

episodeswithina4-weekperiod.

Definitions

Blood specimenswere cultured using a set ofculture

bot-tles(BACTEC92Fand 93F;BDDiagnosticSystems, Franklin

Lakes,NJ,USA)and automated systems(BACTEC9240and

9120;BDDiagnosticSystems)withcontinuousagitationwere

used.Bacterialspecieswereidentifiedthroughseveral

meth-ods,including assessmentofmorphologic appearance and

colonies,andassessmentofbiochemicalcharacteristicsusing

manualproceduresorcommercialkits(APIseries;bioMérieux,

Marcyl’Etoile,FranceandN-IDtestSP-18;Nissui

Pharmaceu-ticalCo.,Ltd., Tokyo, Japan)oran automatedidentification

system (RAISUS system, Nissui Pharmaceutical Co., Ltd.).

Antimicrobialsusceptibility tests were performed by broth

microdilution using the Clinical and Laboratory Standards

Institute’sbreakpoints.11

Patientswerecategorizedashavingbacteremiaifatleast

twobloodculturesetstakenatthesametimeturnedout

pos-itiveforthe same Corynebacteriumspp., orwhen oneblood

culturespecimenandanotherclinicallyrelevantsampletaken

from another site (such as acatheter tip, sputum,or pus)

yieldedpositiveresults.Ifonlyonesetofbloodculturesturned

out positiveand culturespecimenstaken from other sites

werenegative,orifanotherinfectionwasmorelikelyatthe

time,thecasewasdeemedtobecontamination.Thefinal

deci-sionofbacteremiaorcontaminationwasdeterminedbythe

authors,whichincludescertifiedinfectiousdiseases

special-istsontheantimicrobialstewardshipprogramteam.

Evaluatedparameters

We reviewed the medical records to extract data on each

patient’sbackground(age,sex,underlyingdisease,body

tem-perature,clinicaldepartment,presenceofavascularcatheter,

laboratory data), clinical course (response to antimicrobial

therapy),andoutcome.Inaddition,weanalyzed

microbiolog-icaldata,includingtimefromadmissiontocollectionofblood

culturesamplesandtimetopositivity;antimicrobial

suscep-tibilitytestresults;andisolationofbacteriafromsitesother

thanblood.

Statisticalanalysis

Continuousdatawereexpressedasthemedianand

interquar-tile range (IQR), and categorical variables as percentages

or absolute values. Statistical significance was calculated

using the chi-square test for categorical variables and the

Mann–WhitneyUtestforcontinuousvariables.Ap-value<0.05

was considered statisticallysignificant. Statistical analyses

were performedusingStatMateVsoftware(ATMSCo.,Ltd.,

Tokyo,Japan).

Ethicalconsiderations

TheClinicalResearchJudgingCommitteeatNUIHapproved

thestudyprotocolandwaivedtheneedforinformedconsent

giventheretrospectivenatureofthestudy.

Results

Duringthestudyperiod,66patientshadpositiveblood

cul-turesforCorynebacteriumspp.Threepatientswereexcluded

because of a second episode of serial infection. Of the

remaining63patients,28(44%)metthecriteriaforbacteremia

and 35 (56%) met the criteria for contamination. Patients’

baselinecharacteristicsaresummarizedinTable1.The

over-all medianagewas73years,and thecontaminationgroup

wassignificantlyolderthanthebacteremiagroup(p=0.023).

Menconstituted74.6%ofcases.Fourteencaseswere

identi-fiedintheemergencydepartmentandcriticalcaremedicine;

thisdepartmenthadasignificantlyhigherproportionof

con-taminationcasesthandidtheotherdepartments(p=0.049).

Overall,39patientshadacentralvenouscatheterinplace,five

hadaperipheralvenouscatheterinplace,and19didnothave

avenouscatheter;bacteremiawasdiagnosedmorefrequently

in patients who had peripheral or central venous inserted

catheters(p=0.002).Themedianintervalfromadmissionto

bloodculturesamplingwas25days(IQR,6–49);thisinterval

wassignificantlylongerinthebacteremiagroupthaninthe

contaminationgroup(p=0.006).Themediantimetoculture

Table1–CharacteristicsofpatientswithbacteremiaorbloodculturecontaminationwithCorynebacteriumspp.

Total Bacteremia Contamination p-value

Numberofcases,n(%) 63 28 35

Age(years),median(IQR) 73(62.0–81.5) 65.5(57.3–77.0) 75(70.0–83.0) 0.023

Male:femaleratio 47:16 22:6 25:10 0.517

Department,n(%)

Emergencyandcriticalcaremedicine 14(22) 3(11) 11(31) 0.049

Gastrointestinalmedicine 8(13) 4(14) 4(11)

Hematologyandrheumatology 8(13) 6(21) 2(6)

Cardiovascularsurgery 7(11) 5(18) 2(6) Nephrology 5(8) 4(14) 1(3) Cardiovascularmedicine 5(8) 2(7) 3(9) Digestivesurgery 4(6) 2(7) 2(6) Generalmedicine 3(5) 0(07) 3(9) Othera _{9(14) 2(7) 7(20)} Underlyingdiseases,n Malignancy 22 13 9 0.086 DM 6 4 2 0.249

ESRDondialysistherapy 12 8 4 0.085

LC 3 2 1 0.427

Vascularcatheterplacement,n(%)

CVcatheter 39(62) 21(75) 18(51)

Peripheralcatheter 5(8) 4(14) 1(3)

Nocatheter 19(30) 3(11) 16(46) 0.002

Timefromadmissiontosampling(days),median(IQR) 25(6–49) 36(15–61) 13(0–31) 0.006 Timetopositiveculturedetection(days),median(IQR) 1(1–2) 1(1–1) 2(1–2) 0.009

Temperature>38◦C,n(%) 51(81) 25(89) 26(74) 0.132

WBCcount(×109_{/L) 9.2(5.0–13.2) 8.9(3.1–12.5) 9.2(7.3–13.8) 0.290}

CRP(mg/dL),median(IQR) 6.6(3.3–15.9) 6.1(3.2–13.5) 7.1(4.4–16.4) 0.481 Hospitalstay(days),median(IQR) 57(27–97) 81(38–135) 36(17–63) 0.002

Abbreviations:IQR,interquartilerange;DM,diabetesmellitus;ESRD,end-stagerenaldisease;LC,livercirrhosis;CV,centralvenous;WBC,white bloodcell;CRP,C-reactiveprotein.

a _{Other:urology(n=2),respiratorymedicine(n=2),dermatology(n=2),orthopedics(n=1),respiratorysurgery(n=1),andneurosurgery(n=1)}

departments.

thaninthecontaminationgroup(p=0.009).Therewereno

sig-nificantdifferencesinmedianleukocytecountorC-reactive

proteinlevelbetweenthetwogroups.In51ofthe63cases,the

patienthadfever(temperature>38◦C)atthetimetheblood

culturesamplewastaken.

Final identification of the Corynebacterium spp. isolated

wereC.striatum(n=38),C.jeikeium(n=6),andC.argentoratense

(n=2). The species was reported only as “Corynebacterium

sp.” in 19 cases, either because the physician in charge

didnotrequestfurtheridentificationor thelaboratorywas

unabletoidentifythe species.Two species(C.striatumand

Corynebacterium sp.) were identified simultaneously in two

cases(Table2).Therewasasignificantdifferencebetweenthe

differentspeciesregardingratesofbacteremiaversus

contam-ination(p=0.001).Two setsofblood cultureswere obtained

from60patients,andonesetofbloodcultureswasobtained

fromthreepatients.Multiplebloodculturespecimenswere

positive in38% (23/60)of thesepatients. Thesame

organ-ismisolatedfrom bloodsampleswasisolated fromvenous

cathetertipspecimens(n=11), followedbysputum,wound

site,urine,anddrainspecimens.In45patients,onlytheblood

culturespecimenwaspositiveforCorynebacteriumspp.A

cen-tralorperipheralvenouscatheterwasconsideredthesource

of infection in 20 of the 28 patients with bacteremia; the

cathetertipwas culturepositiveforCorynebacteriumspp.in

12casesandculturenegativeinthreecases;thecatheterwas

notremovedandsentforcultureintheremainingfivecases.

The results of the antimicrobial susceptibility tests are

shown in Table3. All isolates were susceptibleto

minocy-cline, vancomycin, and teicoplanin. Most isolates were

resistant to penicillin, imipenem/cilastatin, erythromycin,

clindamycin,andlevofloxacin.Table4showsthe

antimicro-bialagentsadministeredafterthefinalreportwasissuedby

themicrobiologylaboratory.Appropriateantimicrobialswere

administered in all except one case in which the patient

died beforethe final reportwas issued. Ofthe 27 patients

whoreceivedappropriateantimicrobialtherapy,24werecured

whilethreediedasaresultofCorynebacteriumbacteremia.

Discussion

Inthis retrospectivestudy,weanalyzedtheclinical dataof

patients who had Corynebacterium spp. identified on blood

culture. More than 40% of patients were determined to

have bacteremiabasedon theirclinical characteristics and

course. C.striatum was the speciesmostfrequently

identi-fiedinpatientswithbacteremia.Therouteofinfectionwas

via venous cathetersin >50% of patientswith bacteremia;

this infection route has been reported in several

Table2–FinalidentificationofCorynebacteriumspp.,bloodculturepositivitypattern,andsitesfromwhichspecimens, takensimultaneouslywithbloodspecimens,culturedpositiveforCorynebacteriumspp.

Total(n=63) Bacteremia(n=28) Contamination(n=35)

Identifiedspeciesa

Corynebacteriumstriatum 38 22 16

Corynebacteriumjeikeium 6 4 2

Corynebacteriumargentoratense 2 1 1

Corynebacteriumsp. 19 1 18

Positivity[positiveset(s)/set(s)taken]

2/2 23 23 0 1/2 39 5 34 1/1 3 0 3 Isolationsitesb Cathetertip 11 9 2 Sputum 5 2 3 Wound(pus) 3 2 1 Urine 2 2 0 Drain 1 1 0 None 45 15 30

a _{Intwopatients,twospecies(C.striatumandCorynebacteriumsp.)wereidentifiedinthesamebloodculturesampling.}

b _{Infourcases,thesamespecieswereisolatedfrommultiplesites(threecasesinthebacteremiagroupandonecaseinthecontamination}

group).

Table3–AntibioticsusceptibilityofCorynebacteriumspp.isolatedfrombloodculturespecimens(susceptible/tested(%)).

ABPC ABPC/SBT IPM/CS GM EM CLDM MINO VCM TEIC ST LVFX

C.striatum(n=31) 2/31(7) 5/31(16) 5/31(16) 22/22(100) 3/22(14) 3/31(10) 31/31(100) 31/31(100) 31/31(100) 27/31(87) 1/31(3)

C.jeikeium(n=6) 0/6(0) 0/6(0) 1/6(17) 1/6(17) 0/6(0) 0/6(0) 4/6(67) 6/6(100) 6/6(100) 4/6(67) 0/6(0)

C.argentoratense(n=2) 0/2(0) 0/2(0) 0/2(0) 2/2(100) 2/2(100) 2/2(100) 2/2(100) 2/2(100) 2/2(100) 2/2(100) 0/2(0)

Corynebacteriumsp.(n=1) 0/1(0) 0/1(0) 1/1(100) 1/1(100) 0/1(0) 0/1(0) 1/1(100) 1/1(100) 1/1(100) 0/1(0) 0/1(0)

Abbreviations:ABPC,ampicillin;ABPC/SBT,ampicillin–sulbactam;IPM/CS,imipenem/cilastatin;GM,gentamicin;EM,erythromycin;CLDM, clindamycin;MINO,minocycline;VCM,vancomycin;TEIC,teicoplanin;ST,sulfamethoxazole–trimethoprim;LVFX,levofloxacin.

Table4–Antimicrobialtreatmentandoutcomeof patientswithbacteremiacausedbyCorynebacteriumspp.

Antimicrobialdrug n(%) Outcome

Cured Died Vancomycin 19(68%) 17 2 Teicoplanin 4(14%) 3 1 Daptomycin 2(7%) 2 0 Linezolid 1(4%) 1 0 Minocycline 1(4%) 1 0 None 1(4%) 0 1

infections, there is broad consensus that growth of the sameorganisminpairedbloodculturesamples,drawnfrom a peripheral vein and the suspected source, indicates a true or relevant infection.13 _{Corynebacterium spp. can}

colo-nize prostheses, catheter tips, and ventilator and feeding

tubes; however, Corynebacterium spp. isolated from these

prosthesesareusuallyconsideredcontaminants.Ingeneral,

bacterialskincommensalshaverelativelylowvirulence,but

DeSouzaetal.14_{recentlyreportedthatbiofilmproductionby}

antimicrobial-resistantC.striatumisanewvirulencefactor

andisrelatedtonosocomialoutbreaks.Inaddition,this

organ-ismhasbeenreportedtocausepneumoniaandurinarytract

infections.15,16

Asmentioned above,forthe purposeofthis study,

bac-teremiawasdefinedastwobloodculturesetstestingpositive

or one blood culture set testing positive plus a positive

culture result for a specimen from another site. There is,

however, evidence that bacterialskin commensals isolated

from evenone blood culture specimen might reflect

clini-callyrelevantinfection.17,18_{Severalstudieshavereportedthat}

the timetopositivitycanbeused todiscriminatebetween

contaminationand bacteremia.19–21 _{Zhanget al.}21 _reported

that the time to positivity was <36h in 98% of cases of

bacteremiacaused byGram-positivebacteria. In ourstudy,

although the exact time to positivity (in hours) was not

recorded, the time to positivity (in days) was significantly

longer in the contamination group and was within three

daysinallcasesofbacteremia.Inthepresentstudy,atime

to positivity of four days or more suggested

contamina-tion.

Paststudieshavegenerallyreportedonthesusceptibilityof

C.striatumtothe␤-lactamgroupofantimicrobials.1,22,23

How-ever,withincreasinguseofbroad-spectrumantibiotics,recent

studies have shown the emergence ofmultidrug resistant

strains.24,25_{Inourstudy,mostisolatedstrainsweremultidrug}

resistant,andalltestedstrainsweresusceptibleonlyto

gly-copeptides, suchasvancomycin and teicoplanin.Basedon

ourresults(andinaccordancewiththoseofpreviousstudies),

therapyshouldincludevancomycinbecauseinvitroresistance

tovancomycinhasnotbeenreported.2,25

Allbutonepatientinthisstudyreceivedprompttreatment

withanantimicrobialagenttowhichtheisolated

Corynebac-teriumspp.wassusceptible.Nonetheless,threepatientsdied;

theircomorbiditiesweremalignancy(n=2)and

immunosup-pression(n=1).Allthreepatientshadcentralvenouscatheters

in situ; these catheters were not removed because of the

severe clinical condition of the patients. Previous studies

havereportedthatwhileCorynebacteriumspp.infectioncan

beassociatedwithdeath,mostcasesare relativelyeasy to

managewithantimicrobialtherapyandcatheterremoval,if

applicable.26–28 _{Kimura et al.}29 _{also reported that catheter}

removalwithinaweektendedtobeassociatedwithbetter

outcomesinpatientswithacentralvenouscatheter.

Thisstudyhassomelimitations.First,itwasa

retrospec-tivestudy.Second,wecouldnotclearlydistinguishbetween

thetrueinfectiongroupandcontaminationgroupbecauseof

theabsenceofestablishedclinicalandbacteriological

mark-ersofinfectionwithCorynebacteriumspp.18,30_{Therefore,some}

patientswithcontaminationmayhavebeenincludedinthe

bacteremiagroup,andviceversa.However,allpatientsinthe

bacteremiagroupwereconsideredtohavebacteremiaandall

receivedtreatmentforbloodstreaminfectionwith

Corynebac-teriumspp.,basedontheirclinicalcourse,cultureresults,and

therecommendationofinfectiousdiseasespecialists.Third,

speciesidentificationwascarriedout inonlyasmall

num-berofpatientsbecauseitisnotgenerallyperformedinJapan,

especiallyifcontaminationisstronglysuspected.Thus, we

couldnotevaluatetheimpactofdifferentspeciesonclinical

outcomes.Lastly,dataonthetotaldurationoftherapywere

notcollected;thus,animportantdimensioninthetreatment

andcourseofbacteremiawasneglected.

Conclusions

Inconclusion,ouranalysisshowedthatCorynebacteriumspp.

isolatedfrombloodculturespecimenscancausebloodstream

infectionsinaconsiderableproportionofpatients.Younger

age,shortertimetoculturepositivity,andthepresenceofan

indwellingcatheterareassociatedwithbacteremia.Because

multidrug-resistantCorynebacteriumspp.havebecome

com-mon,administrationofappropriateantimicrobialagents,such

as vancomycin, should be initiatedpending the results of

antimicrobialsusceptibilitytestinginpatientswithsuspected

bacteremiacausedbyCorynebacteriumspp.

Funding

Thisresearchdidnotreceiveanyspecificgrantfromfunding

agenciesinthepublic,commercial,ornot-for-profitsectors.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgments

We would like to thank Elsevier

(http://webshop.elsevier.com/languageservices/) for English

languageediting.

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