Severe infective endocarditis with systemic embolism due to community associated methicillin-resistant Staphylococcus aureusST630

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

Case

report

Severe

infective

endocarditis

with

systemic

embolism

due

to

community

associated

methicillin-resistant

Staphylococcus

aureus

ST630

Beiwen

Zheng

_,

_Saiping

_Jiang

_,

_Zemin

_Xu

_,

_Yonghong

_Xiao

_,

_Lanjuan

_Li

b_{CollaborativeInnovationCenterforDiagnosisandTreatmentofInfectiousDiseases,Hangzhou,China}

c_{DepartmentofPharmacy,TheFirstAffiliatedHospital,SchoolofMedicine,ZhejiangUniversity,Hangzhou,China} d_{NingboInstituteofMicrocirculationandHenbane,Ningbo,China}

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Articlehistory:

Received15May2014 Accepted1July2014

Availableonline1September2014

Keywords: Community-acquiredMRSA Infectiveendocarditis ST630 Surgicaltherapy

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Community-associatedmethicillin-resistantStaphylococcusaureus(CA-MRSA)are increas-inglycausinginfectiveendocarditisoverthepastdecade.Herewereportahealthyman whodevelopedasevereacuteinfectiveendocarditiswithsystemicembolismcausedby CA-MRSA.Thestrainwasrecoveredfromrepeatedbloodculturesandwascharacterizedusing moleculardetectionandgenotyping.TheS.aureusisolatewastypedasST630SCCmecVwith

spa-typet4549,agrI/IVandwasPVL-negative.Thisistheonlycasereport,toour knowl-edge,ofCA-MRSAinfectiveendocarditisinChina.Thiscasehighlightstheemergenceand geographicalspreadoflife-threateningCA-MRSAinfectionwithinChina.

©2014PublishedbyElsevierEditoraLtda.

Introduction

Since the first genuine community-associated

methicillin-resistant Staphylococcus aureus (CA-MRSA) infection was

reported inAustralia in the early 1990s, the emergence of

CA-MRSA infection has increased in recent years all over

the world. CA-MRSA is primarily associated with healthy

individualskinandsofttissueinfections.Additionally, inva-sive diseases, including bacteremia, infective endocarditis (IE),osteomyelitis,andhemorrhagicnecrotizingpneumonia,

∗ _{Correspondingauthorat:StateKeyLaboratoryforDiagnosisandTreatmentofInfectiousDisease,TheFirstAffiliatedHospital,Schoolof}

Medicine,ZhejiangUniversity,Hangzhou310003,China.

E-mailaddresses:xiao-yonghong@163.com,ljli@zju.edu.cn(Y.Xiao).

alsohavebeenreported.Infectiveendocarditiscanseriously damageheartvalvesandcauseotherseriouscomplications, associatedwithsignificantmorbidityandmortality,anditis lethal if notpromptly treated with appropriateantibiotics, regardlessofwhethersurgeryisperformed.1_{However,despite}

improveddiagnostictechniquesand advancesintreatment

options,neitheritsincidencenormortalityhasdecreasedin thepastyears.2_{S.aureusisaleadingcauseofleft-sided}

infec-tiveendocarditisindevelopingcountries,nevertheless,only

sporadic cases ofendocarditis caused byCA-MRSA among

healthyindividualshavebeenreported.3_{Herewedescribethe}

http://dx.doi.org/10.1016/j.bjid.2014.07.006

firstcaseofinfectiveendocarditiscomplicatedwithsystemic

embolismduetoanovelCA-MRSAST630inChina,whichwas

successfullytreatedwithacombinationofantimicrobialsand surgicaltherapy.

Case

presentation

A49-year-old previouslyhealthy manwas admittedtothe

hospitalwitha10-dayhistoryofchills,fever,anddyspneain August2011.Hehadnohistoryofsurgeryorintravenousdrug use,andhadnonotablemedicalrecord.Atthetimeof hos-pitaladmission,physicalexaminationrevealedapulserate of62beats permin,respiratoryrateof20breathspermin,

andbloodpressureof125/83mmHg.Asystolicmurmurwas

bestheardattheapex.Hewasfebrile(40.7◦C)andhehada minorabrasion onleft foot.Therestofhisphysical exami-nationwasunremarkable.Pertinentlaboratoryinvestigations revealed white blood cellcount of23,100/mm3_{, with94.5%}

neutrophils,3.2%lymphocytes,and2.3%mononuclearcells, plateletsof40,000/mm3_{andC-reactiveproteinof58.6mg/L.}

The patient was hospitalized for a presumptive diagnosis

ofsepticemia. Empiricalantibiotics were started with van-comycinandlevofloxacin(0.5gq8h)therapy.

Duringthenexttwodays,echocardiographyrevealedlarge vegetationonthe anterior mitralvalveleaflet (3cm×3cm) withmoderatemitralvalveregurgitation(Fig.1A)Spiral

com-putedtomography(CT)showedrenalandsplenicinfarction

(Fig.1B).CTscansofthebraindemonstratedmultiple low-densitybilaterallesionsofthetemporallobes,rightparietal

lobe and occipital lobe, suggestive of cerebral embolism.

Preliminary blood cultures grew S. aureus susceptible to

ciprofloxacin,rifampicin,linezolid,vancomycin,tetracycline,

sulfamethoxazole, levofloxacin and fosfomycin but

resis-tanttopenicillin,oxacillin,clindamycin,cefazolin,cefoxitin,

cefuroxime,and erythromycin,as determinedon the basis

ofCLSIdiscdiffusionstandards.Adiagnosisofacute infec-tiveendocarditiswithsystemicembolismcausedbyCA-MRSA wasthusconsidered.Becauseofhisimpairedrenalfunction and bacterial susceptibility profile,the patient was treated withintravenouslinezolid(600mgq12h)andfosfomycin(8.0g q12h).

Onday10,hisclinical statusworsenedwithepisodesof tachypnea,pinkfrothysputumandoxygensaturation(SpO2)

decreased rapidly to 83% with ventilator support. Further-more, renal function deteriorated, oliguria and right lower extremitytissuenecrosisappeared.Embolizationoftheright commoniliacarteryandrightinternalandexternaliliac arter-ieswasseenonechocardiography(Fig.1C).Hesubsequently

developeda comawith aGlasgow ComaScale (GCS) score

of 6. His clinical condition deteriorated such that he was transferredtotheICU,and replacementofthemitralvalve

was accomplished witha 29-mmCarbomedics mechanical

valve.Consideringthepresenceofcomaand fever(39.8◦C) postoperatively,brainCTwasobtainedandshowedmultiple low-densitylesionsintemporallobes,rightparietallobe,and occipitallobe,suggestiveofcerebralembolism(Fig.1D). Levo-floxacin(0.75gqd)wasaddedtohisantibioticregimen.After 10daysofintravenousantibiotics,thepatientregained con-sciousness(GCSscoreof9)andmadeagoodclinicalrecovery.

Onday35,hewastransferredtoasecondaryhospital,and linezolidtherapywascontinuedforeightweeks.Herecovered uneventfullyandwaswellatthelastfollow-upinNovember 2013.

Microbiological

investigations

The isolate recovered from the vegetation was first

iden-tified by the VITEK 2 system and then identified with

MicroFlex LTinstrument (BrukerDaltonics).Matrix-assisted laserdesorption/ionizationtimeofflightmassspectrometry (MALDI-TOF-MS)basedfingerprintanalysisofextracted pro-teinsyieldedapatternsimilartothatofconfirmedS.aureus

isolates, Flexcontrol3.0softwareandBiotyper 2.0database (Bruker Daltonics)identified the isolateasS. aureuswitha

maximum score value of2.166 (data not shown). In

addi-tion toMALDI-TOF-MS analysis,16S rRNA sequencing was

performed inordertoidentifythe originofthe bacteriain

the vegetation.Thesequenceofthe PCRproductwas

com-paredwithsequencesofcloselyrelatedspeciesinGenBank byusingBLAST.Sequencingofthe16SrRNAgeneofthe iso-latesshowedthattherewas100%identitywiththe16SrRNA genesequenceoftheisolateofS.aureus(GenBankaccession no.JN102565),confirmingthattheisolatewasS.aureus.

Tofurtherinvestigatethegeneticbasisofthestrain,

mul-tilocus sequence typing (MLST),a methodthat uses seven

housekeepinggenes (arcC,aroE, glpF,gmk,pta,tpi and yqiL)

forgeneticidentification,andresultwasassignedby compar-isonwiththeS.aureusMLSTdatabase(http://www.mlst.net/).

The staphylococcal chromosomal cassette (SCC) mec type

(I–V) was also determined. The spa type was analyzed

by sequencing of the PCR product of the spa gene, and

the spa type was assigned using an online spa database

(http://www.spaserver.ridom.de/).Detectionoftheaccessory gene regulator (agr) allelegroup was accordingtoPCR and sequencing.Likewise,theantimicrobialdrugresistancegenes

(mecA, msrA, msrB, ermA,ermB, ermC and blaZ)were

deter-mined. The presenceofgene encodingPVL (lukF/lukS) and

other virulencerelatedgenes(sea,seb,sec,sed,see,seg,seh, sei,sej,sem,sen,seo,sek,sel,sep,seq,hla,hlb,hld,hlg,hlg2,eta, etb,lukE,lukM,bsaAandedin,)wereinvestigatedbyPCR.The presenceofadhesiongenes(cna,clfA,clfB,fnbA,efbandicaA)

werealsodeterminedbyPCRandsequencing.

TheCA-MRSAisolatewastypedassequencetype(ST)630

SCCmecVwithspa-typet4549,agrI/IVandwasPVL-negative.

WeconfirmedthepresenceofmecA,ermCandblaZgenesby

PCRandsequencing.ThegenomeoftheMRSAisolateencoded threehemolysingenes(hlb,hldandhlg2)andfiveadhesion genes(clfA,clfB,fnbA,efbandicaA)(Fig.1E).

Discussion

IE is a rare entity of CA-MRSA presentation, especially in

non-intravenousdrugusers(IVDU),andCA-MRSA

endocardi-tis casesare mostly restricted to IVDUs, especiallyamong

HIV-infected patients with the USA300 strain. To date, 11

previously reported cases of infective endocarditis caused

byCA-MRSA,excludingcasesinIDVUpatientswere

A

B

C

D

Marker _mecA ermC blaZ clfA clfB icaA efb fnbA hlb hld hlg2

E

Fig.1–Infectiveendocarditiscomplicatingsystemicembolism(thearrowsindicateareasofinterest)anddetectionofkey genes.(A)ColorDopplerechocardiographyshowingthevegetationattachedtotheanteriormitralvalveleaflet.(B)Spiral

computedtomographyshowingrenalinfarction.(C)Echocardiographicexaminationshowingembolizationoftheright

commoniliacarteryandrightinternalandexternaliliacarteries.(D)Computedtomographyofthebrainshowingmultiple low-densitylesions.(E).Detectionofantimicrobialgenes,virulence-relatedgenesandadhesiongenesbyPCRamplification. Lane1,molecularweightmarker;lane2,mecA;lane3,ermC;lane4,blaZ;lane5,clfA;lane6,clfB;lane7,icaA;lane8,efb;

lane9,fnbA;lane10,hlb;lane11,hld;lane12,hlg2.

described here) are shown in Table 1. Most reported

CA-MRSAIEcaseswerePVL-positiveinthelist; onlytwocases werePVL-negative,althoughonecasewasuntyped.Ofthe11 casescollected here,sixstrainswereSCCmec typeIV, three

strainswereSCCmectypeVandtwountypedstrains.These

resultsareconsistentwiththe previousfindings.CA-MRSA

infections have mostly been epidemiologically linked with

strainsharboringtheSCCmectypeIV/VandPVL.4_Ontheother

hand,mostCA-MRSAclonesaresusceptibletomanynon-

␤-lactamdrugs,andthepatientinthiscasewastreatedwith

linezolid,vancomycin,levofloxacinandfosfomycinaccording totheguidelines.AcomprehensivestudyofCA-MRSAin

Chi-nesechildrenshowsthatmostoftheCA-MRSAstrainswere

PVL-negative, and ST59-MRSA-IVa witht437 was the most

commonclone.5_{AtpediatrichospitalsinfiveChinesecities}

in2005–2006,ofthe73MRSAclinicalisolates,thedetection rateofthePVLgenewas30%(22/73),andtheseincludedthe ST1,ST910,ST88,ST59,andST338geneticbackgrounds.6

How-ever,theprevalenceofCA-MRSAinBeijingwasrareamong

Table1–SummaryofreportedcasesofCA-MRSAinfectiveendocarditisamongpatientswithnoriskfactors.

Age/sex Country/ region

Symptoms Valve SCCmec type

Treatmenta _pvlb _Sequence

typec

Outcome Ref.

20M Taiwan Septicembolism Mitral NA Va

Vegetationremoval

NA NA Recovered 12

47M Italy Sepsis Mitral NA Va,Ami

Valvereplacement

NA ST5 Recovered 13

22M USA Bacteremia, septicembolism

Aortic TypeIV Cfz,Lnz Pos NA Recovered 14

37M USA Abscesses Mitral TypeIV Va,Lnz Valvularsurgery

Pos NA Recovered 15

44M USA Septicembolism Aortic TypeIV Va

Incisionand drainage

Pos NA Recovered 15

27M Brazil Headache,fever Mitral TypeIV Cro,Va Pos NA Recovered 16

39F Korea Highfever,chill Mitral TypeIV Pen,VaandGen Surgicalintervention

Neg ST72 Recovered 17

61F Italy Fever,weakness, pain,dyspnea

Mitraland aortic

TypeV Va,DapandRif Pericardialpuncture Pos ST152 Recovered 18 79F Argentina Bacteremia, brainabscesses Aorticand mitral

TypeIV Va,Ts Pos ST5 Died 19

19M Australia Brainabscesses, renalmycotic aneurysmand endophthalmitis

Aortic NA Va,Fa,RifandCt Pos ST93 Recovered 20

2M Taiwan Pneumonia Tricuspid TypeV Tei,Ts Pos ST59 Recovered 9

49M China Systemic embolism, bacteremia

Mitral TypeV Lev,Fos,VaandLnz Valvereplacement

Neg ST630 Recovered Current case

F,female;M,male.

a _{Va,vancomycin;Ami,amikacin;Cfz,cefazolin;Lnz,linezolid;Cro,ceftriaxone;Pen,penicillin-G;Gen,gentamicin;Dap,daptomycin;Rif,}

rifampicin;Ts,trimethoprimsulfamethoxazole;Fa,fusidicacid;Ct,co-trimoxazole;Tei,teicoplanin;Lev,levofloxacin;Fos,fosfomycin.

b _{pvl,Panton-Valentineleukocidin;Pos,positive;Neg,negative.} c _{NA,notavailable.}

CA-MRSAamongpatientswithSSTIsinHongKongrevealed

thattheisolatesofCA-MRSAstrainsprimarilybelongedtothe

ST30-HKU100cloneandST59-HKU200clone.8_Incontrast,a

previoushealthypreschoolchildwasdevelopedIEand

pneu-moniawithpleuraleffusionbytheendemicCA-MRSAclone

ST59inTaiwan.9

Inthiscase,wereportthefirstinfectiveendocarditisdueto novelCA-MRSAST630inmainlandChina.ST630clonewas ini-tiallyisolatedamongmethicillinsusceptibleS.aureus(MSSA)

asdescribed inS. aureusMLSTdatabase and hasnotbeen

reportedinassociationwithhumaninfection.UsingMLSTand

eBURST,theST630MRSAlineagecanbegroupedasclonal

complex8(CC8),alargecomplexofrelatedMSSAandMRSA

genotype.ST630cloneisavariantofST8clonewiththeallele atthearcClocus,andST8isdescribedastheputativeancestral

genotypeofanothersubgroupwithinCC8.Frequent

conver-sionofMSSAtoMRSAbyhorizontaltransferofSCCmechas

beendescribed.10_{ItislikelythatST630MRSAoriginatedfrom}

ST630MSSA and ST630 MRSAindependently developedby

multipleevolutionarypathways.Toourknowledge,ourcase wasuniqueinbeingthefirstdocumenteddestructiveinvasive infectioncasecausedbyST630SCCmecV.

ThepathogeneticmechanismsofCA-MRSAinfectionare

notfullyunderstood.However,adhesinshavebeenidentified ascritical mediatorsimplicatedinthe inductionof experi-mentalS.aureusendocarditisinrats.11_{Theisolateofthiscase}

encodes five adhesiongenes mightpartly contributeto its

pathogenesis.Inthepresenthigh-riskpatient,prompt antimi-crobialtreatmentandearlysurgerywerepivotalforavoiding afatalresult.Despitebeingaboutonlyonecase,thisreport

highlights the geographical spread and emergence of

life-threateningCA-MRSAinfectionwithinChina.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgements

This work was supported bythe National Natural Science

FoundationofChina(GrantNos.81361138021and81301461)

andtheScientificResearchFoundationofZhejiangProvincial

HealthBureau(GrantNo.2012KYB083).

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