世卫组织白喉的临床管理指南

Clinicalmanagementofdiphtheria

Guideline

2February2024

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organization

Clinicalmanagementofdiphtheria:guideline,2February2024

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Sections

1.Summaryoftheguideline 4

2.Abbreviations 6

3.Introduction 7

4.Clinicalcharacterization 8

5.Recommendationforantibioticstreatment 9

6.Recommendationsfordiphtheriaantitoxin(DAT) 14

6.1Mechanismofactionofdiphtheriaantitoxin(DAT) 14

6.2Diphtheriaantitoxinsensitivitytesting:rationale 14

6.3RecommendationonDATsensitivitytesting 14

6.4RecommendationonDATdose 17

7.Methods:howthisguidelinewascreated 21

8.Howtoaccessandusetheguideline 23

9.Uncertainties,emergingevidenceandfutureresearch 24

10.Authorship,contributionsandacknowledgements 25

References 26

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1.Summaryoftheguideline

Clinicalquestion:Whatistheroleofantibioticsanddiphtheriaantitoxin(DAT)inthetreatmentofdiphtheria?

Context:Thisclinicalpracticeguidelinehasbeenrapidlydevelopedrecognizingtheglobalincreaseindiphtheriaoutbreaks.

OutbreaksofdiphtheriainNigeria,Guineaandneighbouringcountriesin2023havehighlightedtheurgentneedforevidence-basedclinicalpracticeguidelinesforthetreatmentofdiphtheria.Giventhesporadicnatureofoutbreaks,manycliniciansintheaffected

regionshavenevermanagedacutediphtheriaanditsrelatedcomplications.ThediphtheriacasedefinitionisprovidedintheWHOdocument:

Diphtheria:VaccinePreventableDiseasesSurveillanceStandards

(1).

Scope:Thisguidelinefocusesontheclinicalmanagementofrespiratorydiphtheriaanddoesnotprovideadviceonvaccination.

SeeWHOLaboratorymanualforthediagnosisofdiphtheriaandotherrelatedinfections(2).

Newrecommendations:

•Inpatientswithsuspectedorconfirmeddiphtheria,WHOrecommendsusingmacrolideantibiotics(azithromycin,erythromycin)inpreferencetopenicillinantibiotics[Strongrecommendation,lowcertaintyevidence].

•Inpatientswithsuspectedorconfirmeddiphtheria,WHOrecommendsnottoperformroutinesensitivitytestingpriortoadministrationofdiphtheriaantitoxin(DAT)[Strongrecommendation,moderatecertaintyevidence].

•Inpatientswithsuspectedorconfirmedsymptomaticdiphtheria,WHOsuggestsanescalatingdosingregimenfordiphtheria

antitoxin(DAT)whichisbasedondiseaseseverityandtimesincesymptomonset,incomparisonwithafixeddoseforallpatients[conditionalrecommendation,verylowcertaintyevidence].

Characteristicofdiphtheriadisease

Doseofdiphtheriaantitoxin(IU)

•Laryngitisorpharyngitis

and

•Duration<48hours

20000

•Nasopharyngealdisease(extensivepseudomembrane)

and

•duration<48hours

40000

Oneormoreof:

•Diffuseswellingoftheneck

•Anydisease≥48hours

•Severedisease(respiratorydistress,shock)

80000

Aboutthisguideline:Thisguidelinewasdevelopedaccordingtostandardsandmethodsfortrustworthyguidelines.These

guidelinesarebasedonthesynthesisoftheavailableevidenceonthehealtheffectsofinterventions,andthegradingofthecertaintyofthatevidenceusingtheGRADE(GradingofRecommendationsAssessment,Development,andEvaluation)approach.The

synthesizedandgradedevidenceonthehealtheffectsofinterventions,aswellasanyevidenceoncontextualfactors,isusedto

developanevidence-to-decision(EtD)frameworkforeachrecommendation(3).ThejudgementonthedifferentfactorsintheEtD

framework(includingthecertaintyofevidence)facilitatesthedeterminationofthestrengthanddirectionofeachrecommendation(4).

Expertinputisimportantfortheinterpretationoftheevidence,andthedevelopmentofguidancemayrelyonexpertopinion,

particularlyinareaswheretheevidenceiscurrentlyweak,scarceorabsent.Forexample,theDATdosingrecommendations

presentedintheguidelinesarebasedonaconsiderationoftheevidencegainedfromobservationaldataaswellasthetechnicalknowledgeandexperienceoftheGuidelineDevelopmentGroup(GDG).Detailsofcontributorsareavailableonline

here

.

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Updateandaccess:Thelivingguidelineiswritten,disseminated,andupdatedonanonlineplatform(MAGICapp,

/#/guideline/7759

),withauser-friendlyformatandeasy-to-navigatestructurethataccommodatesdynamicallyupdatedevidenceandrecommendations,focusingonwhatisnewwhilekeepingexistingrecommendationsupdatedwithinthe

guideline.Thisformatshouldalsofacilitateadaptation,whichisstronglyencouragedbyWHO,tocontextualizerecommendationsfromahealthcaresystemperspectivetomaximizecountryimpact.

Aplannedupdateisalreadyongoingtoaddressclinicalquestionsrelatedtothepreventionofinfectioninclosecontactsofpeoplewithdiphtheria.

Broadercontext:

TheguidelinecloselyalignswiththeWHOHealthEmergenciesProgrammegoalofstrengtheningpreparation,preparedness,responseandresilienceinresponsetohealthemergencies,particularlytheabilityofmemberstatestoprovidesafeandscalablecare(5).

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2.Abbreviations

AMR

antimicrobialresistance

AST

antibioticsensitivitytesting

DAT

diphtheriaantitoxin

DOI

declarationofinterest

DST

drugsensitivitytesting

ETD

evidencetodecision

GDG

guidelinedevelopmentgroup

SAE

seriousadverseevent

WHO

WorldHealthOrganization

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3.Introduction

Whattriggeredthisguideline?

Despitetheimplementationofdiphtheriavaccinationearlylastcenturytherehascontinuedtobeoutbreaksofdiphtheriainregions

wherevaccinecoverageisnotoptimal.VaccinecoveragehasbeennegativelyimpactedbytheCOVID-19pandemic,population

displacement,andstructuraldisruptionofhealthsystems.Thereisnowaprolongedoutbreakofdiphtheriainmultiplecountriesin

WestAfricaandsporadicoutbreaksinallWHOregions.Althoughdiphtheriaisbothpreventableandtreatable,successfultreatmentdependsonrapidrecognitionoftheclinicalsyndromeaswellasrapidimplementationoftheappropriatetreatment,whichincludesthetimelyadministrationoftheappropriateantibioticsandDAT.AccesstoDAThasbeenachallengeduetolimitedglobalsupplyand

rapiddistributionsystems.

TheWHOClinicalmanagementofdiphtheriaguidelineaimstoprovide,inasinglereference,thelatestevidence-based

recommendationstosupportcliniciansintheireffortstoprovideacutetreatmentfordiphtheria.Thisguidelinerespondstodirectrequestsfromcliniciansandhealthministriesofaffectedcountries.Currently,cliniciansincountriesaffectedbytheoutbreakhavelimitedornoclinicalexperiencemanagingpatientswithdiphtheriaandlimitedaccesstoantimicrobialsusceptibilitytesting.

Whataretheguideline'sobjectives?

•Toprovideevidence-basedandcontext-sensitiverecommendationsontheappropriatechoice(s)fordiphtheriaclinicalmanagementincludingtheuseofdiphtheriaantitoxin(DAT)andantibiotics.

•TosupporttheadaptationbyWHOMemberStatesoftheseevidence-basedguidelinesintonationaldiphtheriapoliciesfortheclinicalmanagementofdiphtheria.

•Toinformtheclinicalresearchagendabyidentifyingknowledgegapswhichlimitourcapacitytoproduceevidence-basedrecommendations.

Whoisthisguidelinefor?

Theprimaryaudiencefortheguidelineisclinicianstreatingpatientswithdiphtheria.Theguidelineisalsointendedforusebyhealthmanagersatfacilityorjurisdictionleveltodeveloplocaltoolsorprotocolstoassistcliniciansinmanagingpatientswithdiphtheriaandorientprocurementandallocationofrecommendedtreatments.Furthermore,theguidelineisintendedtoguideresearchersand

researchfunderstoaddressthehighlightedevidencegapsanduncertainties.

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4.Clinicalcharacterization

Clinicalcharacterization

RespiratorydiphtheriaiscausedbystrainsofCorynebacteriumdiphtheriae,whichhaveaffinityfortheupperrespiratorytract(noseandthroat)andproduceatoxinwhichcauseslocaldiseaseand,inseverecases,airwaycompromiseandsystemiccomplications.Diphtheriaoccurswhenthebacterialtoxininflamestheepithelialmucosal,causinganexudatewhichcanhaveacharacteristic

greyish-white“pseudomembrane”inthepharynx,nasopharynx,tonsils,orlarynx(oracombinationofthese).Thefibrinous

pseudomembranecanleadtorespiratoryobstruction.Thetoxindisruptsproteinsynthesisandcausescelldeathleadingtothe

breakdownoftheepithelium,andsubsequentspreadtolocallymphnodescancauseaswollenneck.Spreadofthetoxininthebloodcanaffectthemyocardium(heart),kidneys,andnervoussystem.C.diphtheriaecanalsocauseskinandwoundinfections.Cutaneousdiseaseisnotfurtherdiscussedinthisguideline.

TheseverityofdiphtheriaisdescribedinpreviousWHOoperationalguidance.

•Milddisease:localizedlaryngealorpharyngealdiseaseof2daysduration;

•Severe/extensivedisease:durationof3ormoredays,ordiffuseneckswelling(thesocalled“bullneck”),orrespiratorydistress,orhemodynamicinstability”(6)(7).

Arecentsystematicreviewsuggeststhecasefatalityratioinunvaccinatedindividualsinfectedwithtoxin-producingstrainsis

29%(8).Casefatalityratiosinresource-limitedsettingsarehighlyvariablebut,insomeoutbreaks,canbeashighas50%(9)(10).

Transmission:Diphtheriaspreadsfrompersontopersonmostlythroughtheair,andlessfrequentlybydirectcontact.Theincubationperiodisusuallyfrom2to5days.

Currenttreatmentsinclude:

•neutralizationofunboundtoxinwithDAT;

•antibioticstopreventfurtherbacterialgrowth;

•monitoringandsupportivecaretopreventandtreatcomplications,e.g.airwayobstruction,myocarditis.Inpatientswithimminentairwayobstruction,urgentairwayinterventionmaybelifesaving.Thepossibleoptionsincludebasicairwaymanouevres,

endotrachealintubation,cricothyroidotomy(needleorsurgicalapproach),andtracheostomy.Therisksandbenefitsofeachapproachwilldependontheexperienceofthetreatingmedicalpersonnel.

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5.Recommendationforantibioticstreatment

Antibioticsareusedtopreventfurtherbacterialgrowthandtoxinproductionreducingtheriskfromfurtherorgandamage,andtoreducebacterialtransmissiontoothers.Historically,penicillinshavebeenused(includingbenzylpenicillin,procainepenicillinandpenicillinV),butmacrolideshavealsobeenemployed(forexample,erythromycinorazithromycin).Antimicrobialresistance

prevalenceamongststrainsofC.diphtheriaeoccurstobothclasses,andisvariablebyregionandovertime.Localresistancepatternscanthereforeonlybeknownbybacterialsusceptibilitytesting.Recentstudieshavedemonstratedincreasedresistancetopenicillin

overthemacrolideclassofantibiotics(11).Antibioticsarealsousedtopreventthedevelopmentofdiphtheriainclosecontactsofinfectiouspatients;WHOrecommendationsonthistopicareunderdevelopment.

Strongrecommendationfor

Inpatientswithsuspectedorconfirmeddiphtheria,WHOrecommendsusingmacrolideantibiotics(azithromycin,erythromycin)inpreferencetopenicillinantibiotics[Strongrecommendation,lowcertaintyevidence].

Remarks:

•AntibioticsshouldbeadministeredalongsideDATandshouldnotbedelayed.

•Recentevidencesuggeststhatthereisincreasingresistancetopenicillinsandlessresistancetomacrolideantibiotics.Localantimicrobialsusceptibilitytestingisvitaltoensuretheongoingappropriateuseofantibiotics.Adviceonlaboratorytestinginoutbreaksisavailable

here

.

•Thechoiceofmacrolidewilldependonavailabilityandfeasibility.

Practicalinfo

Macrolideantibioticsincludeazithromycinanderythromycin.Parenteraladministrationofmacrolideantibioticsispossible;however,itistypicallyindicatedforwhereoraladministrationisnotpossible,suchaswhenpatientisunabletoswalloworalmedications.Thechoiceofmacrolidewillbebasedonavailabilityandfeasibility.Dosingrecommendationareasfollows:

•Azithromycin:administerorallyorintravenouslyonceaday.

◦Forchildren:10–12mg/kgoncedaily(maximum500mgperday).

◦Foradults:500mgoncedaily.

•Erythromycin:administerorallyorintravenouslyeverysixhours.

◦Dose(childrenandadults):10–15mg/kgevery6hours,maximum500mgperdoseor2gramsaday.

Penicillinantibiotics

Weareprovidingpracticalinformationonpenicillinforthescenariowheremacrolideantibioticsarenotavailableandsusceptibilitytestingdemonstratessensitivitytopenicillin.Penicillincanbegivenorallyorparentally(intravenousorintramuscular).Parenteraladministrationisusedprimarilytoachieveadequatetissueconcentrations,especiallyinpatientswithseveredisease.

•Procainebenzylpenicillin(penicillinG):administerbyintramuscularinjection.

◦Dose(childrenandadults):50mg/kgoncedaily.Maximumis1.2gperday.

•Aqueousbenzylpenicillin(penicillinG):administerbyintramuscularinjectionorslowintravenousinfusion.

◦Dose(childrenandadults):100000units/kgperdayindivideddoseof25000IU/kgevery6hours.Maximumis4MIUor

2.4gperday.

•PhenoxymethylpenicillinV:administerorally.

◦Dose(childrenandadults):50mg/kgperdayindivideddosesadministeredevery6hours(eachdose10–15mg/kg.Maximum500mgperdose).

Inadiphtheriaoutbreakitisimportantthatantibioticstewardshipandmonitoringareimplementedparticularlyinrelationtoanychangesinantibioticresistance,whichcanbedeterminedbyantibioticsensitivitytesting.

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Evidencetodecision

Benefitsandharms

Substantialnetbenefitsoftherecommendedalternative

Inpatientswithsuspectedorconfirmeddiphtheria,theGDGdeemedtheuseofantibioticstobethestandardofcareovernoantibiotics.Theuseofmacrolides,comparedwithpenicillins,probablydoesnotaffectmortalityorrateofseriousside-effects,buterythromycinmayincreasetherateofgastrointestinalside-effects.Thetreatmenteffectofmacrolideantibiotics,comparedwithpenicillinantibiotics,isveryuncertainfortheoutcomesofrateofmyocarditis,hospitalization,needforairwayintervention,newcasesofdiphtheria,ortreatmentfailure.However,thepointestimateoftreatmentfailurefavursmacrolidesoverpencillins.

Thetreatmentburdenofpenicillinsissubstantiallygreaterthanthatofazithromycin,includingtheneedformorefrequent

dosesofpenicillinsgenerally,andtheneedforintravenousadministrationofbenzylpenicillinspecifically.Thoughtheriskof

antibioticresistancewasuncertainanddependentonlocalresistancepatternsthepanelnotedthatcurrentdatasuggeststhattheriskofpenicillinresistanceishigherthanmacrolideresistance,thereforesuggestingpotentialbenefitsofmacrolide

therapy.

Inthecircumstanceswhereantitoxinisunavailableandunlikelytobeaccessibleinashortperiod,thereisaspeculativebenefitofdualantibiotictreatment.Insuchcases,wherebacteriologicalsusceptibilityisunknown,cliniciansmightchoose,pendingsusceptibilitydata,totreatconcurrentlywithbothmacrolideandbeta-lactamantibiotics.

CertaintyoftheEvidence

Low

Theevidencesummaryfortheprioritizedoutcomeswerelargelyinformedbyonerandomizedclinicaltrial(n=86)whichcomparedpenicillin(benzylpenicillinfollowedbypenicillinV)witherythromycinforthetreatmentofdiphtheria.

Certaintyofevidencewasratedas:moderateformortality(rateddownforimprecision),verylowformyocarditis(rateddown

forimprecisionandriskofbias),verylowforhospitalizationandairwayintervention(rateddownforimprecisionand

indirectness),verylowfornewcasesofdiphtheria(rateddownforimprecisionandindirectness)andverylowfortreatment

failure(rateddownforriskofbias,imprecision,andindirectness).Thecertaintyofevidencewasratedas:moderateforseriousside-effects(rateddownforriskofbias),lowforgastrointestinalside-effects(rateddownforriskofbias,imprecision),highforburdenoftreatment,andverylowforantibioticresistance.

Valuesand

preferences

Nosubstantialvariabilityexpected

Patientsplaceahighvalueonreceivingfewerdosesandoraldrugtreatment,ratherthanmultipledosesandparenteraldrugadministration,andtoalesserextentonthespeculativepossibilityofgreatereffectivenesswithmacrolidetreatment.The

panelfeltthatconsiderationsofantimicrobialresistancewereasormoreimportantthanindividualpatientconsiderations.

Resources

Importantissues,orpotentialissuesnotinvestigated

Theresourcesrequiredtoroutinelyusepenicillinantibiotictreatment,withfrequentintramuscularorintravenousdosing,aresubstantiallygreaterthanwithadaily,oraltreatmentsuchasazithromycin.

Theavailabilityandreliabilityofmicrobiologicalsusceptibilitytestingforisolatestoguidetherapywillnotalwaysbeavailableinatimelyfashion,particularlyinoutbreaksettings.Therefore,cliniciansshouldadministertheantibioticwiththelowest

probabilityofresistance.

Equity

Importantissues,orpotentialissuesnotinvestigated

TheGDGdiscussedatlengththeavailabilityofbothpencillinandmacrolideantibiotics,andhowtherewerenosignificant

equity-relatedconcernsastoaccessibilityofthetwotreatmentsinmostsettings.Treatmentburdenbeinghigherwith

penicillinsledconsiderationsforpreferenceofmacrolides,whichhasequityimplicationsforaccessinghealthcareresources.

TheGDGdiscusseddataondiphtheriaresistancetobeta-lactamand/ormacrolideantibiotics,andthepossibilityof

widespreaduseofmacrolidesinworseningantimicrobialresistance,andworseninghealthequitylongerterm.Theagreed

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valuesandpreferencesstatementheavilyweighedontheconsiderationsoftheGDG,whereantibioticresistancewasseenas,ormoreimportantthan,individualpatientconsiderations.TheGDGmadeastrongrecommendationfortheuseof

macrolides,giventhefeasibilityofimplementationandthelikelylimitedimpactofmacrolideusageindiphtheriaoutbreaksonwiderresistancepatterns.

Acceptability

Importantissues,orpotentialissuesnotinvestigated

TheGDGremarkedthatintravenousdosingmaybeappropriateforpatientswhoareseverelyillandadmittedtohospital,orwhomaybeunabletotolerateorallyadministeredmedications.Inaddition,somepanelistscommentedonthepotentialforconcomitantuseofpenicillinandmacrolideantibioticsforseverelyillpatientswhensusceptibilitypatternsareunknown,andparticularlyduringtheearlyphasesofoutbreakswhenDATmaybeunavailable.

Thereareknowngastrointestinalside-effectsofmacrolides,whichmayimpactacceptabilityoftherecommendation,butthesearenotserious(12).

Theacceptabilityofimplementationwasaprimaryconsiderationinmakingrecommendingadministrationofmacrolides,specificallyoralazithromycinratherthanintravenousorintramuscularpenicillin.

ThecurrentWHOAWaReantibioticbookdoesnotlistdiphtheriaasanindicationforazithromycin,andthiswasnoted(13).

Feasibility

Importantissues,orpotentialissuesnotinvestigated

Thefeasibilityofimplementingmacrolideantibiotics,comparedwithpenicillinantibiotics,isveryhigh.Forpatientswhoareseverelyill,feasibilityconsiderationsarelessrelevant,asintravenousroutesofadministrationmaybepreferredandare

availableforeitherantibiotic.Treatmentofseverelyillpatientslargelyfocusedonthepotentiallyhighburdenofresistancetobeta-lactamantibiotics.

Inadiphtheriaoutbreakitisimportantthatantibioticstewardshipandmonitoringareimplementedparticularlyinrelationtoanychangesinantibioticresistance,whichcanbedeterminedbyantibioticsensitivitytesting.

Justification

WhenmovingfromtheevidencetoarecommendationtheGDGemphasizedtherelativetreatmentburdenofpenicillinsand

macrolides.TheGDGdiscussedtheknownandvariableepidemiologyofantibioticresistanceinCorynebacteriumdiphtheriae,inadditiontonocompellingadverseclinicalconsequencesofmacrolideuse.

Typically,WHOdoesnotmakestrongrecommendationswithlowcertaintyevidence.Oneexceptioniswhenlowevidence

suggestsequivalenceorbenefitofatherapy(inthiscasemacrolidesequivalentorsuperiortopenicillins)andthereishigh

certaintyevidenceoflessharmwiththattherapy.Inthiscase,wehavehighcertaintyevidenceofthehigherburdensassociatedwithpenicillinparenteraltherapymultipletimesaday.

TheGDGmadeastrongrecommendationfortheuseofmacrolides,giventhefeasibilityofimplementationandthelikelylimitedimpactofmacrolideusageindiphtheriaoutbreaksonwiderresistancepatterns.

Clinicalquestion/PICO

Population:Personswithsuspectedorconfirmeddiphtheria

Intervention:Macrolideantibiotic

Comparator:Penicillinantibiotic

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Summary

Fullsummaryoftheevidencesynthesisisavailablehere.(14)

Outcome

Timeframe

Studyresultsandmeasurements

Comparator

Penicillin

Intervention

Macrolide

CertaintyoftheEvidence

(Qualityof

evidence)

Summary

Mortality

10days

Relativerisk1

Basedondatafrom86

participantsin1studies.

1(Randomized

controlled)

10

per1000

Difference:

10

per1000

0fewerper1000

CI95%

Moderate

Duetoseriousimprecision.2

Thechoiceofantibiotic

probablydoesnotaffect

mortality.

Myocarditis

Basedondatafrom86participantsin1studies.

68

per1000

Difference:

0

per1000

68fewerper1000

(CI95%166

fewer—29more)

Verylow

Duetoserious

imprecision,Due

toseriousriskof

bias4

Weareveryuncertainif

thechoiceofantibiotic

affectstherateof

myocarditis.

3

(Randomized

controlled)

Treatmentfailure

asinferredfrom

non-clearanceof

colonisationat

day8(higher

valuesuggests

moretreatment

failure)5

Serioussideeffects

Relativerisk

Basedondatafrom238participantsin1studies.

Basedondatafrom86participantsin1studies.

160

per1000

Difference:

0

per100

Difference:

80

per1000

80fewerper1000

(CI95%173fewer—8more)

0

per100

0fewerper100

CI95%

Verylow

Duetoseriousrisk

ofbias,Dueto

serious

indirectness,Due

toserious

imprecision6

Moderate

Duetoseriousrisk

ofbias8

Weareuncertainif

choiceofantibioticaffects

therateoftreatment

failure.

Thechoiceofantibiotic

probablydoesnotaffect

therateofseriousside

effects.

7

(Randomized

controlled)

Gastrointestinalsideeffects

Relativerisk