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ClinicalMicrobiologyandInfection23(2017)131140 e
http://DX.doi.org/10.1016/j.CMI.2016.10.008
ContentslistsavailableatScienceDirect

ClinicalMicrobiologyandInfection
journalhomepage www. clinicalmicrobiologyandinfection. com
http://www.clinicalmicrobiologyandinfection.com

Revisión

Clinicalmanagementofadultsandchildrenwithmultidrug-resistente
andextensivelydrug-resistanttuberculosis
K.Dheda 1, *,k.c.Chang,L.guglielmetti
3 4, 5 6
,J.furin,h.s. 2
Schaaf,D.Chesov, 7

A.Esmail,C.1Lange 8, 9, 10, 11, 12

1
LungInfectionandImmunityUnit,DepartmentofMedicine,DivisionofPulmonologyandUCTLungInstitute,UniversityofCapeTown,GrooteSchuur
Hospital,Observatorio,Sudáfrica
2
DesmondTutuTBCentre,DepartmentofPaediatricsandChildHealth,FacultyofMedicineandHealthSciences,StellenboschUniversity,ciudaddelcabo,sur
África
3
TuberculosisandChestService,CentreforHealthProtection,DepartmentofHealth,Hong-Kong,China
4
Sanatorio,CentreHospitalierdeBligny,Briis-sous-Forges,Francia
5
SorbonneUniversite,UniversitePierreetMarieCurie
 Paris6,
D cr7,INSERM,U1135,CentredImmunologieetdesMaladiesInfectieuses,
' CIMI,TeamE13

(Bacteriologie), París,Francia
6
HarvardMedicalSchool,DepartmentofGlobalHealth,andSocialMedicine,Boston,MA,usa
7
DepartmentofPneumologyandAllergology,StateUniversityofMedicineandPharmacyNicolaeTestemitanu,
' Chisinau,' RepublicofMoldova
8
DivisionofClinicalInfectiousDiseases,GermanCenterforInfectionResearch(DZIF),ResearchCenterBorstel,Borstel,Alemania
9
InternationalHealth/InfectiousDiseases,UniversityofLübeck,Lübeck,Alemania
10
DepartmentofMedicine,KarolinskaInstitute,Estocolmo,Suecia
11
DepartmentofMedicine,UniversityofNamibiaSchoolofMedicine,Windhoek,Namibia
12
GermanCenterforInfectionResearch,ClinicalTuberculosisCenter,Borstel,Alemania

articleinfo A b s t r a c t o

Articlehistory: Fondo: Globallythereisaburgeoningepidemicofdrugmonoresistanttuberculosis(TB),


Received10August2016 multi-fármaco-resistantTB(MDR-TB)andextensivelydrug-resistantTB(XDR-TB).Almost20%
Receivedinrevisedform ofallTBstrainsworldwideareresistanttoatleastonemajorTBdrug,includingisoniazid.
6October2016 InseveralpartsoftheworldthereisanincreasingincidenceofMDR-TB,andalarmingly,
Accepted7October2016
almostathirdofMDR-TBcasesgloballyareresistanttoeitherauoroquinoloneoraminoglycoside.Thistrendcannotbeignore
Availableonline15October2016

resitanTBocdwhgmbypu-
ceptiblTB,aounsfrm25%gy
Montador:F.Allerberger isextrmlycoa,
consumebtailprfdg-
catedonilTBprgms-ujh
reatohlcwks,
Palabrasclave: whoareldyinstupc-g.
Niños Evenmorwyigsthpdc
Clinicalmanagement
ofresitancbydXDR-TB,lugwhqmpvkSAIC.
Diagnóstico
Extensivelydrug-resistanttuberculosis
Fuentes: ArticlesrelatedtoMDR-TBandXDR-TBfoundonPubMedinalllanguagesuptoSeptember
Multidrug-resistanttuberculosis
2016,publishedreviews,ylesoftheauthors.

Aimandcontent: ToreviewtheclinicalmanagementofadultsandchildrenwithMDR-andXDR-TBwith
aparticularemphasisontheutilityofnewerandrepurposeddrugssuchaslinezolid,bedaquilineand
delamanid,aswellasmanagementofMDR-andXDR-TBinspecialsituationssuchasinHIV-infectado
personsandinchildren.
Implicaciones:Thisreviewinformsontheprevention,diagnóstico,andclinicalmanagementofMDR-TBand
TB-XDR. K.Dheda,CMI2017;23:131
© 2016EuropeanSocietyofClinicalMicrobiologyandInfectiousDiseases.PublishedbyElsevierLtd.All
rightsreserved.

Introducción
* Autorcorrespondiente.K.Dheda,unidaddelainfecciónydela
inmunidaddelpulmón,DepartmentofMedicine,DivisionofPulmonologyandUCTLungInstitute,
UniversityofCapeTown,h46.41oldmainbuilding,GrooteSchuurHospital, TuberculosisTheadventofmultidrug(MDR)y
Observatorio,CapeTown7925,Sudáfrica.Tel.:+27214047650;Fax:+2721404 extensivelydrug(XDR)TBhasthreatenedtoreversegains
7651. madeinseveralglobalregionsincludingAsia,AfricaandEurope
E-e-mail: keertan.dheda@uct.ac.za(K.dheda). resistentealaenfermedad.

http://DX.doi.org/10.1016/j.CMI.2016.10.008
1198-743X/© 2016EuropeanSocietyofClinicalMicrobiologyandInfectiousDiseases.PublishedbyElsevierLtd.Allrightsreserved.

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132 K.Dhedaetal./ClinicalMicrobiologyandInfection23(2017)131140 e

Droga-resistantTB(Dr-TB)remainsaseriousthreattocontrol TBdrugs.Itisamatterofdebatewhetherallpatientsshouldreceive
becausethereishigherassociatedmorbidity[1],mortalityisworse pyrazinamideaspartofthetreatmentregimen,especiallywhen
thanmostcancers(40%inMDR-TBand6070%inXDR-TBin e resistancetothisdrugiscommon[10].Dehecho,hightreatment
endemiccountriesusingtraditionalregimens),itisamajorthreat successratescanbeachievedwithindividualizedcomprehensive
tothehealthcareworkforce[2]anditisunsustainablycostlyto DST-guidedtherapeuticregimen[12].
Tratar.Porejemplo,despitecomprisingonly5%ofthetotalglobal Onthebasisofresultsfromrecentobservationalstudiesper-
caseloadtheamountspentondiagnosisandtreatmentofDR-por formedinBangladesh[13],Camerún[14]andNiger[15],theWHO
atleast50%ofwhatisspentondrug-susceptibleTB[3].Semejantemente,en recentlyproposedastandardizedshorterMDR-TBtreatment
SouthAfricaoveronethirdofthetotalTBbudgetisalreadyspent regimenadministeredfor9to12months,tobeprovidedto
onDR-TBcontrol[4].In2014therewereapproximately500000 selectedpatientswhencertainprerequisitesaremet,thatis
prevalentcasesofMDR-TBglobally[3].Thereareseveralworrying composedofsevendrugs(kanamicina,moxioxacin,  prothiona-
Estadísticas.Fifteento20%ofallTBisolatesgloballyareresistanttoat mide,clofazimina,pirazinamida,alto-doseisoniazidandetham-
leastonemajoranti-TBdrug,approximately10%areisoniazid butolfor4to6months,followedbymoxioxacin,clofazimina,

monoresistente,30%ofMDR-TBisresistanttouoroquinolonesand/
 pyrazinamideandethambutolfor56months)
e [11(http:http://www
oraminoglycosidesandapproximately10%arethoughttobeXDR- who.int/TB/Short_MDR_regimen_factsheet.pdf). Aunque Lla
TB[3].ThenumberofdetectedcasesofMDR-TBhavegoneup WHOexpectsthatthemajorityofMDR-TBpatientsworldwidewill
dramaticallybetween2008and2013inseveralcountriesincluding benetfromtheshorterMDR-TBtreatmentregimen,
fl elegibilidad
LaIndia,China,Paquistán,NigeriaandSouthAfrica[3].AlthoughMDR- maybelimitedinsomeregionsoftheworld,e.g.SouthernAfrica
TBisinitiallymainlyacquired,inthematurephasesofregionaland andEurope,asdrugresistancetoanyoneoftheagentsinthe
nationalepidemics,adominantmodeofspreadisprimarytrans- regimenisnotuncommon(C.Lange etal .,inpreparación).
Misión[5,6].Así,rapiddiagnosisandtreatmentinadditionto
preventionareessentialaspectsofcontrol. Medicalmanagement:principlesofdesigninganewregimen

Diagnóstico Inadditiontoselectinganeffectivedrugregimen,laparteposterior
severalfacetsofmedicalmanagementthatarecriticaltosuccessful
ThediagnosisofDR-TBisreviewedindetailelsewhere[7,8]. patientoutcomes,includingadherence-supportingmechanisms
ThereareessentiallytwowaystodiagnoseMDR-TB,esdecir, (patienteducationaboutadverseevents,asesoramiento,etc.),buena
drugsusceptibilitytestingfenotípica(DST),
laboratoryinfrastructurewithaccesstosusceptibilitytestinganda
whereanisolateisgrownonsolid
orliquidmediacontainingaspecicantibiotic, fl orthroughmolec- bienfunctioningprogramme.Theprinciplesofdesigningan
ulardetcionfg-s effectiveregimenareoutlinedinTextBox1.Specicfactorsmay
ntecodigmuas. fl
Thelatrmy havetobetakenintoaccountwhentailoringaregimenincluding
beautomdnpily
intofcare, HIVstatusandCD4count,edad,presenceofextrapulmonaryTBand
likethGnXprMTB/Rf, clinicallikelihoodofresistancetospecicdrug.
fl MDR-andXDR-TB
paíse
whicsnotefrlTBda treatmentisoftencomplicatedbyahighrateofadverseevents
gnosticemayd.
Othermolcuasind [22];theseareoutlinedinTable2.Availablerecommendationsare
ray-bsedpltfom largelybasedonobservationalstudiesandexpertopinion,y
lineprobasy[7].
Majordwbcksfgentypim hencetheminimumnumberofeffectivedrugs,optimaldurationof
thodsare treatmentandspecicdrugsconstitutingaregimenremainun-

thasenivyofrdu
rectlyfomspuai Claro.Sinembargo,ingeneral,improvedoutcomesareassociatedwith
mited
(particulynsme-g theuseofagreaternumberofeffectivedrugs,useofantiretroviral
veTB), terapia(ARV)inHIV-infectedpersonsanduseofdrugswithster-
mutaionspredcgvblhqf,jy-.IADRTBxMNwk
fl ilizingactivity[8,24].Pooroutcomesareassociatedwiththefre-
genomesequencingallowsforindividualizedtherapyandhence quencyofresistancetocoresecond-linedrugs,diseaseextenton
potentialimprovementofpatientoutcomes, butthefeasibilityand chestradiograph,comorbidconditionsandhighinitialmicrobio-
impactofsuchanapproachneedstobetestedindifferentsettings.
logicburden[8].Anaccurateandcompositetooltopredictlong-
termoutcomesisurgentlyrequired.
ManagementofMDR-TBandXDR-TBinAdults Fluoroquinolonesaregenerallywelltoleratedbutmayocca-
sionallybeassociatedwithapainfularthralgia-likesyndrome.Por
Currentempiricregimensinuse contrastaminoglycosidesareassociatedwithsignicantrenaland

ototoxicidad(Tabla2).Althoughclofazimineisassociatedwithster-
Becauseofthelargenumberofdrugsintheregimenandthe ilizingpropertiesinexperimentalstudies,itresultsinQTcprolon-
requirementforinjectionsintheinitialphaseoftreatment,el gationandhyperpigmentation,whichsubstantiallycompromises
currenttherapyofMDR-TBandXDR-TBisnotonlyunpleasantfor
patientsbutalsoresourcedemanding[9,10]. Adherencia.Alto-doseisoniazidisoftenbettertoleratedatadoseof
Intheupdatedtreat-mentguidelineforDR-TB[11] 10to15mg/kg,andtheutilityofethionamideorhigh-doseisoni-
theWorldHealthOrganization(WHO) azidcanbereasonablywellpredictedwithreferenceto KatGand
recommendsthatpatientswithrifampicin-resistanter InhAmutations[25].ThelackofrapidandcomprehensiveDST
MDR-TBshouldbetreatedoveraperiodof20monthsandshould readoutsmeansthatempiricregimensoftenhavetobeused,y
receiveadrugregimenwithatleast fl veeffectiveanti-TBdrugs thismayamplifyresistance.Así,studiestoevaluatetheimpactof
duringtherst8monthsoftreatment
fl (includingpyrazinamideand rapidmolecularreadouts(e.g.XpertXDRcartridgewholegenome
inadditionfourcoresecond-lineTBmedicines,withonechosen secuenciación)areurgentlyrequired.
fromgroupA,onefromgroupBandatleasttwofromgroupC)
(tabla1).Así,clofazimineandlinezolidarenowpartofthecore Surgicalmanagement
#Pages [3](groupC).Incaseofdrugresistanceorinabilityto
MDR-TBdrugs
toleratethisregimenitissuggestedthatadrugfromgroupD2and SurgeryisamongtheoldestmethodsofTBtreatmentbuthas
othersfromD3beincludedtoachieveaminimumof flveeffective becomevirtuallyobsoletewiththeadventofeffectiveanti-TB

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K.Dhedaetal./ClinicalMicrobiologyandInfection23(2017)131140 e 133

Tabla1
WorldHealthOrganizationclassicationofmedicinesrecommendedfortreatment

derifampicin-resistantandmultidrug-resistanttuberculosis TEXTBOX1
Clase Descripción Droga Droga RecommendedprinciplesformedicalmanagementofMDR-y
Abreviatura TB-XDRUn
Un Fluoroquinolonas Levooxacin
 LFX
Moxioxacin
 Mfx
Gatioxacin
 Gfx
MDR-TB
B Segundalínea Amikacina Soy
injectableagents Capreomicina/terizidone Cm  Ideallyuseatleastfourdrugs,inadicionto
Kanamicina(estreptomicina) Km(S) pirazinamida,towhichthestrainhasprovenor
C Othercore Etionamida/prothionamide Eto/PTO likelysusceptibility(drugspreviouslytakenfor
segundo-lineagents cicloserina/terizidone CS/TZD
1montharegenerallyavoided)[16].
Linezolida LZD
Clofazimina Zlc  Useabackboneofalater-generationuoroquinolone
D Add-agente D1 Pirazinamida Z (e.g.moxioxacinorlevooxacin;groupAdrug),m·s
Etambutol E asecond-lineinjectabledrug(amikacina/kanamycinor
Alto-doseisoniazid Hh capreomicina; groupBdrugs; 
usedfor semanales
D2 Bedaquiline Bdq
aftercultureconversionandforaminimumof
Delamanid Dlm
D3 Para-aminosalicylicacid Pas 6months)[16].
Imipenem/cilastin Imp  Addanyrst-linedrugandadditionalgroupCdrugs
Meropenem Mpm (e.g.cicloserina/terizidone,etionamida/prothiona-
Amoxicilina/clavulanate AMX-CLV
mide,clofazimineand/orlinezolidifappropriate)a
(Thioacetazone) T
whichtheisolateissusceptible.
 TheWHO recommendedtreatmentdurationis
20months(Low-qualityevidence)[16].
Drogas.Sinembargo,theemergenceoftheMDR-andXDR-TBepidemic  A9-to12-monthregimen(conditionalWHOrecom-
hasrekindledinterestintheuseofsurgicalinterventionasan mendationwithlow-qualityevidence)maybeusedin
adjunctivetherapy,mainlyforpulmonaryTB,butalsoinappro- selectedpatients,inappropriatecountrysettings,
priatecasesofextrapulmonaryTB[26,27].Currentindicationsfor withprovenorhighlylikelyFQandAGsusceptibility
surgeryinDR-TBpatientsarebasedonexpertopinionandobser- inwhomresistancetoanyofthecomponentsofthe
vationalstudies(TextBox2)[28,29]. rÈgimen(exceptH)isunlikely,takingintoaccount
Preoperativeassessmentshouldconrmlikelyadequatecar-
fl previoustreatmentandlocalresistanceproles[11].
diopulmonaryreserveafterlungresection[26].Althoughtheideal  Oxazolidinonas(linezolid)maybeused(groupC
timeforsurgeryisaftercultureconversion[3032],irrealidad
e droga),particularlyinFQ-resistantMDR-TBorXDR-
conversionisoftenunlikelyinpatientswithextensiveresistance, TB,butmonitoringfortoxicity(neuropathyandbone
anddelayinginterventionisnotrecommended[29].Sinembargo,un marrowdepression)isrequired[9,17,18].
minimumof2to6monthsofpreoperativechemotherapyisusually  Bedaquilineordelamanid(groupD2)canbeaddedto
proporcionado[30,33].Despitethelackofcontrolledtrialsandthe theregimeniftoxicityorresistanceprecludes
methodologicshortcomingsofpublishedstudies,severalmeta- formulationofaregimencontaining 4drugslikely
analyseshavesuggestedanincreasedlikelihoodofsuccessful tobeeffective,particularlyifagroupAorgroupB
treatmentoutcomesinMDR-TBpatientsundergoingsurgery drugcannotbeused(bothprolongQTintervaland
[3436].
e Partiallungresection,whenappropriate,wasfoundtobe thusrequiremonitoring)[19,20].
associatedwithtreatmentsuccess[31].Evenwithsuccessful  Elapoyopsicosocialynancialson
resección,thetotaltreatmentduration,includingtheintensive elementstomaintainadherencecrÌticos.
fase,shouldbeensured[29].Irrealidad,andparticularlyinTB- RÈgimende
 Asingledrugshouldnotbeaddedtoafailing.
endemicsettings,fundingandaccesstoappropriateexpertisere-
mainsabarriertosurgery.
XDR-TBandresistancebeyondXDR-TB
 Regimensshouldbeconstructedonthebasisof
Useofnewandrepurposeddrugsandhowbesttoprevent prevailingpatternsofdrugresistanceandonsimilar
amplicationofresistance principlestothatoutlinedforMDR-TB (useof  4

drugslikelytobeeffective).
Repurposedagents  Werecommendabackboneofbedaquilineor
Beforetheadventofnoveldrugs,linezolid,clofazimineand delamanid þlinezolid inclusionofalater-
þ
carbapenemshadbeenrepurposedforthetreatmentofcompli-catedM generationFQ,andadditionofotheragentssuchas
DR-andXDR-TBcases.Theefcacyoflinezolidhasbeen clofazimina,para-aminosalicylicacid,pirazinamida

demonstraiyc andhigh-doseHandotherdrugs,dependingonthe
viewsofbratnlud likelihoodoforprovensusceptibility[21].
s[17,83]awelintocr9buzdhgvfmyp/
 GroupD3drugslikemeropenem/clavulanicacidmay
opticneuropathythatarecausallyrelatedtoinhibitionofmito- utilizado,
buttheirclinicaleffectivenessisuncertain.AG,
chondrialproteinsynthesis[1,3].Therapeuticdrugmonitoringmay aminoglucÛsidos;FQ,uoroquinolone;H,
helpreducetoxicityinwell-resourcedsettings[40,41].Clofazimina isoniazida;MDR,multidrugresistente;TB,
tuberculosis;
Un WHO,WorldHealthOrganization;
hasbeenincludedintheWHOshorterMDR-TBregimen[42]Andis AdaptedwithpermissionfromDheda
XDR,exten-sivelydrugresistant.
etal .[5,7].
efcacydemonstratedinaclinicaltrial
fl [43],butitisassociatedwith
hyperpigmentationandcaninducebedaquilineresistance,posiblemente
byup-regulatingamultisubstrateefuxpump
 [44].Carbapenemes

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134 K.Dhedaetal./ClinicalMicrobiologyandInfection23(2017)131140 e

plusamoxicillin/clavulanatemaybebenecialinthetreatmentof
fi Second-lineinjectabledrugsandethionamideshouldbeavoi-
XDR-TB[45,46]. dedinpregnancybecauseofconcernsaboutfoetalototoxicityand
teratogenicity,respectively.Theseagentsmaybereintroducedafter
delivery.Bedaquilinemaybeatreatmentoptioninselectedpa-
Newerdrugs
tients(categoryBdrug).However,itssafetyinpregnancyhasnot
Bedaquiline(adiarylquinoline)anddelamanid(anitro-
imidazole)arenoveldrugsapprovedforthetreatmentofadult beenfullyestablished[68].
pulmonaryMDR/XDR-TB.BedaquilinedepletesintracellularATPby Inchronicstableliverdysfunction,anti-TBagentssuchasethi-
inhibitingmycobacterialATPsynthase.Delamanidinhibitsmycolic onamide(orprothionamide),high-doseisoniazid,para-amino-
acidsynthesisandproducesreactivenitrogenspecies.Bedaquiline salicylicacid,bedaquilineandlinezolidmaybeusedwithclose
signicantlyincreasedthe120-weekcultureconversionandcure
monitoringofliverfunctiontests.Pyrazinamideshouldbeavoided

entirely.Clinicaltrialsofpretomanidhavetemporarilybeensus-
ratesinaphase2bplacebo-controlledclinicaltrial
[47].TheWHO
hasrecommendedaddingbedaquilineforamaximumof24weeks pendedbecauseofconcernsabouthepatotoxicityinHIV-infected
toaWHO-recommendedMDR-TBregimenwhenthereisuo- persons.Inpatientswithrenalimpairment,frequencyand/or

istance,orpl qu dosageofanti-TBagentsshouldbeadjustedaccordingtocreatinine
ncotaigfurem p clearance[69].Bedaquilineisoftenusedasasubstituteincasesof
d-linerugsatvco f
nedamicotbsgpyrz [20] .
aminoglycoside-relatedrenaldysfunction.
Delamanidsignicantlyimproved2-monthcultureconversion

inaclinicaltrial[48]andtreatmentoutcomes(treatmentsuccess Monitoringtreatmentandoutcomedenitions

andmortality)inanobservationalstudy [49,50].TheWHOhas
recommendedaddingdelamanidtoaWHO-recommendedMDR- Standardizedtreatmentmonitoringisimportanttodocument
TBregimenwhenaneffectiveandreasonablywell-tolerated theresponsestotherapyandtoidentifyadverseeventsassoonas
regimencannotbeestablished,inparticularMDR-TBpatients possible.Treatmentmonitoringtableshavebeenpublishedand
withadditionalresistanceto fl uoroquinolonesorsecond-linein- areavailableonline[15].PresentlytheWHOoutcomedenitionsfi
jectablesandthoseatincreasedriskofpoortreatmentoutcome forMDR-TBdenetreatmentsuccessasthesumofcureand
fi ‘ ’ ‘ ’
[19]. ‘treatmentcompleted’[70].Thedenitionofcurerequiresat
fi ‘ ’
BothbedaquilineanddelamanidcauseQTintervalprolongation, leastthreeconsecutivenegativecultures(eachtakenatleast
althoughassociationwith torsadesdepointes hasnotbeen 30daysapart)aftertheintensivephaseoftherapyintheabsence
demonstrated.Aplacebo-controlledclinicaltrialreporteda oftreatmentfailure.BecausemostpatientswithMDR-TB
‘ ’ ndit

signicantlyhighermortalityriskinthebedaquiline-treatedarm
fi difculttoproducesputuminthecontinuationphaseoftreat-

[47],butanuncontrolledphase2btrial [51]andobservational ment,collectionofthreesputumsamplesisnotroutinelyper-
studieshavesuggestedthatbedaquilineissafeandefcacious fi formed,andthemajorityofpatientsarenoteligibletobe
[5254](C.Hewison e etal .,paperpresentedatUnionWorldCon- evaluatedforthiscriterionofcure.Inarecentclinicaltrialon
‘ ’
ference,CapeTown,SouthAfrica,2015).Delamanidhasbeensafely MDR-TB,thedenitionofcureincludedaperiodofatleast
fi ‘ ’
usedinchildrenaged8to17years[55]. 12monthsofbeingfreeofdiseaserecurrenceafterthecomple-
Althoughnotsupportedbysubstantialdataorcontrolled tionoftherapy[47].Thiswouldalsobeadequateforclinical
studies,thecombineduseofbedaquilineanddelamanid [56,57] practice;otherwisetreatmentsuccessreliespredominantlyon
‘ ’
anduseofbedaquilinebeyond24weeks [58](L.Guglielmetti,
paperpresentedattheEuropeanCongressofClinicalMicrobiology completingthetreatmentwithoutabiologicalendpoint.The
andInfectiousDiseases,Amsterdam,TheNetherlands2016),may WHOdenitionoftreatmentfailurerequiresearlytreatment
fi ‘ ’
bebenecialinselectedcaseswithlimitedtherapeuticalterna- terminationorneedforpermanentregimenchangeofatleast
fi twodrugsinthecourseofMDR-TBtreatment.Lateculturecon-
tives [59] Resita.ncobd versionisrelatedtonegativetreatmentoutcomes [71,72].Ac-
delamnquihsr
scribedayn [60] fi.Tosutainherb ,mpot cordingtothe fi ndingsofthePETTSstudy[73,74]andtheTBNET
implentadsgxo MDR-TBcohortstudy(G.Günther etal .[96]),treatmentfailureis
licesandtohrg
princlesofmbTBat bestpredictedbynoncultureconversionbeyond6monthsof
eatmn [61] .Olingocatr swfyheolpcidrugntma eofMDR-TB
fi anti-TBtherapy.
(Table3).
ResistancebeyondXDR-TBandprogrammaticallyincurableTB
ManagingMDR-TBinspecialsituationsincludingHIV
Therealityismostoftheworld'sMDR-TBpatientsdonothave
ManagementofMDR-TBinspecicclinicalscenarioscanbe
fi accesstonewerandrepurposeddrugssuchasbedaquiline,
challenging.InpatientswithMDR-TBHIVcoinfection,ARVmustbe delamanidandlinezolid.Evenwiththeavailabilityofsuchdrugs,
commencedirrespectiveofCD4count,usuallywithin8weeksof treatmentfailuresarealreadybeingreported,andtherehavebeen
initiatingTBtreatment[62].Giventheirhigherriskofdeath,pa- severalcasereportsoffailurewithdocumentedresistancetoboth
tientswithadvancedHIV(CD4countof 50< L/mL),shouldhave
m delamanidandbedaquiline[60,75].Consequentlythereisabur-
moreexpeditedinitiationofARVdespitetheincreasedriskofim- geoningpoolofXDR-TBfailures(withvaryingdegreesofresis-
munereconstitutioninammatorysyndrome
fl [6365].Theuseof
e tancebeyondXDR-TB)inpatientsremaintherapeuticallydestitute
efavirenziscontraindicatedwhenusingbedaquiline [66].The andwithsignicantlongevity(monthstoyears)
fi [76].In endemic
choiceofcompanionARVwithbedaquilinecouldincludenevira- countries,becauseTBhospitalsarefull,thesepatientsareoften
pine[67],lopinavir/ritonavir[67](usewithcautiongivenincreased home-dischargedbackintothecommunity.Thisraisesseveral
levels)oranintegrasestrandtransferinhibitorincombinationwith ethicalandmedicolegalissues [8].Transmissionofdiseaseun-
dualnucleosidereversetranscriptaseinhibitors.Delamanidmay derscorestheneedforbuildingcommunity-basedcontainment
potentiallybesafeforcoadministrationwithARV( http://www. facilities(new-stylesanatoriums)[77]andfasteraccesstonewer
ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_ drugsanddiagnostictechnologies,inadditiontoantibioticstew-
Information/human/002552/WC500166232.pdf ). ardshipandpreventativestrategies.
K.Dhedaetal./ClinicalMicrobiologyandInfection23(2017)131140 e 135

Table2
AdversereactionstoantituberculosisdrugsforMDR-TBtreatment
[5,19,20,23]

Drug Adversereactions Precautions Renaldosing(creatinineclearance


<30mL/minute)

Fluoroquinolones *
 Jointandtendon:tendonrupture,arthralgia *  TakeprecautionsforG6PDdeciencyifenzyme
fi Reducedosingfrequencyto3times
 Gastrointestinal:metallictaste,nausea,bloating, activity < 60%(classI,II,III)orassociatedwith aweek(exceptformoxioxacin)

diarrhea,colitis * knownhistoryofrelatedhaemolysis
 Haematologic:haemolyticanaemiainG6PD  PotentialdrugdruginteractionswithotherQT-
e
deciency
fi * prolongingdrugs
 Hepatotoxicity(moxioxacin)
fl *  Hypokalaemia increases the risk of QT
 Neurologic:headache,dizziness,tremulousness, prolongation
insomnia,convulsion, *
 QTprolongation(especiallymoxioxacin) fl
Second-line  Neurologic:ototoxicity,vestibulartoxicity  Ototoxicityriskincreaseswitholdageanda Avoidorreducedosingfrequency
injectabledrugs  Renal: nephrotoxicity, hypokalaemia, hypo- * largercumulativedosage;thriceweeklydosing to3timesaweek
*
magnesaemia,hypocalcaemia * mayhelpreducetoxicity
 Softtissue:localinjection-relatedpain
Ethionamide/ *
 Endocrineeffects:acne, hairloss, *
menstrual  Neurotoxicitysideeffectsmaybeexaggerated
prothionamide * *
irregularity,hypoglycaemia,reversiblehypo- whencycloserineisused
thyroidism,*  Closelymonitorliverbiochemistryinpatients
*
gynaecomastia,impotence * withliverdisease
 Gastrointestinal: metallic taste, salivation,  Ifpossible,thedrugisgenerallyavoidedduring
gastrointestinalupset,anorexia pregnancy(especially firsttrimester)dueto
 Hepatotoxicity concernsaboutteratogenicityandworseningof
*
 Neurologic:convulsion,mentalsymptoms * pregnancy-associatednausea/vomiting
Pyrazinamide  Cutaneous:rash,photosensitivity  Avoidifpossibleinpatientswithliverdisease Reducedosingfrequencyto3times
 Joint and tendon: gout (hyperuricaemia), aweek
arthralgias
 Gastrointestinalupset
 Haematologic:sideroblasticanaemia *
 Hepatotoxicity
Cycloserine  Cutaneous: lichenoid eruptions, * Stevens-  Toxicitymaybeincreasedwhenethionamideis Reducedosingfrequencyto3times
Johnsonsyndrome * used aweek
 Haematologic:sideroblasticanaemia *
 Neurologic:inabilitytoconcentrate,lethargy,
dizziness,depression,memoryloss,psychosis,
suicidalideation,
seizure,peripheralneuropathy
Para-aminosalicylic  Endocrine:reversiblehypothyroidism *  Increased risk of hypothyroidism when
acid  Fluidandelectrolyte:hypokalaemia, *sodium ethionamideisalsoused
*
overload,metabolicacidosis *  Closelymonitorliverbiochemistryinpatients
 Gastrointestinaldistress withliverdisease
 Haematologic: coagulopathy, * haematologic
reactions*
 Hepatotoxicity*
Ethambutol  Arthralgia*  Ifpossible,avoidinpatientswhocannotreport Reducedosingfrequencyto3times
 Cutaneousreaction * visualsymptoms aweek
 Hepatotoxicity*
 Peripheralneuropathy *
 Retrobulbarneuritis(oftendoserelated)
Isoniazid  Arthralgia*  Avoidifpossibleinpatientswithliverdisease
 Cutaneous:hypersensitivity,lupoidreaction *
 Endocrine:acne,gynaecomastia *
*
 Gastrointestinal:diarrhoea,abdominalcramps *
 Haemolyticanaemia *
 Hepatotoxicity(age-related)
 Neurologic: peripheral neuropathy, optic
* *
neuritis,convulsion,giddiness,mental*
symptoms*
Clofazimine  Cutaneous: dry skin,  Potentialdrugdruginteractions:otherQT-
e
hyperpigmentation, prolongingdrugs
pruritus,rash,photosensitivity,eyeirritation
 Gastrointestinal: gastrointestinal reactions,  Hypokalaemia increases the risk of QT
diarrhoea(highdose),tastedisorder,bowel * prolongation
obstruction*  Usewithcautioninpatientswithliverdiseaseas
 Neurologic:giddiness,retinopathy thedrugismetabolizedintheliver
 QTprolongation
Linezolid  Gastrointestinal:diarrhoea,nausea  Thrice-weekly dosing may help reduce
 Hepatotoxicity:increasedtransaminase * mitochondrialtoxicity
 Myelosuppression: aplastic anaemia,
thrombocytopenia
 Neurologic:optic/peripheralneuropathy
(continuedonnextpage )
136 K.Dhedaetal./ClinicalMicrobiologyandInfection23(2017)131140 e

Table2 (continued )

Drug Adversereactions Precautions Renaldosing(creatinineclearance


<30mL/minute)

Bedaquiline  Hepatotoxicity  Causeofincreasedmortalityriskremainsunclear


 QTprolongation  Usedwithcautioninpersonsaged 65yearsand
peoplelivingwithHIV,comorbidities,alcohol/
substanceuse(limited/noinformation)
 Potential drugdrug
e interactions: CYP3A4
inhibitors,CYP3A4inducers,otherQT-
prolongingdrugs
 Hypokalaemia increases the risk of QT
prolongation
 Closelymonitorliverbiochemistryinpatients
withliverdisease
 Usewithcautioninpatientswithsevererenal
impairment.
Delamanid  QTprolongation  Usewithcautioninpersonsaged 65years,
thosewithcomorbidities(e.g.diabetesmellitus,
moderatetoseverehepaticimpairmentorsevere
renalimpairment),thosewithalcohol/substances
(limited/noinformation)
 PotentialdrugdruginteractionswithotherQT-
e
prolongingdrugs
 Hypokalaemia increases the risk of QT
prolongation
 Contraindicated:serumalbumin <2.8g/dL,QTcF
>500ms,metronidazoleallergy
 Notcurrentlyadvisedforchildren,pregnant
womenandbreast-feedingwomen
 Useinsevererenalimpairmentisnot
recommended.

G6PD,glucose-6-phosphatedehydrogenase.
*
Thesearerare.

TEXTBOX2 implementationofpostexposurehouseholdmeasuresandinsuf- fi
Broadindicationsforsurgicalinterventioninpatientswithpre-
viousorcurrentdrug-resistantTB cientfunding[7981].
e
WhenchildrenarediagnosedwithandtreatedforMDR-TB,they
havegoodoutcomes[82].AlthoughbacterialconrmationofMDR-

TBinchildrenisachallenge,thediagnosisofTBisrelatively
straightforwardandisbasedonhistory,physicalexaminationand
 PersistentlypositiveAFBsmearorsputumculture
chestradiography[83].IfachildhassignsandsymptomsofTBand
despiteadequatechemotherapy.
hasaknownclosecontactwithMDR-TB,thatchildshouldbe
 Highriskofrelapse(basedondrugresistancepattern
treatedforMDR-TBwitharegimenconstructedonthebasisofthe
andradiologicfeatures).
drugsusceptibilitytestpatternofthesourcecase [84].Thebasic
 LimiteddiseasefoundonchestX-rayorchest
principlesoftreatmentinthepaediatricpopulationarethesameas
computedtomography.
thoseforadults[85].Childrenwithnonseverediseasemaybenet fi
 ComplicationsofpulmonaryTB(bronchiectasis,
fromashorterregimen(1215months)orashorterperiodof
e
empyema,haemoptysis,etc.).
injectableadministration(24months)
e [86].Ofnote,therecent
 LatecomplicationsofextrapulmonaryTB(obstructive
WHOrecommendationsontheshorter9-to12-monthregimenfor
uropathy,hydrocephalus,neurologicinvolvement
MDR-TBwithoutadditionalresistancealsoapplytochildren.
fromspineTB,constrictivepericarditis).
AFB,acid-fastbacilli;TB,tuberculosis. Monitoringchildrenforadverseeventsisessentialbutchal-
lenging.Mostimportantishearingevaluation,asupto25%of
childrentreatedforMDR-TBwithaninjectableagentdevelop
hearingloss[87].Adverseeffectsoforalsecond-linedrugsin
childrenandhowtomanagethesehavebeenrecentlyreviewed
ManagementofDR-TBinChildren [88].Childrenmayalsoneedadditionalfamilycounsellingand
socialsupport d especiallyadolescentswhohavebeenshownto
Estimatessuggestthatapproximately25000childrendevel- haveworseoutcomesthanadults [89,90] d althoughthereare
opedMDR-TBin2014,andtwomillionchildrenwereinfectedwith encouragingstudiesthatshownosignicantlong-termsocialor

MDR
Mycobacteriumtuberculosis [78].Onlyaroundathousand developmentaleffectsamongchildrenwhohavebeentreatedfor
childrenhavebeenreportedtoreceiveMDR-TBtreatment(E.P. MDR-TB[91].Familiesandcaregiversalsoneedtargetedsupport
Harausz etal .,paperpresentedatthe46thUnionWorldConference aroundregimenadministrationbecausemostofthesecond-line
onLungHealth,CapeTown,SouthAfrica,2015).Manyrecentar- drugsmustbecrushedorsplitandmixedwithliquidsforde-
ticlesexaminethebarrierstodiagnosisandtreatmentamong liverytothechild[92].
childrenwithMDR-TB,includingabsenceofapredictivescreening Thereisemergingevidenceonthedoseandsafetyofthenew
tool,difcultiesobtainingsamplesforbacteriologicconrmation,
fi fi drugsdelamanidandbedaquiline,especiallyintheadolescent
lackofasensitivediagnostictest,providers'fearsabouttreating population;thedosingandshort-termsafetyofdelamanidhave
children,lackofpaediatricformulationsofmedications,limited beenestablishedinchildrenasyoungas6yearsofage( Table4)
Table3
KeytherapeuticclinicaltrialsinadultswithMDR-orXDR-TB

Studyname Design Studypopulation Comparator Experimentalarms Samplesize Sponsor Currentstatus

Otsuka213 Doubleblind,randomized, MDR-TBpatients(XDR-TB OptimizedMDR-TBbackground  Optimized MDR-TB back- 511 Otsuka Studycompleted
placebo-controlledphase3 patientsareexcluded) regimen þ
placebo groundregimen þ
Dlm follow-upforprimary
clinicaltrial endpoint;dataanalysis
ongoing
endTB Open-label,randomized, Rifampicin-resistant,FQ- WHOMDR/XDR-TBstandardof  Bdq þLzd Mfx
þ Z þ 750 MSF,PIH Recruitmentnotyet
controlled,Bayesianadaptive susceptibleTBpatients care  Bdq þCfz Lzd
þ Lfx Zþ þ started
phase3clinicaltrial  Bdq þDlm Lzdþ Lfx Zþ þ
 Dlm þCfz Lzd
þ Lfx Zþ þ
 Dlm þCfz Mfx
þ Z þ
 Treatment duration:
36weeks
TB-PRACTECAL Open-label,randomized, Rifampicin-resistantTB WHOMDR/XDR-TBstandardof  Bdq þPa Lzd
þ Mfx þ 630 MSF Recruitmentnotyet
controlled,multi-armphase2/3 patients care  Bdq þPa Lzd
þ Cfz þ started
clinicaltrial  Bdq þPa Lzd
þ
 Treatment duration:

K. Dheda et al. / Clinical Microbiology and Infection 23 (2017) 131e140


24weeks
STREAMI Open-label,randomized, Rifampicin-resistant,FQ-and WHOMDR/XDR-TBstandardof  hMfx þ Cfz þ E þ Zfor 400 IUATLD Recruitmentcomplete;
controlledphase3clinicaltrial SLI-susceptibleTBpatients care 40weeks,hH Km þ Pto þ follow-upongoing
for16weeks a
STREAMII Open-label,randomized, Rifampicin-resistant,FQ-and MDR/XDRWHOStandardof  Bdq þ Lfx þ Cfz þ E þ Zfor 1155 IUATLD Recruitmentongoing
controlledphase3clinicaltrial SLI-susceptibleTBpatients care 40weeks;hH þPtofor
hMfx þ
Cfz E þZforþ 16weeks
40weeks;hH Km þ Ptofor
þ  Bdq þ Lfx þ Cfz þ Zfor
16weeks a 28weeks;hH þKmfor
8weeks
NEXT Randomized,controlled,open Rifampicin-resistant,FQ-and WHOMDR/XDR-TBstandardof  Lzd þ
Bdq Lfxþ Z (Etoor
þ þ 300 UniversityofCape Recruitmentongoing
label SLI-susceptibleTBpatients care hHorTzd,accordingto Town
genotype)
 Treatment duration: 6
e9months,accordingto
microbiologicresponse
STAND Open-label,partially DR-TBarmofthestudy: DS-TBcontrolarm:  MDR-TBexperimentalarm: 1500(including GlobalAlliancefor Currentlyonhold
randomized,controlledphase3 Rifampicin-resistant,FQ-andZ- Mfx þ
Pa Z þ Mfx þPa Z þ DS-TB cases) TBDrug becauseofepisodesof
study susceptibleTBpatients  Treatment duration: Development severelivertoxicity;
26weeks suspendedparticipant
recruitment
Nix-TB Openlabel,nonrandomized, XDR-TBpts,failedMDR-TB Nocontrolarm  Bdq þ
Pa Lzdþ 200 GlobalAlliancefor Recruitmentongoing
uncontrolledphase3study patients,MDR-TBpatientswith  Treatment duration: 6 TBDrug
intolerancetosecondlinedrugs e9months,accordingto Development
microbiologicresponse
MDR-END Openlabel,randomized, Rifampicin-resistant,FQ- WHOMDR/XDR-TBstandardof  Dlm þLzd Lfxþ Z þ 238 SeoulNational Currently enrolling
controlledphase2study susceptibleTBpatients care  Treatment duration: 9 UniversityHospital participants
e12months,accordingto
microbiologicresponse
Opti-Q Double-blind,randomized, Rifampicin-resistant, FQ- OptimizedMDR-TBbackground  Optimized MDR-TB back- 120 BostonUniversity Currentlyenrolling
controlledphase3clinicaltrial susceptibleTBpatients regimen þ Lfxatstandarddose groundregimen þLfxat
higerdos(14,7an20m/ky) participants
(11mg/kg/day)

Bdq,bedaquiline;Cfz,clofazimine;Dlm,delamanid;DR-TB,drug-resistantTB;DS-TB,drug-susceptibleTB;E,ethambutol;Eto,ethionamide;FQ, fl uoroquinolone;hH,high-doseisoniazid;hMfx,high-dose(800mgdaily)
moxioxacin;IUATLD,InternationalUnionagainstTuberculosisandLungDisease;Lfx,levooxacin;Lzd,linezolid;MDR-TB,multidrug-resistantTB;Mfx,standard-dose(400mgdaily)moxioxacin;MSF,MedecinsSans
fl fl fl 

Frontieres;Pa,pretomanid;PIH,PartnersinHealth;Pto,prothionamide;SLI,second-lineinjectabledrugs;TB,tuberculosis;Tzd,terizidone;XDR-TB,extensivelydrug-resistantTB;WHO,WorldHealthOrganization;Z,
pyrazinamide.
a
Intheeventofdelayedsmearconversion,theintensivephaseofthestudyregimencanbeextended4or8weeks,allowingamaximumtotaldurationof48weeksoftreatment.

137
138 K.Dhedaetal./ClinicalMicrobiologyandInfection23(2017)131140 e

Table4
Recommendeddosingofsecond-linedrugsinchildren

Drug Recommendedmaximumdailydose

Pyrazinamide  3040mg/kg/day
e
Kanamycin/amikacin/capreomycin  1820mg/kg/day(750mg)
e
Levooxacin
fl  1520mg/kg/day(1000mg)
e
Moxioxacin
fl  10mg/kg/day(400mg)
Ethionamide/prothionamide  1520mg/kg/day(1000mg)
e
Cycloserine/terizidone  1520mg/kg/day(1000mg)
e
Para-aminosalicylicacid  150200mg/kg/day(8gm)
e
Clofazimine  25mg/kgdaily(100mg)
e
 Inyoungerchildrencouldbedosedeverysecondorthirddaytoadaptforcapsulemgsize,asclofaziminehasalonghalf-life
Linezolid  10yearsofage:10mg/kg/day(600mg)
 <10yearsofage:10mg/kgtwicedaily(600mg)
Delamanid  35kg:100mgtwicedaily
 2034kg:50mgtwicedaily
e
 <20kg:consultwithexpert
Bedaquiline  33kg:400mgdailyfor14days,followedby200mgthreetimesaweekfor22weeks
 <33kg:consultwithexpert
Amoxicillin/clavulanicacid  80mg/kgofamoxicillincomponentdividedinto2doses(4000mgamoxicillin/500mgclavulanicacid)
 Shouldbeprovidedwithmeropenem
Meropenem  2040mg/kgIVevery8hours(6000mg)
e
 Mustbeprovidedwithclavulanicacid

AdaptedwithpermissionfromDheda etal .[5].

[55].Thereisaneed,however,tobetterimplementpostexposure Qiagen),grantsfromeNoseCompany,grantsfromStatensSerum
interventionsforchildrenwhoareclosecontactsofpeoplewith Institut,grantsfrombioMeriux,grantsandpersonalfeesfrom
infectious MDR-TB [93]. Observational studies show that Cepheid,grantsandpersonalfeesfromAntrumBiotec,grantsand
fluoroquinolone-basedregimensarebotheffectiveinpreventing personalfeesfromHainLifescience,alloutsidethesubmittedwork.
MDR-TBandwelltoleratedbychildrenandtheircaregivers [94,95]. Inaddition,Dr.DhedahasapatentCharacterisationofnovelTB-
Randomizedclinicaltrialsarebeingplannedtoformallyassessthe specicurinarybiomarkersissued,andapatentAsmartmaskfor

impactofuoroquinolone-basedtreatmentofTBinfection,but
fl monitoringcough-relatedinfectiousdiseasesissuedunrelatedto
withtheresultsofsuchtrialslikelyyearsaway,thereisanurgent thesubmittedwork.Noneoftheotherauthorshaveanyconictstofl
needtosupportstrongerprogrammaticassessmentandfollow-up declare.
ofexposedchildren(http://impaactnetwork.org/DocFiles/Index/
StudyStatusTbl.pdf).
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