9/7/2015

Treatmentofstreptococcaltoxicshocksyndrome

OfficialreprintfromUpToDate
www.uptodate.com2015UpToDate

Treatmentofstreptococcaltoxicshocksyndrome
Author
DennisLStevens,MD,
PhD

SectionEditor
DanielJSexton,MD

DeputyEditor
ElinorLBaron,MD,DTMH

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Jun2015.|Thistopiclastupdated:Sep16,2014.
INTRODUCTIONStreptococcaltoxicshocksyndrome(TSS)isaclinicalillnesscharacterizedbyshock
andmultiorganfailureitoccursasaresultofcapillaryleakandtissuedamageduetoreleaseofinflammatory
cytokinesinducedbystreptococcaltoxins.
StreptococcalTSSoccursmostfrequentlyinthesettingofinfectionduetogroupAStreptococcus(GAS
Streptococcuspyogenes).GAStypicallycausespharyngitisorskinandsofttissueinfectiontheseare
generallyresponsivetoappropriateantibiotictherapy[1].Lesscommonly,GAScausesinvasivediseasesuch
asnecrotizinginfectionoftheskinandfascia,gangrenousmyositis,bacteremia,orpneumonia[2].Invasive
diseaseiscomplicatedbyTSSinapproximatelyonethirdofcases[35].
Thetreatmentofstreptococcaltoxicshocksyndromewillbereviewedhere.Theepidemiology,clinical
manifestations,anddiagnosisofstreptococcaltoxicshocksyndromearediscussedseparately.(See
"Epidemiology,clinicalmanifestations,anddiagnosisofstreptococcaltoxicshocksyndrome".)
MANAGEMENTManagementofstreptococcaltoxicshocksyndrome(TSS)includestreatmentofseptic
shockandassociatedcomplications,surgicaldebridementofinfection(iffeasible),andantimicrobialtherapy
(table1).Suchcasesfrequentlyrequirecoordinatedcarefromateam,includingindividualswithclinical
expertiseincriticalcare,surgery,andinfectiousdisease.
TreatmentofsepticshockStreptococcalsepsisleadstodiffusecapillaryleakandintractablehypotension.
Therefore,largequantitiesofintravenous(IV)fluidsmaybenecessarytomaintainperfusion(upto10to20
L/day)vasopressorsmayalsoberequired.Theapproachtomanagementofsepticshockisdiscussed
separately.(See"Evaluationandmanagementofseveresepsisandsepticshockinadults".)
SurgicaldebridementStreptococcalTSSmayoccurinthesettingofsofttissueinfection,suchas
necrotizingfasciitisormyonecrosis.Theseentitiesshouldbesuspectedinpatientspresentingwithfeverand
pain,followedbyprogressiontosofttissueswelling,andformationofviolaceousvesiclesandbullae.Surgical
explorationthroughasmallincisionwithvisualizationofmuscleandfasciaandGramstainofinvolvedtissue
mayprovideanearlyanddefinitivediagnosis[1].
Earlyaggressivesurgicalinterventioniscritical.Insomesettings,serialdebridementsareperformeduntil
tissuenecrosisisnolongerevident.Latedebridementmaybeprecludedbyhemodynamicinstabilityor
extensionofinfectiontoareasthataredifficulttodebride,suchastheheadandneck,thorax,orabdomen.In
addition,thebenefitofdebridementmaybediminishedoncesystemictoxicityandovertnecrosishave
developed.Inoneretrospectiveseriesincluding20patientswithstreptococcalTSS,majorsurgicalprocedures
werewarrantedinmorethanhalfofcasestheseincludedfasciotomy,surgicaldebridement,exploratory
laparotomy,intraocularaspiration,amputation,orhysterectomy[3].(See"Necrotizingsofttissueinfections".)
AntibiotictherapyEmpiricantimicrobialtherapyshouldbeinitiatedpendingcultureresultsthereafter,
antimicrobialtherapyshouldbetailoredaccordingly.Regimensforempiricandtailoredtherapyaresummarized
below.(See'Empirictherapy'belowand'Tailoredtherapy'below.)
GeneralprinciplesIngeneral,antimicrobialtreatmentofstreptococcalTSSconsistsofabetalactam
agent(whichinhibitscellwallsynthesis)incombinationwithclindamycin(whichinhibitsproteinsynthesis).
S.pyogenesisexquisitelysusceptibletobetalactamantibioticshowever,useofpenicillinmonotherapyis
associatedwithhighmortalityandextensivemorbidityinthesettingofaggressiveinfectionsassociatedwith
TSS(suchasnecrotizingfasciitis,empyema,burnwoundsepsis,subcutaneousgangrene,andmyositis)[3,6
http://www.uptodate.com/contents/treatmentofstreptococcaltoxicshocksyndrome?topicKey=ID%2F3169&elapsedTimeMs=6&source=search_result&s

1/9

9/7/2015

Treatmentofstreptococcaltoxicshocksyndrome

11].Inonereportincluding25casesofstreptococcalmyositistreatedwithpenicillinalone,themortalityrate
was85percent[9].
Studiesofexperimentalinfectionhavenotedanassociationbetweenpenicillinandtreatmentfailureinthe
presenceoflargenumbersoforganisms[12,13].InamousemodelofmyositisduetoS.pyogenes,penicillin
treatmentwasnoteffectivewhenadministeredtwohoursafteronsetofinfection[13].Incontrast,thesurvival
rateofclindamycintreatedmicewithtreatmentdelayof0,2,6,or16.5hourswas100,100,80,and70
percent,respectively[13,14].
Theseobservationshavebeenattributedtoinoculumsize[12,15,16].Penicillinandotherbetalactam
antibioticsarebelievedtobemosteffectiveagainstrapidlygrowingbacteria.Thus,efficacyislikelygreatestin
theearlystagesofinfectionwhenorganismsaremultiplyingquickly.Theefficacyofbetalactamsmaybe
diminishedashigherconcentrationsoforganismsaccumulateandtherateofbacterialgrowthslows.Inthe
settingofdeepseatedinfection,theconcentrationofstreptococcalorganismsmaybesufficientlyhighto
reducetheeffectivenessofbetalactamantibiotics[12].
Ithasbeensuggestedthatdiminishedpenicillinefficacyinthesettingofhighinoculummaybeattributableto
theavailablenumbersofpenicillinbindingproteins(PBPs)ontheorganismsurfacethatareavailableatvarious
pointsduringthephasesofbacterialgrowth.Inonelaboratorystudy,fewerPBPswereobservedduring
stationaryphasegrowthinvitro[15].
Thus,clindamycinisgenerallyusedinadditiontobetalactamsinthetreatmentofinvasivegroupA
streptococcal(GAS)infection.Severalobservationalstudieshavedemonstratedaclinicalbenefittothe
additionofclindamycin[5,17,18].Asanexample,inaretrospectivestudyof84patientswithsevereinvasive
GASinfection,useofclindamycinwasassociatedwithalower30daymortality(15versus39percentamong
thosewhodidnotreceiveclindamycin)[18].
ClindamycinhasseveralpotentialadvantagesfortreatmentofGASinfection.Theefficacyofclindamycinis
notaffectedbyinoculumsizeorstageofgrowth[15,19],itsuppressessynthesisofbacterialtoxins[2022],
anditisassociatedwithalongerpostantibioticeffectthanbetalactamagents.Inaddition,clindamycin
suppressessynthesisofPBPs,whichareinvolvedincellwallsynthesisanddegradation(inadditiontoserving
asbindingtargetsforpenicillin)[19].
AntibioticregimensEmpiricantimicrobialtherapyshouldbeinitiatedpendingcultureresultsthereafter,
antimicrobialtherapyshouldbetailoredaccordingly.
EmpirictherapyPatientspresentingwithclinicalmanifestationsofstreptococcalTSSshould
receiveempirictherapyasfollows,pendingcultureresults:
Clindamycin(900mgIVeveryeighthours)
plusoneofthefollowing:
Acarbapenem(eg,imipenem500mgintravenouslyeverysixhoursORmeropenem1gintravenously
everyeighthours)
Acombinationdrugcontainingapenicillinplusbetalactamaseinhibitor(eg,ticarcillinclavulanate3.1g
everyfourhoursORpiperacillintazobactam4.5geverysixhours)
Patientswithknownhypersensitivitytopenicillinmaybetreatedwithclindamycinplusacarbapenem.If
carbapenemsarenottolerated,clindamycinplusvancomycinorclindamycinplusdaptomycinmaybeused.
TailoredtherapyOnceadiagnosisofstreptococcalTSSisestablished,treatmentconsistsof
clindamycin(900mgIVeveryeighthours)inadditiontopenicillinG(4millionunitsIVeveryfourhours).
Penicillinisincludedtogetherwithclindamycinincasetheinfectionisduetoanorganismthatisresistantto
clindamycinthisoccursinlessthanonepercentofisolatesintheUnitedStates[23].Patientswithknown
hypersensitivitytopenicillinmaybetreatedwithclindamycinaloneiftheorganismisknowntobeclindamycin
susceptible.Inthesettingofclindamycinresistance,acarbapenemmaybeused.Itisimportanttonotethat
anincreasingnumberofGASisolateswithconstitutiveorinducibleresistancetomacrolidelincosamide
streptograminB(MLS)antibiotics,includingclindamycin,havebeenidentifiedinEurope[24].Thereareno
http://www.uptodate.com/contents/treatmentofstreptococcaltoxicshocksyndrome?topicKey=ID%2F3169&elapsedTimeMs=6&source=search_result&s

2/9

9/7/2015

Treatmentofstreptococcaltoxicshocksyndrome

additive,synergistic,orantagonisticeffectsofclindamycinandpenicillininvitro.
DurationoftherapyTherearenoclinicalstudiesaddressingtheoptimaldurationofantibiotictherapyin
streptococcalTSSthedurationofantibiotictherapyshouldbeindividualized.Patientswithbacteremiashould
betreatedforatleast14days.Inpatientswithcomplicatingdeepseatedinfections,suchasnecrotizing
fasciitis,lengthoftherapydependsontheclinicalcourseandtheadequacyofsurgicaldebridementtherapyis
usuallycontinuedfor14daysfromthelastpositivecultureobtainedduringsurgicaldebridement.
AdjunctivetherapyAdjunctivetherapiesusedforpatientswithstreptococcalTSSincludeintravenous
immuneglobulin(IVIG),hyperbaricoxygen,andantitumornecrosisfactor(TNF)antibody.
IntravenousimmuneglobulinDataontheroleofintravenousimmuneglobulinfortreatmentof
streptococcalTSSarelimited,asdiscussedbelow[18,2530].Ingeneral,wefavoradministrationof
intravenousimmuneglobulinforpatientswithstreptococcalTSStherationaleistoboostantibodylevelsvia
passiveimmunityinthesettingofoverwhelminginfection.
Onerandomizedtrialincluding21patientscomparedIVIGtoplaceboinadultswithstreptococcalTSS(IVIG
dosingwas1g/kgondayone,and0.5g/kgondaystwoandthreeallpatientsalsoreceivedintravenous
clindamycinandpenicillinforatleast14days)[30].Themortalityrateswere10versus36percent,but
statisticalsignificancewasnotreached.
AsubsequentprospectiveobservationalstudycomparedIVIGtherapy(23patients)withplacebo(44patients)
IVIGcontributedtosignificantlyimprovedsurvival(oddsratio5.6,p=0.03)[31].
Oneretrospectivestudyincluding192childrenwithstreptococcalTSSdidnotnoteimprovedoutcomes
associatedwithIVIG,althoughtheoverallmortalityduetothisdiseaseisloweramongchildrenthanadults
[32].Twootherretrospectivestudiesdescribed27patientswithstreptococcalTSStreatedwithIVIG(median
dose2g/kg)comparedwithhistoricalcontrols[25,29].MortalitywasloweramongpatientstreatedwithIVIG,
buttheuseofhistoricalcontrolsposedpotentialdifficultiesininterpretingtheresultssincefewerpatientsinthe
controlgroupweremanagedwithclindamycinorsurgery.
SeveralmechanismsforIVIGinstreptococcalTSShavebeensuggested,includingneutralizationof
streptococcaltoxins,inhibitionofTcellproliferation,andinhibitionofotherputativevirulencefactorssuchas
TNFalphaandinterleukin(IL)6[25,3337].SomeIVIGpreparationscontainneutralizingantibodiesagainst
severalstreptococcaltoxinssuchasthepyrogenicexotoxins(SPEA,SPEB,SPEC,andMF),streptolysinO,
andDNaseBspecificantibodypreparationsarenotcommerciallyavailable[38].(See"Generalprinciplesin
theuseofimmuneglobulin".)
DifferencesbetweenneutralizingactivitieshavebeenobservedindifferentbatchesofIVIGfromdifferent
manufacturers.Inonestudy,VigamS(obtainedfromplasmacollectedfromdonorsintheUnitedStates)had
consistentlyhighinhibitionagainstallsuperantigens,whileEuropeanIVIGpreparationshadthelowestactivity
anAustralianpreparationhadintermediateactivity[39].
OthertherapiesTheuseofhyperbaricoxygenhasbeenreportedinasmallnumberofpatientswith
streptococcalTSS[1].Therearenocontrolleddata,andtheefficacyofthistreatmentisnotknown.(See
"Hyperbaricoxygentherapy".)
UseofantiTNFantibodyhasbeenstudiedinananimalmodelofstreptococcalTSSwithpromisingresults
[40]furtherstudyisneeded.
PROGNOSISThereportedmortalityrateforstreptococcaltoxicshocksyndrome(TSS)rangesfrom30to
70percent[2,3,26,4143].Mortalityratesarelowerinchildrenthanadultsoneseriesincluding144children
notedamortalityrateof18percent[44].
Oneretrospectiveincluding66patientswithstreptococcalTSScomparedphysicalandlaboratoryfindingsof
survivors(36cases)andpatientswhodied(30cases)[43].Patientswhodiedhadlowermeansystolicblood
pressure(99versus120mmHg),lowermeanbodytemperature(37.0versus38.3C),highermeanserum
creatinine(3.0versus2.0mg/dL),lowermeanwhitebloodcellcount(1000versus16,000cellspermicroL),
andlowerplateletcount(120,000versus170,000cellspermicroL).
http://www.uptodate.com/contents/treatmentofstreptococcaltoxicshocksyndrome?topicKey=ID%2F3169&elapsedTimeMs=6&source=search_result&s

3/9

9/7/2015

Treatmentofstreptococcaltoxicshocksyndrome

MortalityduetostreptococcalTSSissubstantiallyhigherthanstaphylococcalTSS.StreptococcalTSSis
frequentlyassociatedwithdeepsofttissueinfection,sosourcecontrolcanbedifficult.Inaddition,
streptococcalTSSoccursmorefrequentlyamongpatientswithunderlyingmedicalconditionsthan
staphylococcalTSS.(See"Staphylococcaltoxicshocksyndrome".)
MANAGEMENTOFHOUSEHOLDCONTACTSGroupAStreptococcus(GAS)isahighlycontagious
organismithascausedepidemicsofpharyngitisandscarletfeverinschools,rheumaticfeverinmilitary
recruits,andsurgicalwoundinfectionsinhospitalizedpatients.ClosecontactsofacaseofinvasiveGAS
infectionhaveahighlikelihoodofbecomingcolonizedwithavirulentstrain.Theriskofdevelopingasecondary
caseoftoxicshocksyndromeisverylowbuthigherthanforthegeneralpopulation[45].
Theroleofpostexposureprophylaxishasnotbeenstudied,andtheoptimalapproachisuncertain[46].For
highlysusceptibleindividuals(suchasimmunocompromisedindividualsorpatientswithrecentsurgery)who
areclosehouseholdcontactsofapatientwithtoxicshocksyndrome,administrationofprophylaxiswith
penicillin(250mgorallyfourtimesdailyfor24to48hours)isreasonable.Thegoalisreductioninlikelihoodof
asecondaryinfectionratherthantreatmentofestablishedinfection.
SUMMARYANDRECOMMENDATIONS
Managementofstreptococcaltoxicshocksyndrome(TSS)includestreatmentofsepticshockand
associatedcomplications,surgicaldebridementofinfection(iffeasible),andantimicrobialtherapy.Early
aggressivesurgicalinterventioniscritical.(See'Management'above.)
Empiricantimicrobialtherapyshouldbeinitiatedpendingcultureresultsthereafter,antimicrobialtherapy
shouldbetailoredaccordingly.Werecommendanempiricregimenconsistingofclindamycinpluseithera
carbapenemorcombinationdrugcontainingapenicillinplusbetalactamaseinhibitor(Grade1B).(See
'Empirictherapy'above.)
OnceadiagnosisofstreptococcalTSSisestablished,werecommendtreatmentwithclindamycin(900
mgIVeveryeighthours)inadditiontopenicillinG(4millionunitsIVeveryfourhours)(Grade1B).The
durationofantibiotictherapydependsonindividualpatientcircumstances.(See'Empirictherapy'above
and'Tailoredtherapy'above.)
ForpatientswithstreptococcalTSS,wesuggestadministrationofintravenousimmuneglobulin(Grade
2B).Dosingconsistsof1g/kgdayone,followedby0.5g/kgondaystwoandthree.(See'Intravenous
immuneglobulin'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
REFERENCES
1. BisnoAL,StevensDL.Streptococcalinfectionsofskinandsofttissues.NEnglJMed1996334:240.
2. DarenbergJ,LucaHarariB,JasirA,etal.MolecularandclinicalcharacteristicsofinvasivegroupA
streptococcalinfectioninSweden.ClinInfectDis200745:450.
3. StevensDL,TannerMH,WinshipJ,etal.SeveregroupAstreptococcalinfectionsassociatedwitha
toxicshocklikesyndromeandscarletfevertoxinA.NEnglJMed1989321:1.
4. DaviesHD,McGeerA,SchwartzB,etal.InvasivegroupAstreptococcalinfectionsinOntario,Canada.
OntarioGroupAStreptococcalStudyGroup.NEnglJMed1996335:547.
5. WongCJ,StevensDL.Seriousgroupastreptococcalinfections.MedClinNorthAm201397:721.
6. GroupAstreptococcalinfectionsandatoxicshocklikesyndrome.NEnglJMed1989321:1545.
7. MartinPR,HibyEA.StreptococcalserogroupAepidemicinNorway19871988.ScandJInfectDis
199022:421.
8. HrbalovV.Streptococcuspyogenesandthetoxicshocksyndrome.AnnInternMed1988108:772.
9. AdamsEM,GudmundssonS,YocumDE,etal.Streptococcalmyositis.ArchInternMed1985
145:1020.
10. StevensDL.InvasivegroupAstreptococcusinfections.ClinInfectDis199214:2.
http://www.uptodate.com/contents/treatmentofstreptococcaltoxicshocksyndrome?topicKey=ID%2F3169&elapsedTimeMs=6&source=search_result&s

4/9