The
Brazilian
Journal
of
INFECTIOUS
DISEASES
w w w. e l s e v ie r . c o m / l o c a t e / b j i d
Special
article
Multidrug-resistant
tuberculosis
Antônio
Carlos
Moreira
Lemos
a,b,∗,
Eliana
Dias
Matos
a,c aHospitalEspecializadoOctavioMangabeira,Salvador,BA,BrazilbMedicalSchool,UniversidadeFederaldaBahia,Salvador,BA,Brazil
cDepartmentofMedicine,EscolaBahianadeMedicinaeSaúdePública,Salvador,BA,Brazil
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t
i
c
l
e
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n
f
o
Articlehistory:
Availableonline9March2013
Keywords: Multidrug-resistanttuberculosis Review Diagnosis Treatment
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Despitetheeffortsmadeworldwidetoreducethenumberofcasesofdrug-susceptible tuber-culosis,multidrug-resistanttuberculosis(MDR-TB)constitutesanimportantpublichealth issue.Around440,000newcasesofMDR-TBareestimatedannually,althoughin2008only 7%ofthese(29,423cases)werenotified.Thelaboratorytestsfordiagnosingresistancemay bephenotypic(basedonculturegrowthinthepresenceofdrugs)orgenotypic(i.e. identi-ficationofthepresenceofmutationsthatconferresistance).Theurgentneedforarapid meansofdetectingresistancetoanti-TBdrugshasresultedinthedevelopmentofmany genotypicmethodsoverrecentyears.ThetreatmentofMDR-TBisexpensive,complex, pro-longed(18–24months)andassociatedwithahigherincidenceofadversereactions.Some basicprinciplesmustbeobservedwhenprescribinganadequatetreatmentregimenfor MDR-TB:(a)theassociationofatleastfourdrugs(threeofwhichshouldnothavebeenused previously);(b)useofafluoroquinolone;and(c)useofaninjectableanti-TBdrug.InBrazil, thetherapeuticregimenforMDR-TBhasbeenstandardizedandconsistsoffivedrugs: ter-izidone,levofloxacin,pyrazinamide,ethambutolandanaminoglycoside(streptomycinor amikacin).Pulmonaryresectionisanimportanttoolinthecoadjuvanttreatmentof MDR-TB.Whilearecentmeta-analysisrevealedanaveragecurerateofMDR-TBof69%,clinical studiesarecurrentlybeingconductedwithnewdrugsandwithdrugsalreadyavailableon themarketbutwithanewindicationforTB,withencouragingresultsthatwillenablemore effectivetreatmentregimenstobeplannedinthefuture.
©2013 ElsevierEditoraLtda.Allrightsreserved.
Introduction
Theemergence ofdrug-resistant tuberculosis (TB) is often attributedto afailure to implementadequate control pro-gramsfortuberculosisandtoappropriatelymanagecasesof thedisease.Therefore,resistancetoTBaccuratelyreflectsthe
∗ Correspondingauthorat:Associac¸ãoBaianadeApoioaoControledaTuberculose(ABACONTT),NúcleodePesquisaemPneumologia
(NUPEP)– HEOM,Prac¸aConselheiroJoãoAlfredo,s/n◦,PauMiúdo,Salvador,BA40320-350,Brazil. E-mailaddresses:[email protected],[email protected](A.C.M.Lemos).
poorqualityofcontrolprogramsandisadirectconsequence ofpoortherapeuticpracticeswithrespecttotheuseofanti-TB drugs.1,2
Despitetheeffortsmadeworldwidetoreducethenumber of cases of drug-susceptible tuberculosis (TB),3 multidrug-resistant tuberculosis (MDR-TB)constitutes apublic health problem andrepresents asevere obstacleto thecontrolof
1413-8670/$–seefrontmatter©2013 ElsevierEditoraLtda.Allrightsreserved.
TB,particularlyincountriesinwhichtheprevalenceofthis disease remainshigh.4 Overthe past twodecades,various publicationshaveregisteredtheemergenceofMDR-TB world-wide. MDR-TB is defined as casesof tuberculosis that are resistanttoatleastrifampicinandisoniazid.5–8
In2008,29,423newcasesofMDR-TBwerenotified world-wideinthe127countriesinwhichatleastonecaseofthis formofthediseasewasreportedtotheWorldHealth Organi-zation(WHO).Thesefiguresaccountforonly7%ofthe440,000 newcasesofMDR-TBestimatedforthatyearand,ofthese, onlyone-fifth(1.2%ofthetotalnumber)wastreatedin accor-dancewiththeWHOrecommendations.Around50%ofthe globalburdenofMDR-TB isconcentrated intwocountries, IndiaandChina,followedbyRussia(9%).TheWHOestimates thataround150,000deathsoccurred inpatientswith MDR-TBin2008.9Thedifferencebetweenthenumberofestimated casesandthenumberoftreatedcasesshouldbeinterpretedas potentialdisseminatingsourcesofmultidrug-resistantstrains and may beresponsible forthe increase inthe number of cases.
Morerecently,cases havebeen described ofextensively drug-resistanttuberculosis(XDR-TB)inwhichMycobacterium tuberculosis is resistant to rifampicin, isoniazid, a fluoro-quinoloneand a second-line injectable drug (capreomycin, kanamycin or amikacin). An epidemic of XDR-TB was describedforthefirsttimeinKwaZulu-NatalinSouthAfrica inapopulation ofHIV/AIDS patients,wherethemean sur-vivaltimebetweendiagnosisbysputumsmearmicroscopy anddeathwas16days.10
AccordingtoarecentdocumentissuedbytheWHO,963 casesofXDR-TBwerereportedin2008worldwide,thesedata referringtoallofthe41countriesinwhichatleastonecase was notified.9 Only 6 ofthese 41 countries (15%)reported morethan 10 casesofXDR-TB.Theproportion ofcasesof MDR-TBthatareinfactXDR-TBexceeds10%inthefollowing countries:Estonia(19.7%),Latvia(15.1%),SouthAfrica(10.5%) andTajikistan(21%).11Nevertheless,consideringthedifficulty inperformingsusceptibilitytestsforsecond-linedrugsin rou-tineservicesinthemajorityofcountries,thesedataareinfact underestimated.
Theworldwide trend ofanti-TB drug resistance can be estimatedforonly59countriesinwhichmorethanone inves-tigationofresistancewasperformedbetween1994and2009.9 OverthelastdecadeinBrazil,anincreasehasoccurredin pri-maryisoniazid(H)-resistancefrom4.4%(NationwideSurvey intoAnti-TBDrugResistance,1995–97)to6%,withanincrease inrifampicin(R)-resistancefrom1.3%to1.5%.Withrespectto MDR-TB,aslightincreasewasfound,from1.1%atthefirst surveyto1.4%atthesecond.12
Resistance
to
anti-TB
drugs
Resistancetoanti-TBdrugsistheresultofspontaneous muta-tionsinthegenomeofM.tuberculosisandnottheresultof horizontalgenetransfer.13Themutationsthatproduce resis-tance occur atrates that are predictable foreach drug, as showninTable1.So,forexample,theoccurrenceofamutant microorganismresistanttoHoccursforevery105or106bacilli andamutantresistanttoRforevery107or108 bacilli.The
Table1–Frequencyofdrug-resistantmutantstoanti-TB drugs.a
Rifampicin 1drug-resistantmutantforevery107–8bacilli
Isoniazid 1drug-resistantmutantforevery105–6bacilli
Ethambutol 1drug-resistantmutantforevery105–6bacilli
Pyrazinamide 1drug-resistantmutantforevery102–4bacilli
Streptomycin 1drug-resistantmutantforevery105–6bacilli
Ethionamide 1drug-resistantmutantforevery103–6bacilli a AdaptedfromCanettietal.Advances intechniquesoftesting
mycobacterialdrugsensitivity,andtheuseofsensitivitytestsin tuberculosiscontrolprogrammes.85
mutationofM.tuberculosisoccursindependentlyforeachone ofthedrugs;hencethepossibilityoftheoccurrenceof asso-ciatedresistanceisequaltotheproductoftheirrespective resistance rates. Therefore, for a mutantto appearthat is naturallyandsimultaneouslyresistanttobothRandH, the-oreticallyapopulationof1012or1014microorganismswould benecessary,makingthepossibilitythatitwouldlodgeinthe humanbodyhighlyunlikely.1
With selection, particularly as a result of inappropriate treatment management, drug-resistant organisms multiply and becomedominant.Oncecreated,drug-resistantstrains may be transmitted to individuals who were not previ-ouslyexposedtoanti-TBdrugs(primaryresistance).14,15The typesofresistancetoM.tuberculosismaybesummarizedas follows:16
• Natural resistance: resulting from naturalmutation irre-spectiveofpreviousdrugexposureanddirectlyproportional tothenumberofmutantbacilli;
• Primaryresistance:casesofresistanceinindividualsknown nottohavebeenpreviouslyexposedtoanti-TBdrugs; • Acquiredresistance:casesofresistanceinwhichpatients
werepreviouslysubmittedtoTBtreatment,generally inad-equately.
Resistance toH ismoreoften duetoa mutationinthe katGgenethatcodifiesthekatGenzyme,acatalase-peroxidase enzyme.StudiesconductedbyZhangetal.atthebeginningof the1990sshowedthatHis,infact,apro-drugthatisactivated bythe katGenzyme.17,18 Alaterstudy conducted byHeym etal.identifiedthekatGgeneinthechromosomeofvarious mycobacteriaincludingM.tuberculosisand,inaddition,these investigatorsstudiedthemutationsthataffectthisgeneinthe isolatesofclinicalspecimensthatareH-resistant.19Agreat numberofreportsindicatethatmutationsinthekatGenzyme areresponsibleforaround60%ofcasesofisoniazid-resistant strainsisolatedfrompatients.19–25Nevertheless,some muta-tionsinothergeneshavebeenidentifiedinisoniazid-resistant strains,includingtheinhAgene,whichcodifiestheenzymeof mycolicacidinvolvedintheformationoftheM.tuberculosis cellwall,andtheahpCgenethatcodifiesalkyl hydroperoxi-dase,amongothers.23,26,27AstudycarriedoutinBrazilusing isoniazid-resistant strains (n=69) from threestates (Rio de Janeiro,SãoPauloandRioGrandedoSul)revealeda predom-inanceofthekatGgenemutation,althoughothermutations (intheinhAandahpCgenes)havealsobeenidentified.23
Rifampicin inhibits the beta subunit of the RNA poly-merase.TherpoBgenecodifiesthisenzymeandwasinitially identifiedinEscherichiacoliandMycobacteriumlepraeand,later, inM.tuberculosis.28TherpoBgenemutationsareidentifiedin 90–98%ofrifampicin-resistantstrains.Withtheadvancesin molecularbiologytechniques,thefragmentsequencingofthe rpoBgenehasproventoconstitutearapidwayofdetecting R-resistance,substitutingtheslowerclassicmethod(the pro-portionmethod)thatisusedroutinelyinmostservices.29,30
Inrecentdecades,knowledgeonthegeneticmechanisms ofM.tuberculosisresistancetoanti-TBdrugshasgrown,and this hasalsofacilitated the developmentofmoreaccurate andfastertechniquesfordetectingresistance.31–40 Neverthe-less,thelimitedavailabilityoflaboratorieswiththecapacityto routinelyofferthesenewtechniquesofdiagnosingresistance representsanimpedimenttotheirwideruseincountriesin whichtheburdenofthisdiseaseishigh.
Diagnosis
of
resistance
to
anti-TB
drugs
Laboratorymethodsofdiagnosingresistancetoanti-TBdrugs maybeclassified asphenotypic(basedonculturegrowth in thepresenceofdrugs)or genotypic(i.e.identificationofthe presenceofmutationsthatconferresistance).
Phenotypicmethods
Phenotypicmethods,alsoreferredto asdrugsusceptibility tests,canbeperformedinsolidorliquidmedia.The suscepti-bilitytestsusedinsolidmediacultures(Lowenstein–Jensen and Ogawa–Kudoh) are: (a) the proportionmethod, (b)the absoluteconcentration method,and(c)theresistanceratio method.Theclassicproportionmethodisthemostcommonly usedbothworldwideandinBrazil.Oneofthelimitationsof thedrugsusceptibilitytestsperformedinsolidmediaisthe delay,asthesetestsgenerallyrequirearoundtwomonthsfor resultstobereleased.
Liquidmedium,usingtheBACTECMGIT960system, signif-icantlyreducesthetimeinvolvedindetectingM.tuberculosis totwoweeksandafter1–2weekstheresultsofthe suscepti-bilitytestareavailable.2Thesensitivityandspecificityofthe MGIT960system(96%and94.6%,respectively)aresimilarto thosefoundwiththeproportionmethod,andthistechnique hasalreadybeenvalidatedforuseinBrazil.41Thegreatest dis-advantageoftheliquidmediumtechniqueisitshighcost.2 Theaccuracy ofsusceptibility testing varies in accordance withthedrug tested,accuracybeing greaterinthe caseof rifampicinandisoniazidandpoorerinthecaseofethambutol andstreptomycin.2
Genotypicmethods
Thegenotypicmethods,alsoreferredtoasmolecular meth-ods,arebasedonthedetectionofthemutationsthatconfer resistancetoanti-TBdrugs. Manygenotypicmethods have beendevelopedoverrecentyearsinresponsetotheurgent needtobeabletodetectresistancetoanti-TBdrugsrapidly. Themoleculartestsmostcommonlyusedworldwidearethe GenoTypeMTBDRplus,the INNO-LiPARif.TB,and theXpert
MTB/RIFassays.TheGenoTypeMTBDRplusassay(Hain Life-science)detectsmutationsinthekatG,inhAandrpoBgenes, identifyingR-andH-resistance.Thesensitivityandspecificity ofthemethodforthedetectionofR-resistanceare98%and 99%,respectively,whileforthedetectionofH-resistance, sen-sitivity is 85% and specificity 99%.42 TheINNO-LiPA Rif.TB assay(sensitivity97%,specificity99%)detectsR-resistanceby detectingtherpoBgenemutation.42Finally,theXpertMTB/RIF assayidentifies R-resistance,withresultsbeingavailablein aroundtwohoursandwithoutanyneedforasophisticated laboratoryinfrastructure,allowingthetesttobeperformedat thesitewherethepatientisreceivingcare.Thereported sen-sitivityforadiagnosisofTBusingtheXpertMTB/RIFassay variesaccording tothe study,rangingfrom70%to100%in casesofpositivecultureand around60% incasesofTBin whichcultureisnegative.Thespecificityofthemethodranges from91%to100%.ForthedetectionofR-resistance,sensitivity andspecificityare98%and99%,respectively.32–40,43
Despitethepromisingperspectiveoftheuseofmolecular tests,alsoknownasrapidmoleculartesting,forthediagnosis ofresistance,theWHOhaswarnedthatthesetestsneedto bevalidatedinthe countriesinwhichtheyaretobeused, sincethefrequencyofthemutationsmayvaryinaccordance withtheregion.32 InBrazil,validationstudiesofthesenew rapidtestsforthediagnosisofresistancearecurrentlybeing conductedandmayconstituteanimportantsteptowardtheir futureuseinthiscountry.
In Brazil, the classic proportion method has been the techniquemostcommonlyusedinthe healthcarenetwork; however,thenewmethodsarealreadyavailableinsome ref-erencecenters.Increasingaccesstothesenewmethodsfor therapiddetectionofresistanceinroutineconditionsshould constituteanimportantchallengefortheNationalProgram fortheControlofTuberculosis(PNCT).
The
treatment
of
MDR-TB
MDR-TB isbothcostlyand complex totreat,since second-line drugs are required that are associated with a higher incidenceofadversereactions.44,45Inaddition,treatmentis moreprolongedcomparedtowhenfirst-linedrugregimens are used. The accumulatedevidence ofMDR-TB treatment outcomeremainstenuousandisbasedonobservational stud-iesandexpertopinions.Thelackofuniformitywithrespect tothedrugsandregimensused(durationoftreatment, super-visedadministrationversusself-administration),represents an importantobstacle whencomparing the different stud-ies.Nevertheless,somepublicationshaveindicatedthatthe organizationofthehealthcareservicesandtheuseof super-visedtreatmentarefactorsthatcontributetowardincreasing success rates.46–48 In addition, mathematical models have suggestedthatthistreatmentmaybecost-effective,evenin countrieswithlimitedfinancialresources.49
ThecontrolofresistantTB,particularlyincasesofMDR-TB andXDR-TB,representsanimportantchallenge thathasto beconfronted.Effortsmustbemadetoimprovemanagement ofthesecases,focusingparticularlyonidentifyingnewdrugs thatwouldpermitshorter,moreeffectivetreatmentregimens tobeimplementedincasesofMDR-TBandXDR-TB.50,51
The idealtreatment for MDR-TB, defined as TBthat is simultaneously R-and H-resistant (associated or not with resistancetootherfirst-linedrugs),remainsachallengethat hastobeconfrontedwithinthecontextofcurrentknowledge. Theprincipaldifficultiesinclude:thehighcostoftreatment, its relatively poor efficacy,the side effectsof the available drugsandtheprolongeddurationoftreatment.Arecent meta-analysis based on retrospective cohort studies on MDR-TB treatmentoutcomeshowedameansuccessrateof69%and, furthermore, the superiority of supervised treatment regi-mensofatleast18months’duration.52
Somebasicprinciples mustbeobserved whenplanning anadequatetreatmentregimenforMDR-TB:(1)the associa-tionofatleastfourdrugsproventohaveantimycobacterial efficacy, three of which should not have previously been usedbythe patient;(2)use ofafluoroquinolone with anti-TBactivity (ofloxacin,levofloxacinormoxifloxacin);(3) use ofaninjectabledrug(streptomycin,amikacin,kanamycinor capreomycin);and(4)prolonged,supervisedtreatment(18–24 months)carriedoutinatertiaryreferralunit.53
Prior to 1995 in Brazil, some experiences were initi-atedin reference centers in São Paulo, Riode Janeiro and Porto Alegre inanattempt toelaborate MDR-TBtreatment regimens,andbetween1995and1998amulticenter proto-col was implemented.54 In 2000, the Brazilian Ministry of Health considered the standardized 18-month, 5-drug reg-imen (amikacin, clofazimine, terizidone, ethambutol and ofloxacin)asvalidated andadopteditforuseinthis coun-try.TheMDR-TBepidemiologicalsurveillancesystemwasalso implementedinthatyear,withfurtherimprovementsbeing includedin2004.
The modifications introduced by the Brazilian Ministry ofHealth’sNationalProgramfortheControlofTuberculosis (PNCT)in2009withrespecttothetreatmentofMDR-TBwere: (a)tosubstitutethefluoroquinoloneofloxacinforhigh-dose levofloxacin;and(b)topromotetheuseofstreptomycin(S) ratherthan amikacin (AM),although theuse ofAMis still recommended intwo situations:(1) for patientswho have already used S inprevious treatments; and (2) incases of proveninvitroresistancetostreptomycin.55Inrelationtothe fluoroquinolone,thedecisionwasmadetousehigh-dose levo-floxacinfortworeasons:(a)fewstudieshadbeenconducted ontheprolongeduseofmoxifloxacinand(b)therewas evi-dencesuggestingthisdrugasafuturealternativeforreducing thedurationoftreatmentintreatment-naïvepatients.56
Therefore,thetreatmentregimencurrentlyusedfor MDR-TB in Brazil consists of five drugs in the intensive phase (streptomycin, ethambutol, levofloxacin, pyrazinamide and terizidone)andthreeinthemaintenancephase(ethambutol, levofloxacinandterizidone),asdescribedinTable2. Strepto-mycinoramikacinisusedforfivedaysaweekinthefirsttwo monthsandthenthreetimesaweekforthenextfourmonths. Theduration oftheMDR-TBtreatmentregimenis18–24 monthsandtreatmentadministrationshouldbesupervised inthereferenceunitwherethepatientisbeingtreatedorin thebasichealthcareunitclosesttothepatient’shome(shared supervision).55
Accordingto theMDR-TB data system, 6136caseswere notifiedinBrazilbetweenJanuary1992and June2012.The cohortanalysisofthetreatmentoutcomesofpatientsentering
thesystembetweenJanuary1992andDecember2010showed ameansuccessrateof60.6%,althoughtherewereregional differencesbetweenstatesattributedtofactorssuchasthe organizationofthehealthcareservice,thepresenceof comor-biditiesandadelayindetectingcasesofresistance.57
Treatment
of
extensively
drug-resistant
tuberculosis
(XDR-TB)
Extensivelydrug-resistanttuberculosis(XDR-TB), definedas TBthatisresistanttoR,H,afluoroquinoloneanda second-line injectabledrug(amikacin,kanamycin orcapreomycin), representsaserious publichealthissueinsomeregionsof theworldtoday.StudiesevaluatingthetreatmentofXDR-TB have,ingeneral,showndisappointingresults,withpoor suc-cessrates,58,59althoughastudyconductedinPeruwithasmall numberofpatientsreportedacurerateof60%.60Arecent, ret-rospectivecohortstudy(n=174)conductedinSouthAfricaina populationwithanelevatedTB/HIVco-infectionrate,showed an earlymortality rateof32% and identified thefollowing independent factors as being responsible for reducing the numberofdeaths:theuseofmoxifloxacininthetherapeutic schemeandaregimencontainingagreaternumberofdrugs. Ontheotherhand,thepresenceofapretreatmentculturewith provenmultidrug-resistancewasfoundtobeafactor indica-tiveofpoorerprognosis.61Morerecentstudieshaveindicated theimportanceoflinezolid,anoxazolidinone,inassociation withotheranti-TBdrugsinindividualizedregimens. Never-theless, thehigh costofthis drugand thedevelopmentof severeadverseeffectssuchasmyelosuppressionand periph-eralneuropathyconstituteimportantobstaclestoitsusein themajorityoftertiaryTBmanagementcenters.62–70
In summary, there is still no consensus on the most appropriatetreatmentregimenforXDR-TB.Ongoingresearch studies with new drugs may show promise in the future andmaypermitmorerationaltreatmentregimensforthese patients.50,51CasesofXDR-TBshouldbemonitoredina ter-tiaryreferencecenter,withindividualizedtreatmentregimens consistingofcombinationsofreservedrugs.9
Adjuvant
surgical
treatment
of
MDR-TB
and
XDR-TB
ParticularlyinMDR-TB,anegativesputumsmearora signifi-cantreductioninthebacillaryloadisdesirablepriortosurgery in order to minimize the incidence of recurrences, bron-chopleuralfistulaandpostoperativeempyema.Theprincipal indications forthe adjuvant surgical treatmentof MDR-TB are:(a)persistentlypositivesputumdespiteoptimized treat-ment;(b)localizeddisease,cavitarypulmonarytuberculosis withahighriskofrecurrenceandcavitieswithnosignsof regressionduringtreatment,andincasesofunilaterallung destruction; (c) profileof resistanceto atleast four drugs; (d)multiplerecurrences;(e)repeatedhemoptysisand/or sec-ondaryinfections.71–78
Thepresenceofacavitarylesionreinforcestheneedfor early surgery in view of the difficulty of drug penetration and the greater population ofbacilli. The drugsshould be
Table2–Treatmentregimensformultidrug-resistanttuberculosis(MDR-TB).
Regimen Drug Dosesperweightrange Months
≤20kg 21–35kg 36–50kg >50kg 2S5ELTZ
Intensivephase 1ststage
Streptomycin 20mg/kg 500mg/day 750–1000mg/day 1000mg/day
2 Ethambutol 25mg/kg 400–800mg/day 800–1200mg/day 1200mg/day
Levofloxacin 10mg/kg 250–500mg/day 500–750mg/day 750–1000mg/day Pyrazinamide 35mg/kg 1000mg/day 1500mg/day 1500mg/day Terizidone 20mg/kg 500mg/day 750mg/day 750mg/day 4S3ELTZ
Intensivephase 2ndstage
Streptomycin 20mg/kg 500mg/day 750–1000mg/kg 1000mg/day
4 Ethambutol 25mg/kg 400–800mg/day 800–1200mg/day 1200mg/day
Levofloxacin 10mg/kg 250–500mg/day 500–750mg/day 750–1000mg/day Pyrazinamide 35mg/kg 1000mg/day 1500mg/day 1500mg/day Terizidone 20mg/kg 500mg/day 750mg/day 750mg/day 12ELT
Maintenancephase
Ethambutol 25mg/kg 400–800mg/day 400–800mg/day 1200mg/day
12 Levofloxacin 10mg/kg 250–500mg/day 500–750mg/day 750–1000mg/day
Terizidone 20mg/kg 500mg/day 750mg/day 750mg/day
Thenumberprecedingtheabbreviationindicatesthenumberofmonthsoftreatment.Thesubscriptnumberaftertheletterindicatesthe numberofdaysperweekonwhichthedrughastobeadministered.S,streptomycin;E,ethambutol;L,levofloxacin;Z,pyrazinamide;T, terizidone.
maintainedforaprolonged periodfollowingsurgery(18–24 months).Themostrecentstudiesconductedwithamore care-fulselectionofpatientsshowbetterresultswithrespectto mortalityrates,complicationsandrecurrences.74–76
Althoughfewstudieshavebeenpublished,theindications ofsurgeryasadjuvanttherapyincasesofXDR-TBaresimilar tothoseforMDR-TB:patientswithalocalizedlesionandlack ofaninitialresponsetotreatment.75,76,78
New
drugs
for
the
treatment
of
TB
Thedevelopmentandvalidationofnewdrugsforthe treat-mentofTBarenecessarytoallowmoreappropriatetreatment
regimens tobeelaborated,focusingonthefollowing objec-tives:(a) shorteningthetreatmenttime incasesofTBand oflatentTBinfection(LTBI);(b)reducingdruginteractionwith antiretroviraldrugs;andc)identifyingmoreeffectiveandsafer therapeuticoptionsforMDR-TBandXDR-TB.55
Some newdrugs and others already established on the marketforotherindicationsarecurrentlybeingevaluatedin clinicaltrialsforTBtreatment.Fig.1showssomeofthedrugs thatappearpromisingforfutureuseinTB.79,81Atpresent,two newdrugsareshowingresultspromisinginclinicaltrialsfor treatmentofMDR-TB:bedaquiline(TMC207)anddelamanid (OPC67683).InDecember2012,bedaquiline,adiarylquinoline withanovelmodeofactionspecificallyinhibiting mycobacte-rialATPsynthase,receivedapprovalfromtheFoodandDrug
Preclinical development
Good Laboratory Pratice toxicity
Phase I Phase II Phase III
CPZEN-45 DC-159a Q-201 SQ-609 SQ-641 BTZ-043 TBA-354 Bedaquiline (TMC207) Rifapentine Linezolid PA-824 Sutezolid (PNU-100480) AZD-5847 SQ-109 classes:
Chemical fluoroquinolone, rifamycin, oxazolidinone, nitroimidazole, diarylquinoline, benzothiazinone.
Sources: WHO. Global Tuberculosis Report 2012; Stop TB Partnership Working Group on New TB Drugs.79,80 Gatifloxacin Moxifloxacin Rifapentine Delamanid (OPC-67683)
Fig.1–ThedevelopmentpipelinefornewTBdrugs.
Administration(FDA)forthetreatmentofpulmonaryMDR-TB aspartofcombinationtherapyinadults.82,83Initsturn, dela-manid,anewnitroimidazolederivative,thatinhibitsmycolic acidsynthesis, wasassociatedwithanincrease insputum conversionat2monthsamongpatientswithMDR-TB(45.4% as comparedwith 29.6% ofpatients who received a back-grounddrugregimenplusplacebo).84
Conclusions
Inviewoftheepidemiologicalcontextoftuberculosis, partic-ularlyincountrieswithahighburdenofthedisease,theuseof morerapidmethodsfordiagnosingthediseaseandmolecular resistancetests,particularlyR-andH-resistance,isurgently required.Furthermore,newdrugsneedtobedevelopedforthe treatmentofMDR-TBandXDR-TB.
Conflict
of
interest
Theauthorshavenoconflictofinteresttodeclare.
r
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n
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e
s
1. CamineroLunaJA.GuíadelatuberculosisparaMédicos Especialistas.Paris:UnionInternacionalContrala TuberculosisyEnfermedadesRespiratorias;2003.
2. WorldHealthOrganization.Guidelinesfortheprogrammatic managementofdrug-resistanttuberculosis–emergency update.Geneva:WorldHealthOrganization,StopTB Department;2008.
3. WHO.Globaltuberculosiscontrol:shortupdateto2009report. Geneva,Switzerland:WorldHealthOrganization;2009. 4. NathansonE,Lambregts-vanWeezenbeekC,RichML,etal.
Multidrug-resistanttuberculosismanagementin
resource-limitedsettings.EmergInfectDis.2006;12:1389–97. 5. CentersforDiseaseControl.Nosocomialtransmissionof
multidrug-resistanttuberculosisamongHIV-infectedpersons –FloridaandNewYork,1988–1991.JAMA.1991;266:1483–5. 6. FriedenT,SterlingT,Pablos-MendezA,etal.Theemergence
ofdrug-resistanttuberculosisinNewYorkCity.NEnglJMed. 1993;328:521–6.
7. RitaccoV,DiLonardoM,RenieroA,etal.Nosocomialspread ofhumanimmunodeficiencyvirus-related
multidrug-resistanttuberculosisinBuenosAires.JInfectDis. 1997;176:637–42.
8. RullánJ,HerreraD,CanoR,etal.Nosocomialtransmissionof multidrug-resistantMycobacteriumtuberculosisinSpain. EmergInfectDis.1996;2:125–9.
9. WorldHealthOrganization.Multidrugandextensively drug-resistantTB(M/XDR-TB):2010globalreporton surveillanceandresponse.Geneva:WorldHealth Organization;2010.
10.GandhiNR,MollA,SturmAW,etal.Extensivelydrug resistanttuberculosisasacauseofdeathinpatients co-infectedwithtuberculosisandHIVinaruralareaofSouth Africa.Lancet.2006;368:1575–80.
11.ZignolM,vanGemertW,FalzonD,etal.Surveillanceof anti-tuberculosisdrugresistanceintheworld:anupdated analysis,2007–2010.BullWorldHealthOrgan.2012;90:111–9D. 12.Brasil.MinistériodaSaúde.IIInquéritoNacionalde
ResistênciaaosFármacosanti-TB,2007–2008,dadosnão publicados.
13. DavidHL.Probabilitydistributionofdrug-resistantmutants inunselectedpopulationsofMycobacteriumtuberculosis.Appl Microbiol.1970;20:810–4.
14.CoxHS,NiemannS,IsmailovG,etal.Riskofacquireddrug resistanceduringshort-coursedirectlyobservedtreatmentof tuberculosisinanareawithhighlevelsofdrugresistance. ClinInfectDis.2007;44:1421–7.
15.SupplyP,WarrenRM,BanulsAL,etal.Linkagedisequilibrium betweenminisatellitelocisupportsclonalevolutionof Mycobacteriumtuberculosisinahightuberculosisincidence area.MolMicrobiol.2003;47:529–38.
16. DalcolmoMP,AndradeMKN,PiconPD.Tuberculose multirresistentenoBrasil:históricoemedidasdecontrole. RevSaudePublica.2007;41Suppl.1:34–42.
17.ZhangY,HeymB,AllenB,etal.Thecatalase-peroxidasegene andisoniazidresistanceofMycobacteriumtuberculosis.Nature. 1992;358:591–3.
18.ZhangY.Geneticbasisofisoniazidresistanceof Mycobacteriumtuberculosis.ResMicrobiol.1993;144:143–9. 19.HeymB,AlzariPM,HonoreN,etal.Missensemutationsin
thecatalase-peroxidasegene,katG,areassociatedwith isoniazidresistanceinMycobacteriumtuberculosis.Mol Microbiol.1995;15:235–45.
20.AhmadS,MokaddasE.ContributionofAGCtoACCandother mutationsatcodon315ofthekatGgenein
isoniazid-resistantMycobacteriumtuberculosisisolatesfrom theMiddleEast.IntJAntimicrobAgents.2004;23: 473–9.
21. FerrazoliL,PalaciM,TellesMA,etal.Catalaseexpression, katG,andMICofisoniazidforMycobacteriumtuberculosis isolatesfromSaoPaulo,Brazil.JInfectDis.1995;171: 237–40.
22.GotoM,OkaS,TachikawaN,etal.KatGsequencedeletionis notthemajorcauseofisoniazidresistanceinJapaneseand YemeniMycobacteriumtuberculosisisolates.MolCellProbes. 1995;9:433–9.
23.SilvaMS,SennaSG,RibeiroMO,etal.MutationsinKatG,inhA andahpCgenesofBrazilianisoniazidresistantisolatesof Mycobacteriumtuberculosis.JClinMicrobiol.2003;41:4471–4. 24.HoflingCC,PavanEM,GiampagliaCM,etal.Prevalenceof
katGSer315MycobacteriumtuberculosisisolatesfromBrazil.Int JTubercLungDis.2005;9:87–93.
25.JaberM,RattanA,KumarR.PresenceofkatGgeneinresistant Mycobacteriumtuberculosis.JClinPathol.1996;49:945–7. 26.BanerjeeA,DubnauE,QuemardA,etal.InhA,agene
encodingatargetforisoniazidandethionamidein Mycobacteriumtuberculosis.Science.1994;263:227–30.
27.RinderH,ThomschkeA,Rüsch-GerdesS,etal.Significanceof ahpCpromotermutationsforthepredictionofisoniazid resistanceinMycobacteriumtuberculosis.EurJClinMicrobiol InfectDis.1998;17:508–11.
28.TelentiA.Geneticsofdrugresistanceintuberculosis.Clin ChestMed.1997;18:55–64.
29.CarvalhoWS,SpindolaMS,deCostaKM,etal. Low-stringencysingle-specificprimerPCRasatoolfor detectionofmutationsintherpoBgeneofrifampin-resistant Mycobacteriumtuberculosis.JClinMicrobiol.2003;41:
3384–6.
30.McCammonMT,GilletteJS,ThomasDP,etal.Detectionof rpoBmutationsassociatedwithrifampinresistancein Mycobacteriumtuberculosisusingdenaturinggradientgel electrophoresis.AntimicrobAgentsChemother. 2005;49:2200–9.
31.ZhangY,YoungD.Moleculargeneticsofdrugresistancein Mycobacteriumtuberculosis.JAntimicrobChemother. 1994;34:313–9.
32. WHO.TuberculosisdiagnosticsautomatedDNAtest.WHO endorsementandrecommendations.Geneva,Switzerland: WorldHealthOrganization;2010.
33.OgwangS,AsiimweBB,TraoreH,etal.Comparisonofrapid testsfordetectionofrifampicin-resistantMycobacterium tuberculosisinKampala,Uganda.BMCInfectDis.2009;9:139. 34.LawnSD,NicolMP.Xpert®MTB/RIFassay:development,
evaluationandimplementationofanewrapidmolecular diagnosticfortuberculosisandrifampicinresistance.Future Microbiol.2011;6:1067–82.
35.VassallA,vanKampenS,SohnH,etal.Rapiddiagnosisof tuberculosiswiththeXpertMTB/RIFassayinhighburden countries:acost-effectivenessanalysis.PLoSMed. 2011;8:e1001120.
36.Al-MutairiNM,AhmadS,MokaddasE.Performance comparisonoffourmethodsfordetecting
multidrug-resistantMycobacteriumtuberculosisstrains.IntJ TubercLungDis.2011;15:110–5.
37.FriedrichSO,VenterA,KayigireXA,etal.SuitabilityofXpert MTB/RIFandgenotypeMTBDRplusforpatientselectionfora tuberculosisclinicaltrial.JClinMicrobiol.2011;49:2827–31. 38.BodmerT,StröhleA.Diagnosingpulmonarytuberculosiswith
theXpertMTB/RIFtest.JVisExp.2012;62:e3547,
http://dx.doi.org/10.3791/3547.
39.TukvadzeN,KempkerRR,KalandadzeI,etal.Useofa moleculardiagnostictestinAFBsmearpositivetuberculosis suspectsgreatlyreducestimetodetectionofmultidrug resistanttuberculosis.PLoSOne.2012;7:e31563.
40. SkendersGK,HoltzTH,RiekstinaV,etal.Implementationof theINNO-LiPARif.TB®line-probeassayinrapiddetectionof
multidrug-resistanttuberculosisinLatvia.IntJTubercLung Dis.2012;15:1546–52,i.
41.PottathilS,AnroopN,VarshaS,etal.Evaluationofrapid techniquesforthedetectionofmycobacteriainsputumwith scantybacilliorclinicallyevident,smearnegativecasesof pulmonaryandextra-pulmonarytuberculosis.MemInst OswaldoCruz.2011;106:620–4.
42.WorldHealthOrganization.Pathwaystobetterdiagnosticsfor tuberculosis.BytheNewDiagnosticsWorkingGroupofthe StopTBPartnership.Geneva:WorldHealthOrganization; 2009.
43.WorldHealthOrganization.Rapidimplementationofthe XpertMTB/RIFdiagnostictest.Technicalandoperational ‘How-to’.Practicalconsiderations.Geneva:WorldHealth Organization;2011.
44.YeeD,ValiquetteC,PelletierM,etal.Incidenceofseriousside effectsfromfirst-lineantituberculosisdrugsamongpatients treatedforactivetuberculosis.AmJRespirCritCareMed. 2003;167:1472–7.
45.NathansonE,GuptaR,HuamaniP,etal.Adverseeventsinthe treatmentofmultidrug-resistanttuberculosis:resultsfrom theDOTS-Plusinitiative.IntJTubercLungDis.2004;8:1382–4. 46.MitnickC,BayonaJ,PalaciosE,etal.Community-based
therapyformultidrug-resistanttuberculosisinLima.PeruN EnglJMed.2003;348:119–28.
47.MunsiffSS,AhujaSD,LiJ,etal.Public-privatecollaboration formultidrug-resistanttuberculosiscontrolinNewYorkCity. IntJTubercLungDis.2006;10:639–48.
48.ShinSS,PasechnikovAD,GelmanovaIY,etal.Adverse reactionsamongpatientsbeingtreatedforMDR-TBinTomsk. RussiaIntJTubercLungDis.2007;11:1314–20.
49.ReschSC,SalomonJA,MurrayM,etal.Cost-effectivenessof treatingmultidrug-resistanttuberculosis.PLoSMed. 2006;3:e241.
50.LienhardtC,VernonA,RaviglioneMC.Newdrugsandnew regimensforthetreatmentoftuberculosis:reviewofthedrug developmentpipelineandimplicationsfornational
programmes.CurrOpinPulmMed.2010;16:186–93.
51. MaZ,LienhardtC,McIlleronH,etal.Globaltuberculosisdrug developmentpipeline:theneedandthereality.Lancet. 2010;375:2100–9.
52.OrensteinEW,BasuS,ShahNS,etal.Treatmentoutcomes amongpatientswithmultidrug-resistanttuberculosis: systematicreviewandmeta-analysis.LancetInfectDis. 2009;9:153–61.
53.ChungWS,ChangYC,YangMC.Factorsinfluencingthe successfultreatmentofinfectiouspulmonarytuberculosis. IntJTubercLungDis.2007;11:59–64.
54.DalcolmoMP,FortesA,MeloFF,etal.Estudodeefetividadede esquemasalternativosparaotratamentodatuberculose multirresistentenoBrasil.JPneumol.1999;25:70–7. 55.CondeMB,deMeloFAF,MarquesAMC,etal.IIIDiretrizes
paraTuberculosedaSociedadeBrasileiradePneumologiae Tisiologia.JBrasPneumol.2009;35:1018–48.
56.CondeMB,EfronA,LoredoC,etal.Moxifloxacinversus ethambutolintheinitialtreatmentoftuberculosis:a double-blind,randomised,controlledphaseIItrial.Lancet. 2009;373:1183–9.
57.Brasil.MinistériodaSaúde.SecretariadeVigilânciaem Saúde.ProgramaNacionaldeControledaTuberculose(PNCT). SistemadeInformac¸ãoemTuberculoseMultirresistente (SITBMR).Availableat:
http://tbmr.ensp.fiocruz.br/tbmr/Relatorios
58.MiglioriGB,BesozziG,GirardiE,etal.Clinicalandoperational valueoftheextensivelydrug-resistanttuberculosis
definition.EurRespirJ.2007;30:623–6.
59. SotgiuG,FerraraG,MatteelliA,etal.Epidemiologyand clinicalmanagementofXDR-TB:asystematicreviewby TBNET.EurRespirJ.2009;33:871–81.
60.BonillaCA,CrossaA,JaveHO,etal.Managementof extensivelydrug-resistanttuberculosisinPeru:cureis possible.PLoSOne.2008;3:e2957.
61.DhedaK,SheanK,ZumlaA,etal.Earlytreatmentoutcomes andHIVstatusofpatientswithextensivelydrug-resistant tuberculosisinSouthAfrica:aretrospectivecohortstudy. Lancet.2010;375:1798–807.
62.KohWJ,KwonOJ,GwakH,etal.Daily300mgdoseoflinezolid forthetreatmentofintractablemultidrug-resistantand extensivelydrug-resistanttuberculosis.JAntimicrob Chemother.2009;64:388–91.
63.MiglioriGB,EkerB,RichardsonMD,etal.Aretrospective TBNETassessmentoflinezolidsafety,tolerabilityandefficacy inmultidrug-resistanttuberculosis.EurRespirJ.
2009;34:387–93.
64.SchecterGF,ScottC,TrueL,etal.Linezolidinthetreatment ofmultidrug-resistanttuberculosis.ClinInfectDis. 2010;50:49–55.
65.AlffenaarJW,vanAltenaR,HarmelinkIM,etal.Comparison ofthepharmacokineticsoftwodosageregimensoflinezolid inmultidrug-resistantandextensivelydrug-resistant tuberculosispatients.ClinPharmacokinet.2010;49:559–65. 66.AngerHA,DworkinF,SharmaS,etal.Linezolidusefor
treatmentofmultidrug-resistantandextensively drug-resistanttuberculosis,NewYorkCity,2000–06.J AntimicrobChemother.2010;65:775–83.
67.VillarM,SotgiuG,D’AmbrosioL,etal.Linezolidsafety, tolerabilityandefficacytotreatmultidrug-andextensively drug-resistanttuberculosis.EurRespirJ.2011;38:730–3. 68.AbbateE,VescovoM,NatielloM,etal.Successfulalternative
treatmentofextensivelydrug-resistanttuberculosisin Argentinawithacombinationoflinezolid,moxifloxacinand thioridazine.JAntimicrobChemother.2012;67:473–7. 69.SinglaR,CamineroJA,JaiswalA,etal.Linezolid:aneffective,
safeandcheapdrugforpatientsfailingmultidrug-resistant tuberculosistreatmentinIndia.EurRespirJ.2012;39: 956–62.
70. TanggSJ,ZhangQ,ZhengL,etal.Efficacyandsafetyof linezolidinthetreatmentofextensivelydrug-resistant tuberculosis.JpnJInfectDis.2011;64:509–12.
71.LeiteLP,CostaAL,AndradeRN,GalvãoT.Tratamento cirúrgicoadjuvantedetuberculosepulmonar multirresistente.JPneumol.1997;23:11–4. 72.DewanR,PratapH.Surgicalinterventionsin
multidrug-resistanttuberculosis:retrospectiveanalysisof74 patientstreatedatatertiarylevelcarecenter.IndJThorac CardiovascSurg.2006;22:15–8.
73.SomocurcioJG,SotomayorA,ShinS,etal.Surgeryfor patientswithdrug-resistanttuberculosis:reportof121cases receivingcommunity-basedtreatmentinLima.PeruThorax. 2007;62:416–21.
74. WangH,LinH,JiangG.Pulmonaryresectioninthetreatment ofmultidrug-resistanttuberculosis:aretrospectivestudyof 56cases.AnnThoracSurg.2008;86:1640–5.
75.MitnickCD,ShinSS,SeungK,etal.Comprehensivetreatment ofextensivelydrug-resistanttuberculosis.NEnglJMed. 2008;359:563–74.
76.GegiaM,KalandadzeI,KempkerRR,etal.Adjunctivesurgery improvestreatmentoutcomesamongpatientswith
multidrug-resistantandextensivelydrug-resistant tuberculosis.IntJInfectDis.2012;16:
e391–6.
77.ShiraishiY,KatsuragiN,KitaH,etal.Aggressivesurgical treatmentofmultidrug-resistanttuberculosis.JThorac CardiovascSurg.2009;138:1180–4.
78. DravnieceG,CainKP,HoltzTH,etal.Adjunctiveresectional lungsurgeryforextensivelydrug-resistanttuberculosis.Eur RespirJ.2009;34:180–3.
79.WorldHealthOrganization(WHO).Globaltuberculosisreport 2012.Geneva,Switzerland:WorldHealthOrganization;2012. Availableat:http://www.who.int/tb/publications/global report/en/index.html
80.StopTBPartnershipWorkingGrouponNewTBDrugs. Availableat:http://www.newtbdrugs.org
81. LienhardtC,RaviglioneM,SpigelmanM,HafnerR,Jaramillo E,HoelscherM.Newdrugsforthetreatmentoftuberculosis: needs,challenges,promise,andprospectsforthefuture.J InfectDis.2012;205Suppl.2:S241–9.
82.DiaconAH,DonaldPR,PymA,etal.Randomizedpilottrialof eightweeksofbedaquiline(TMC207)treatmentfor
multidrug-resistanttuberculosis:long-termoutcome, tolerability,andeffectonemergenceofdrugresistance. AntimicrobAgentsChemother.2012;56:3271–6.
83. LounisN,LounisE,DePaepeB,VanBaelenK,AndriesK.A phaseII,open-labeltrialwithTMC207aspartofamulti-drug resistanttuberculosis(MDR-TB)treatmentregimenin subjectswithsputumsmear-positivepulmonaryinfection withMDR-TB.ClinicalMicrobiologyReport.JanssenResearch andDevelopment;8May2012.
84.GlerMT,SkripconokaV,Sanchez-GaravitoE,etal.Delamanid formultidrug-resistantpulmonarytuberculosis.NEnglJMed. 2012;366:2151–60.
85.CanettiG,FoxW,KhomenkoA,etal.Advancesintechniques oftestingmycobacterialdrugsensitivity,andtheuseof sensitivitytestsintuberculosiscontrolprogrammes.Bull WorldHealthOrgan.1969;41:21–43.