Multilizer PDF Translator Free version - translation is limited to ~ 3 pages per translation.

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.
fl
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.

Multilizer PDF Translator Free version - translation is limited to ~ 3 pages per translation.
 Multilizer PDF Translator Free version - translation is limited to ~ 3 pages per translation.
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-
fl
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
fl
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

Multilizer PDF Translator Free version - translation is limited to ~ 3 pages per translation.
 Multilizer PDF Translator Free version - translation is limited to ~ 3 pages per translation.
K.Dhedaetal./ClinicalMicrobiologyandInfection23(2017)131140 e 133

Tabla1
WorldHealthOrganizationclassicationofmedicinesrecommendedfortreatment
fl
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
fi
drugslikelytobeeffective).
Repurposedagents
Werecommendabackboneofbedaquilineor
Beforetheadventofnoveldrugs,linezolid,clofazimineand delamanid þlinezolid inclusionofalater-
þ
carbapenemshadbeenrepurposedforthetreatmentofcompli-catedM generationFQ,andadditionofotheragentssuchas
DR-andXDR-TBcases.Theefcacyoflinezolidhasbeen clofazimina,para-aminosalicylicacid,pirazinamida
fl
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

Multilizer PDF Translator Free version - translation is limited to ~ 3 pages per translation.
 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
fi
entirely.Clinicaltrialsofpretomanidhavetemporarilybeensus-
ratesinaphase2bplacebo-controlledclinicaltrial
[47].TheWHO
hasrecommendedaddingbedaquilineforamaximumof24weeks pendedbecauseofconcernsabouthepatotoxicityinHIV-infected
toaWHO-recommendedMDR-TBregimenwhenthereisuo- persons.Inpatientswithrenalimpairment,frequencyand/or
fl
istance,orpl qu dosageofanti-TBagentsshouldbeadjustedaccordingtocreatinine
ncotaigfurem p clearance[69].Bedaquilineisoftenusedasasubstituteincasesof
d-linerugsatvco f
nedamicotbsgpyrz [20] .
aminoglycoside-relatedrenaldysfunction.
Delamanidsignicantlyimproved2-monthcultureconversion
fi
inaclinicaltrial[48]andtreatmentoutcomes(treatmentsuccess Monitoringtreatmentandoutcomedenitions
fi
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
fi
signicantlyhighermortalityriskinthebedaquiline-treatedarm
fi difculttoproducesputuminthecontinuationphaseoftreat-
fi
[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)
fl
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
Table2 (continued )
Drug Adversereactions
Bedaquiline
Hepatotoxicity

QTprolongation
Delamanid
QTprolongation
G6PD,glucose-6-phosphatedehydrogenase.
*
Thesearerare.
TEXTBOX2
Broadindicationsforsurgicalinterventioninpatientswithpre-
viousorcurrentdrug-resistantTB

PersistentlypositiveAFBsmearorsputumculture
despiteadequatechemotherapy.

Highriskofrelapse(basedondrugresistancepattern
andradiologicfeatures).

LimiteddiseasefoundonchestX-rayorchest
computedtomography.

ComplicationsofpulmonaryTB(bronchiectasis,
empyema,haemoptysis,etc.).

LatecomplicationsofextrapulmonaryTB(obstructive
uropathy,hydrocephalus,neurologicinvolvement
fromspineTB,constrictivepericarditis).
AFB,acid-fastbacilli;TB,tuberculosis.
ManagementofDR-TBinChildren
Estimatessuggestthatapproximately25000childrendevel-
opedMDR-TBin2014,andtwomillionchildrenwereinfectedwith
MDR
Mycobacteriumtuberculosis [78].Onlyaroundathousand
childrenhavebeenreportedtoreceiveMDR-TBtreatment(E.P.
Harausz etal .,paperpresentedatthe46thUnionWorldConference
onLungHealth,CapeTown,SouthAfrica,2015).Manyrecentar-
ticlesexaminethebarrierstodiagnosisandtreatmentamong
childrenwithMDR-TB,includingabsenceofapredictivescreening
tool,difcultiesobtainingsamplesforbacteriologicconrmation,
fi fi
lackofasensitivediagnostictest,providers'fearsabouttreating
children,lackofpaediatricformulationsofmedications,limited
e
Precautions Renaldosing(creatinineclearance
<30mL/minute)

Causeofincreasedmortalityriskremainsunclear

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.

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.
implementationofpostexposurehouseholdmeasuresandinsuf- fi
cientfunding[7981].
e
WhenchildrenarediagnosedwithandtreatedforMDR-TB,they
havegoodoutcomes[82].AlthoughbacterialconrmationofMDR-
fi
TBinchildrenisachallenge,thediagnosisofTBisrelatively
straightforwardandisbasedonhistory,physicalexaminationand
chestradiography[83].IfachildhassignsandsymptomsofTBand
hasaknownclosecontactwithMDR-TB,thatchildshouldbe
treatedforMDR-TBwitharegimenconstructedonthebasisofthe
drugsusceptibilitytestpatternofthesourcecase [84].Thebasic
principlesoftreatmentinthepaediatricpopulationarethesameas
thoseforadults[85].Childrenwithnonseverediseasemaybenet fi
fromashorterregimen(1215months)orashorterperiodof
e
injectableadministration(24months)
e [86].Ofnote,therecent
WHOrecommendationsontheshorter9-to12-monthregimenfor
MDR-TBwithoutadditionalresistancealsoapplytochildren.
Monitoringchildrenforadverseeventsisessentialbutchal-
lenging.Mostimportantishearingevaluation,asupto25%of
childrentreatedforMDR-TBwithaninjectableagentdevelop
hearingloss[87].Adverseeffectsoforalsecond-linedrugsin
childrenandhowtomanagethesehavebeenrecentlyreviewed
[88].Childrenmayalsoneedadditionalfamilycounsellingand
socialsupport d especiallyadolescentswhohavebeenshownto
haveworseoutcomesthanadults [89,90] d althoughthereare
encouragingstudiesthatshownosignicantlong-termsocialor
fi
developmentaleffectsamongchildrenwhohavebeentreatedfor
MDR-TB[91].Familiesandcaregiversalsoneedtargetedsupport
aroundregimenadministrationbecausemostofthesecond-line
drugsmustbecrushedorsplitandmixedwithliquidsforde-
liverytothechild[92].
Thereisemergingevidenceonthedoseandsafetyofthenew
drugsdelamanidandbedaquiline,especiallyintheadolescent
population;thedosingandshort-termsafetyofdelamanidhave
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

STREAMI Open-label,randomized,
controlledphase3clinicaltrial
STREAMII Open-label,randomized,
controlledphase3clinicaltrial
NEXT Randomized,controlled,open
label
STAND Open-label,partially
randomized,controlledphase3
study
Nix-TB Openlabel,nonrandomized,
uncontrolledphase3study
MDR-END Openlabel,randomized,
controlledphase2study
Opti-Q Double-blind,randomized,
controlledphase3clinicaltrial
24weeks
Rifampicin-resistant,FQ-and WHOMDR/XDR-TBstandardof
hMfx þ Cfz þ E þ Zfor 400 IUATLD Recruitmentcomplete;
SLI-susceptibleTBpatients care 40weeks,hH Km þ Pto þ follow-upongoing
for16weeks a
Rifampicin-resistant,FQ-and MDR/XDRWHOStandardof
Bdq þ Lfx þ Cfz þ E þ Zfor 1155 IUATLD Recruitmentongoing
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
Rifampicin-resistant,FQ-and WHOMDR/XDR-TBstandardof
Lzd þ
Bdq Lfxþ Z (Etoor
þ þ 300 UniversityofCape Recruitmentongoing
SLI-susceptibleTBpatients care hHorTzd,accordingto Town
genotype)

Treatment duration: 6
e9months,accordingto
microbiologicresponse
DR-TBarmofthestudy: DS-TBcontrolarm:
MDR-TBexperimentalarm: 1500(including GlobalAlliancefor Currentlyonhold
Rifampicin-resistant,FQ-andZ- Mfx þ
Pa Z þ Mfx þPa Z þ DS-TB cases) TBDrug becauseofepisodesof
susceptibleTBpatients
Treatment duration: Development severelivertoxicity;
26weeks suspendedparticipant
recruitment
XDR-TBpts,failedMDR-TB Nocontrolarm
Bdq þ
Pa Lzdþ 200 GlobalAlliancefor Recruitmentongoing
patients,MDR-TBpatientswith
Treatment duration: 6 TBDrug
intolerancetosecondlinedrugs e9months,accordingto Development
microbiologicresponse
Rifampicin-resistant,FQ- WHOMDR/XDR-TBstandardof
Dlm þLzd Lfxþ Z þ 238 SeoulNational Currently enrolling
susceptibleTBpatients care
Treatment duration: 9 UniversityHospital participants
e12months,accordingto
microbiologicresponse
Rifampicin-resistant, FQ- OptimizedMDR-TBbackground
Optimized MDR-TB back- 120 BostonUniversity Currentlyenrolling
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
interventionsforchildrenwhoareclosecontactsofpeoplewith
infectious MDR-TB [93]. Observational studies show that
fluoroquinolone-basedregimensarebotheffectiveinpreventing
MDR-TBandwelltoleratedbychildrenandtheircaregivers [94,95].
Randomizedclinicaltrialsarebeingplannedtoformallyassessthe
impactofuoroquinolone-basedtreatmentofTBinfection,but
fl monitoringcough-relatedinfectiousdiseasesissuedunrelatedto
withtheresultsofsuchtrialslikelyyearsaway,thereisanurgent
needtosupportstrongerprogrammaticassessmentandfollow-up
ofexposedchildren(http://impaactnetwork.org/DocFiles/Index/
StudyStatusTbl.pdf).
Qiagen),grantsfromeNoseCompany,grantsfromStatensSerum
Institut,grantsfrombioMeriux,grantsandpersonalfeesfrom
Cepheid,grantsandpersonalfeesfromAntrumBiotec,grantsand
personalfeesfromHainLifescience,alloutsidethesubmittedwork.
Inaddition,Dr.DhedahasapatentCharacterisationofnovelTB-
specicurinarybiomarkersissued,andapatentAsmartmaskfor
fi
thesubmittedwork.Noneoftheotherauthorshaveanyconictstofl
declare.
References

Conclusions [1]SinglaN,SinglaR,FernandesS,BeheraD.Posttreatmentsequelaeofmulti-
drugresistanttuberculosispatients.IndianJTuberc2009;56:206 12. e
[2]O'DonnellMR,JarandJ,LovedayM,PadayatchiN,ZelnickJ,WernerL,etal.
TheincreasingburdenofMDR-TBinseveralregionsoftheworld Highincidenceofhospitaladmissionswithmultidrug-resistantandexten-
isamajorthreattoTBcontrol.Whilsttheintroductionofnewer sivelydrug-resistanttuberculosisamongSouthAfricanhealthcareworkers.
automatedmoleculartechnologiesandnext-generationwhole AnnInternMed2010;153(8):516 22. e
genomesequencingispromising,thiswillrequireconrmationof [3]WorldHealthOrganization.Globaltuberculosisreport,2016.WorldHealth
fi Organization;2016.
feasibilityandclinicalimpact.Evenmoreimportantwillbetheeld fi [4]PooranA,PietersonE,DavidsM,TheronG,DhedaK.Whatisthecostof
tingaprolcfsuhe diagnosisandmanagementofdrugresistanttuberculosisinSouthAfrica?
ntheacsdirmpo PLoSOne2013;8:e54587.
ison.Prchafpmyt [5]DhedaK,GumboT,MaartensG,DooleyKE,McNerneyR,MurrayM,etal.Fro
arep-vntisg m
swilnedmout,bhrapc manageablebugstonodrugs:newinsightsintothepathogenesis,diagnosis
ingtobeadrs,clu andmanagementofMDR-TB,XDR-TB,andincurablecasesofTB.LancetResp
adminstrlevog Med2016.Inpress.
imzeatonprchs [6]KendallEA,FofanaMO,DowdyDW.Burdenoftransmittedmultidrugresis-
atchndprmokies tanceinepidemicsoftuberculosis:atransmissionmodellinganalysis.Lancet
motingberadhc-p RespirMed2015;3:96372.
egiswlmchan.Sutr e
tivensbrqudfhc [7]DhedaK,Barry3rdCE,MaartensG.Tuberculosis.Lancet2016;387:1211 26. e
drugsitofnewap [8]er
contrlfube onG,Udxte wad e
h D
iaZ,etal.Gob da d
n a T o b m u G , K T y a r u M , R N i h
eon-bmaitd.Thurg drrculosi:fme
tube e
n a L . i s o l u c r ug-retRe sitanourensive
e
M r i p s atblelyd2014;2()
:321 38 .
calyinugpofrmt
alityndrbeTBcsow [9]othamleyG,CamineroJA,Cavlh LangeC,AbuakrIlfenarJW,B e
icalw.potems,vryndkfughTBjiotaelbpdmcfMDR-wns.kgr et
dal.Mnge rug-eme sitan/entofpaie
xtentswihmul nsivelydrug-
rie
NETconsesitanube
nsutaerculosinEpe
me:aTBnt.EurRespirJ
2014;():36 .

[10] C.Treatmentofuberculosi.NEng orsbughJCR,Bay3d

H CE,Lan e
ge
JMed 015;37:2496 .
TransparencyDeclaration [1] atmentguidelineWorld e
re
nttuberculosi:2016pdate.WHO/TM sfordHerug-ealthOrgnizo.WH sita
B/20164.Ge ne
althOrgnizo;2016 va:World OlaruID,LngeC,IndraA,Meidlin
[12]He .
Dr.LangereportspersonalfeesfromChiesi,personalfeesfrom esoftre
ratge rL,HuhleatmescuS,RmetshofesinpulmoarrR.High
rug-esitanubentsuce
yymultid rculosib
Gilead,personalfeesfromAbbvie,personalfeesfromMSD,per- dns.AmThoracS2016;3: ivdualytioredtreatmentregi
mine
1278 .
sonalfeesfromBectonDickinson,personalfeesfromJanssen,
outsidethesubmittedwork.Dr.DhedareportsgrantsfromFIND,
grantsandpersonalfeesfromALERE,grantsandpersonalfeesfrom e
OxfordImmunotec,grantsandpersonalfeesfromCellestis(now [13]VanDeunA,AungKJM,HalimMA,KumarDasP,RanjanSarkerM,DaruP,
etal.Short,highlyeffective,andinexpensivestandardizedtreatmentof
 K.Dhedaetal./ClinicalMicrobiologyandInfection23(2017)131140 e 139

multidrug-resistanttuberculosis.AmJRespirCritCareMed2010;182: inthetreatmentofchronicextensivelydrug-resistanttuberculosis.EBioMe-
68492. e dicine2015;2(11):162733 e.
[14]KuabanC,NoeskeJ,RiederHL,Ait-KhaledN,AbenaFoeJL,TrebucqA.High [41]BolhuisMS,vanAltenaR,AlffenaarJW.Commenton:daily300mgdoseof
effectivenessofa12-monthregimenforMDR-TBpatientsincameroon.IntJ linezolidformultidrug-resistantandextensivelydrug-resistanttuberculosis:
TubercLungDis2015;19:517 24. e updatedanalysisof51patients.JAntimicrobChemother2012;67:2055 6. e
[15]PiubelloA,HarounaSH,SouleymaneMB,BoukaryI,MorouS,DaoudaM,etal. [42]AungKJ,VanDeunA,DeclercqE,SarkerMR,DasPK,HossainMA,etal.
Highcureratewithstandardisedshort-coursemultidrug-resistanttubercu- Successful9-monthBangladeshregimenformultidrug-resistanttuberculosis
‘ ’
losistreatmentinNiger:norelapses.IntJTubercLungDis2014;18(10): amongover500consecutivepatients.IntJTubercLungDis2014;18(10):
118894. e 11807. e
[16]WorldHealthOrganization.WHOupdatedreferencesonmanagementof [43]TangS,YaoL,HaoX,LiuY,ZengL,LiuG,etal.Clofazimineforthetreatmentof
drug-resistanttuberculosis:guidelinesfortheprogrammaticmanagementof multidrug-resistanttuberculosis:prospective,multicenter,randomized
drug-resistanttuberculosis d 2011update.Geneva:WorldHealthOrganiza- [4] versT,VanckxLetal.Acquire controlledstudyinChina.ClinInfectDis2015;60(9):1361 7. e
sK,Ge dAndriesK,VilelasC,oeckN,Thy
tion;2011. eda
sitobre
e1
sitanceofmycbate
5 3 1 2 0 quilneriumtbe .PLoSOnerculo 2014;9(7): .
[17]SotgiuG,CentisR,D'AmbrosioL,AlffenaarJW,AngerHA,CamineroJA,etal. osiL,AlarcnGuz[45]d
,etal.Efe oV,AlfenarJW TiberiS,PayenMC,SotgiuGD'Ambr
Efcacy,safetyandtolerabilityoflinezolidcontainingregimensintreating fi netre
inthe m/clavuntective -contaigrene gimesand ns safetyofmerope
espirJ2016;47():35 atmentofMDR-adXDR-TB.Eur 43 .
MDR-TBandXDR-TB:systematicreviewandmeta-analysis.EurRespirJ
2012;40(6):143042 e.
[18]ChangKC,YewWW,TamCM,LeungCC.Whogroup5drugsanddifcult fi [46] -BidlingmaerF,LangeC, DiaconAH,vderMerweL,BarndM, e
multidrg-esanbco: vonGrte
Garci-BsterculosineiroAL,ewtrickfoantal.Beta-lcms
ystemaicrvwhonl aginstube
[19] fdelandmet-lysi.AcrobgCh2013;57:49 amindintheWorld
eo treHe atmealthOrgnizo.Te ntof us
e 104 . e
drimpolcygud
ntmutlie althOrgnizo;2014 ance.GeneWorld
rug-esitanuberculosi: va:World olddog?NEnglJMed2016;375(4):393 4. e
[20]He
eo e
H e
T . o z i n g r O h t l a s u .
[47]DiaconAH,PymA,GrobuschMP,delosRiosJM,GotuzzoE,VasilyevaI,etal.
dfbe
ntmultie rimpolcygud rug-eda sitanubequilne rculosi: inthetre atmentof
[21]He althOrgnizo;2013 ance.GeneMüle va:World
rB,SteicherEM,HoekKG,Tai . Multidrug-resistanttuberculosisandcultureconversionwithbedaquiline.N
ermutaions:ge
promttM,TrolipABsmanEe tal.Inh waytoextens
ivercLungDis201lydrugesitanuberculosin
SouthAfrica?InJTbe
;15:34 51 . EnglJMed2014;371(8):72332. e
[48]GlerMT,SkripconokaV,Sanchez-GaravitoE,XiaoH,Cabrera-RiveroJL,Var-
gas-VasquezDE,etal.Delamanidformultidrug-resistantpulmonarytuber-
culosis.NEnglJMed2012;366(23):2151 60. e
[49]SkripconokaV,DanilovitsM,PehmeL,TomsonT,SkendersG,KummikT,etal.
[2] ronG,etal. SheanK,StreicherE,PietersonE, e Delamanidimprovesoutcomesandreducesmortalityinmultidrug-resistant
SymonsG,vaZlitRThe
Drug-asocitelationshpwucme
ire
elyd
dasinpa- dverseeventsadthe tuberculosis.EurRespirJ2013;41(6):1393 400. e
vtie ntsreceivngtreatmentforextensi
outhAfrica.PLoSOne2013;8(5):e63057 rug-esitanuberculosinS [50]WellsCD,GuptaR,HittelN,GeiterLJ.Long-termmortalityassessmentof
[23]tidrug-esitanuberculosi:p- YewW,LeungC.Maementofmul .
da
. te,207.Respirolgy208;13: 46 multidrug-resistanttuberculosispatientstreatedwithdelamanid.EurRespirJ
2015;45:1498501
e .
[51]PymAS,DiaconAH,TangSJ,ConradieF,DanilovitsM,ChuchottawornC,etal.
[24] rWaltM,KvsnokyC YuenCM,KurbatovEVTpsi e Bedaquilineinthetreatmentofmultidrug-andextensivelydrug-resistant
oilJC,VanDe
etal.Asocitnbe
ositnad
erculosi:ape tretwe
atme enre
rug-entre
gimencomp
sitanu sponein tuberculosis.EurRespirJ2016;47(2):564 74. e
bpatie ntswihmuld
dctivecohrtsud NiehausAJ,MlinKGdhiNR,M [52]GuglielmettiL,LeDuD,JachymM,HenryB,MartinD,CaumesE,etal.
[25]y.PLoSMe 2015;():e10932 .
inhathemaB,rustJC.Highpevalenceof Compassionateuseofbedaquilineforthetreatmentofmultidrug-resistant
andextensivelydrug-resistanttuberculosis:interimanalysisofaFrench
cohort.ClinInfectDis2015;60(2):18894. e
Apromotermutationsamongpatientswithdrug-resistanttuberculosisin [53]NdjekaN,ConradieF,SchnippelK,HughesJ,BantubaniN,FerreiraH,etal.
Kwazulu-Natal,SouthAfrica.PLoSOne2015;10:e0135003 . Treatmentofdrug-resistanttuberculosiswithbedaquilineinahighHIV
[26]KempkerRR,VashakidzeS,SolomoniaN,DzidzikashviliN,BlumbergHM prevalencesetting:aninterimcohortanalysis.IntJTubercLungDis
. 2015;19(8):97985e.
Surgicaltreatmentofdrug-resistanttuberculosis.LancetInfectDis2012;12: e 15766. [54]GuglielmettiL,LeDuD,VezirisN,CaumesE,Marigot-OuttandyD,
[27]FryDE.Extra-pulmonarytuberculosisanditssurgicaltreatment.SurgInfect YazdanpanahY,etal.Isbedaquilineaseffectiveas fluoroquinolonesinthe
[28] rventiohe (Larchmt)2016;17:394
antzM.Surgicle IsemanMD,dsenL,GobleM,Pomer 401.
e treatmentofmultidrug-resistanttuberculosis?EurRespirJ2016;48(2):
eatme
bytrd rug-entofpulmaryd
sitan iseasecaused 5825.
e
Mycobacterium [55]TadoliniM,Garcia-PratsAJ,D'AmbrosioL,HewisonC,CentisR,SchaafHS,
tuberculosis.AmRevRespirDis1990;141:623 5. e etal.Compassionateuseofnewdrugsinchildrenandadolescentswith
[29]MitnickCD,ShinSS,SeungKJ,RichML,AtwoodSS,FurinJJ,etal.Compre- multidrug-resistantandextensivelydrug-resistanttuberculosis:earlyexpe-
hensivetreatmentofextensivelydrug-resistanttuberculosis.NEnglJMed riencesandchallenges.EurRespirJ2016 .
2008;359(6):56374 e. [56]TadoliniM,LingtsangRD,TiberiS,EnweremM,D'AmbrosioL,SadutshangTD
[30]ManMA,NicolauD.Surgicaltreatmenttoincreasethesuccessrateof ,etal.Firstcaseofextensivelydrug-resistanttuberculosistreatedwithboth
delamanidandbedaquiline.EurRespirJ2016 .
multidrug-resistanttuberculosis.EurJCardiothoracSurg2012;42:e9 12. e [57]LachatreM,RiouxC,DuDL,Frechet-JachymM,VezirisN,BouvetE,etal.
[31]FoxGJ,MitnickCD,BenedettiA,ChanED,BecerraM,ChiangCY,etal.Surgery BedaquilineplusdelamanidforXDRtuberculosis.LancetInfect
asanadjunctivetreatmentformultidrug-resistanttuberculosis:anindividual Dis 2016;16(3):294.
patientdatametaanalysis.ClinInfectDis2016;62:887 95. e [58]LewisJM,HineP,WalkerJ,KhooSH,TaegtmeyerM,SquireSB,etal.First
[32]CalligaroGL,MoodleyL,SymonsG,DhedaK.Themedicalandsurgical experienceofeffectivenessandsafetyofbedaquilinefor18monthswithinan
optimisedregimenforXDR-TB.EurRespirJ2016;47(5):1581 4.
treatmentofdrug-resistanttuberculosis.JThoracDis2014;6:186 95. e
[33]KangMW,KimHK,ChoiYS,KimK,ShimYM,KohWJ,etal.Surgicaltreatment e
formultidrug-resistantandextensivedrug-resistanttuberculosis.AnnThorac [59]MatteelliA,DAmbrosioL,CentisR,TadoliniM,MiglioriGB.Compassionate ’
Surg2010;89(5):1597602 e. andoptimusefwbrcl
[34]MarroneMT,VenkataramananV,GoodmanM,HillAC,JerebJA,MaseSR. isdrug.LancetIfD2015;: e 132 .
Surgicalinterventionsfordrug-resistanttuberculosis:asystematicreview [60]BloembergGV,KellerPM,StuckiD,TraunerA,BorrellS,LatshangT,etal.
andmeta-analysis.IntJTubercLungDis2013;17:6 16. e Acquiredresistancetobedaquilineanddelamanidintherapyfortuberculo
[35]FalzonD,GandhiN,MiglioriGB,SotgiuG,CoxHS,HoltzTH,etal.Resistanceto sis.NEnglJMed2015;373(20):1986e8.
[61]Guglie
elme
achymM,itnkC.Prd vetiL,e ntigacqureDu,Frechet-J
fluoroquinolonesandsecond-lineinjectabledrugs:impactonmultidrug- re e
c n a t i s inmultdrug-esitanubequilne
e
b o t da rculo anddelamn
resistantTBoutcomes.EurRespirJ2013;42(1):156 68. siid
espirCtae
e t.AmJRtre atmeMe ntred
quiresoptimalngemen
[36]HarrisRC,KhanMS,MartinLJ,AllenV,MooreDA,FieldingK,etal.Theeffect /10.64rcm2-8LE2016;94:7. htp:/dx.doi.rg .
ofsurgeryontheoutcomeoftreatmentformultidrug-resistanttuberculosis:a [62]linesfortheprogamticnemento WorldHealthOrgnizo.Gude e
systematicreviewandmeta-analysis.BMCInfectDis2016;16(1):262 . fdrug-resitanuberculosi.Geneva:
[37]ZhangX,FalagasME,VardakasKZ,WangR,QinR,WangJ,etal.Systematic [63]World HealthOrgnizo;201
aytchiN,BxerC,GayALetal AbdolKarimS,NdoK,Grbler
.
.A,Pad
reviewandmeta-analysisoftheefcacyandsafetyoftherapywithlinezolid fi
Interculosite
withube grationfetrovialherapy
Medatment.NEglJ 201;365():49 .
contaigremsh
tofmulidrg-esanx
[38],SongTetal.Linezolidivelydrug-stanbco.JThD2015;7(4):63 forteatmeLe eM,LeeJ,CarolMWhiHnS e [64]orandL,RekacewiczC,NerieBlancFX,SokTLure ilardD,B e 15 .
fchroniextensivelydrug-entositanu l.Earlierversulaterstaofniet netE,eta
be
1508 rculosi.NEngJMed2012;367(): . rovialthe
tswihtuberapyinHIV-fe ctedadul
6):147 rculosi.NEngJMed201;365( 81 .
e [65]daJ,SwindellsS,Qabetal.Timng HavlirDV,KendalMA,IveP,Kumwen e
[39]TangS,YaoL,HaoX,ZhangX,LiuG,LiuX,etal.Efcacy,safetyandtolerability fi ofantire e
h l a i v o r t n i 1
201;365():489ectionadtuberculosi.NEngJMed
- V I H o f y p a r
oflinezdrtham .
fXDR-TB:astudyinCh.Ere
[40]LE,DartoisVetal.LinezolidspirJ troug SongT,LeeM,JeonHS,ParkYDdd 2015;4():67 e . [6]anF,DoleyKE,arlsonMO.del- SvensoEM,AweekaF,PrkJGMz e
hconentraioscelatewithmoc base
nzobedes daquilnetimae
pharmcokinesofthe
tics effectsofefavire
hond
vents rialtoxcy-elatedadversee
140 K.Dhedaetal./ClinicalMicrobiologyandInfection23(2017)131140 e

andsuggesteddoseadjustmentsforpatientscoinfectedwithHIVand [81]McKennaL,FrickM,SeaworthB,FurinJ.Theinvisibilityofchildrenwith ‘ ’
tuberculosis.AntimicrobAgentsChemother2013;57:2780 7. e tuberculosis.JPublicHealthPolicy2015;36:123 5. e
[67]SvenssonEM,DooleyKE,KarlssonMO.Impactoflopinavirritonavirorne- e [82]EttehadD,SchaafHS,SeddonJA,CookeGS,FordN.Treatmentoutcomesfor
virapineonbedaquilineexposuresandpotentialimplicationsforpatients childrenwithmultidrug-resistanttuberculosis:asystematicreviewand
withtuberculosis-HIVcoinfection.AntimicrobAgentsChemother2014;58: meta-analysis.LancetInfectDis2012;12:449 56. e
640612. e [83]SeddonJA,HesselingAC,SchaafHS.Retoolingexistingtuberculosisdrugsfor
[68]CentersforDiseaseControlandPrevention.ProvisionalCDCguidelinesforthe children.ClinInfectDis2013;56:167 8. e
useandsafetymonitoringofbedaquilinefumarate(Sirturo)forthetreatment [84]SentinelProjectonPediatricDrug-ResistantTuberculosis.Managementof
ofmultidrug-resistanttuberculosis.MMWRRecommRep2013;62:1 12. e drug-resistanttuberculosisinchildren:a fi eldguide.2nded.Boston,MA:
[69]WorldHealthOrganization.Companionhandbooktothewhoguidelinesfor SentinelProjectonPediatricDrug-ResistantTuberculosis;2015
.
theprogrammaticmanagementofdrug-resistanttuberculosis.Geneva:World [85]SeddonJA,FurinJJ,GaleM,DelCastilloBarrientosH,HurtadoRM,
HealthOrganization;2014. AmanullahF,etal.Caringforchildrenwithdrug-resistanttuberculosis:
practice-basedrecommendations.AmJRespirCritCareMed2012;186(10)
[70]WorldHealthOrganization.Denitionsandreportingframeworkfortuber- fi : 95364.
culosisd 2013revision.Geneva:WorldHealthOrganization;2013
. e
[71]HorneDJ,RoyceSE,GoozeL,NaritaM,HopewellPC,NahidP,etal.Sputum [86]SeddonJA,HesselingAC,Godfrey-FaussettP,SchaafHS.Hightreatment
monitoringduringtuberculosistreatmentforpredictingoutcome:systemat successinchildrentreatedformultidrug-resistanttuberculosis:anobserva-
icreviewandmeta-analysis.LancetInfectDis2010;10(6):38794. e tionalcohortstudy.Thorax2014;69:458 64. e
[72] rwothAE,lainTJetal.
hoSH,Bute SloanDJ,MwdumbaHC,GrtonNJK [87] selingAC,SchafH.earinglos
,He SeddonJA,TheeS,JacobsKErhimA
dimnatore
Pharmcoel ynamicod sand eldet ingofbaclry e ctionf drculosi.JInfe
tanubinchle rect2013;6: ntreatedformultidrug-esi
bacterialpd
ctand d
n u bod
er iesinputmore
d
n a t s e
m c t u o di
n i s 3209 .
tre
inIfeatme
ctDis2015;6(): ntofpulmaryberculosi.C 8 .
[8]elingAC,Garc-PtsJ.dverseefSchafH,Te eeS,vanderLan,Hes
e ectsofrale
sifd cond-lineantiube-rculo
[73]dtC,AksilpRBayonJeceraMC,etal KurbatovEV,CegielskiJP,Lenhar 2016;5:398 rugsinchldren.ExpOiDrugSaf .
.Sputmclreconversionapgt
einpate
outcmicmarke rfoentswihmuld ndrug-e -oftresiatment
stanube
drculosi:ae atfromwbsecondrvationl ary e
cohrtsuanlysiofd
2015;3():9 ies.LancetRespirMed .
[89] tal.
orH,MangliVykthAe
PorutcmesinacohrtfHIV-e cteda
IsakidisP,arynRKhSMo
do
dle rug-esce ntsudergointreatment
Mumbai,Informultid
e6 9 6 8 ia.PLoSOne 2013;8(7):sitanuberculosin
ymanL,Mul[90]e MoyS,FurinJHghesJ,DanielsJ,Sn .
drO,e
g-rae oletal.Oucome scesin ntsudergointreatmentfordru
[74] ceraMC,DnilovtzF
,Be KurbatovEV,GminMByJ e Town,SuthAfrica208-13.Pesitanube
atrInfe dirculosinCape
e
: ) B T ( 3 ; 4 1 0 2 s i D t c 4 3 9 7 1 .
etrsionamgpte
ve al.Prediate
drcLungDis201;6():35 rug-entsre
ctorsfpumlecon
sitanuberculosi.I dfor afHS,kin[91]e
therD,Re impactofuld ynold rug-esL.Ae sitanubesingrc
FranckC,SeddonJA,HeselingAC,Sch
ntJTubmultie 4 ulosinchd ren:ae y.BMCInfexploratyctDis2014; .
3 . :426qualitve
[92] tal.Abierpil
stud
FurinJ,MafkdzeA,BrigdenG,duCro
sP,GolinRHaruzEe
toswal:he
[75] rkerM,BeckertP,JaonKetal. Hofman,KhlTA-ielS,
Me
e dne
chilford rug-eedf
re sitanubercLungDis2015;9(Srculosin orbetermedications
n.ItJTube
inDe mycobatelamnid rculosi and
riumtbeijnge bedaquilneresitance pl.1):5 60 .
e
vance stralbe
lyd rug-enotype
sitanubecausinge
rculosina xtensi
6;193():7Tibetanrefugee.AmJRespirCtaeMed201 40 .

[76] anilmX,PorAeta PietersenE,IgatiusSreicherE e

M,astrpBPd
Long-tl.e
ermoutce sofpatientswihexte
014;38:2 inSouthAfrca:snsivdlyd
y.Lancet2rug-esitanuberculosi 9 .
[7] ofextensivelydDhe e e
ise
ertime cu- tobringacks rug-eda
sitanub K,MiglorGB.Theglobar [93] khA,SaluddinN,Lotia-FrukhI AmanulhF,sfqMKowjSP
are
,etal.Hightuberculosipevalenceinc
losi:the
735rianowverdue?Lancet201;379: . dsitanube
rhile
ungDis2014;8(5):
rerculosi.IntJTbe
nercL xposedathometodrug-
7 .
[78] enofdrug-esitanubeDod edPJ,SismandisC,SeddonJA.Glo [94] ldingK,CoxHuhesJ,etal.PreSe e
balurd
is ren:amthematiclodelrculoslingst H,Fie
ventive - ddonJA,HeselingAC,Fayso
inchld ltid rug-ethesitanuberapyfochild
rculosi:a contasfmu
19320udy.LancetInfectDis2016;: . is2013;57():6prosectivecohrtsudy.ClinIfectD 84 .
e [95] tal.Treat- BamrhS,ostRDinFe e
tikL,SongRKawmurMe
[79]BrigdenG,FurinJ,VanGulikC,MaraisB.Gettingitrightforchildren: ments,Fe
ie
209
ntforLTBIicasMDR-p deratedStaesofMicrnesia,
201.IntJTubercLungDis2014;
improvingtuberculosistreatmentaccessandnewtreatmentoptions.Exp 8():912 8 .
ertRevAntiInfectTher2015;13:451 e61. e e
[80] tsframework:dismantlg BeceraMC,Swminth.oent
ary:tge
theinvsbltyrapfochd
dr
HealthPoicy2014;35: e
r - g u rerculosi.JPbnwith
e
b u n a t i s 54 . [96]GüntherG,LangeC,AlexandruS,AltetN,AvsarK,BangD,etal.,forTBNET.
Treatmentoutcomesinmultidrug-resistanttuberculosis.NEnglJMed2016
e Sep15;375(11):11035.http://dx.doi.org/10.1056/NEJMc1603274
e .