QUICK REFERENCE FOR HEALTHCARE PROVIDERS

Ministry of Health Malaysia Academy of Medicine Malaysia Malaysian Thoracic Society

Management of Tuberculosis (Third Edition)

2

KEY MESSAGES

1. Tuberculosis (TB) is a notifiable infectious disease. Timely diagnosis, prompttreatment&adherencetomedicationarekeyfactorsincombatingTB.

2. ScreeningofTBshouldbedoneinhighriskgroupsincludingallclosecontacts(especiallyhouseholdcontacts).

3. Patients with symptoms of TB should have sputum smear for acid fast bacilli(AFB),mycobacterium culture & sensitivity (C&S), & chest x-ray (CXR) done.Nucleic Acid Amplification Tests (NAAT) plays a role in rapid detection ofMycobacterium tuberculosis & multidrug-resistantTB(MDR-TB).

4. TB serology should not be used to diagnose pulmonary TB (PTB) orextrapulmonarytuberculosis(EPTB).

5. ForlatentTBinfection(LTBI),tuberculinskintest(TST)isthepreferredmethodfordiagnosis.InterferonGammaReleaseAssaymaybeusedasanalternative.Treatmentshouldbeconsideredforhighriskpatients.

6. AdailyantiTBregimenisrecommendedforbothintensive&maintenancephases.Aproperdefaultertracingsystemshouldbeinplacetodetectearlyinterruptionintreatmentandfollow-up.PoorlymanagedTBwillleadtodrug-resistantTB.

7. Fixed-DoseCombinations are preferred to separate-drugs combination for thetreatmentofTB.

8. Infants & children under 5 years of agewith close contact are at high risk ofdevelopingactiveTB.

9. ActiveTBshouldberuledoutinallHIV-positivepatients.

10. PreventivemeasuresshouldbeemployedtoreduceTBriskamonghealthcareworkers.

ThisQuickReferenceprovideskeymessagesandasummaryofthemainrecommendationsintheClinicalPracticeGuidelines(CPG)ManagementofTuberculosis(3rdEdition).

Detailsof theevidencesupporting these recommendations canbe found in theaboveCPG,availableonthefollowingwebsites:MinistryofHealthMalaysia:www.moh.gov.myAcademyofMedicineMalaysia:www.acadmed.org.myMalaysianThoracicSociety:www.mts.org.my

CLINICAL PRACTICE GUIDELINES SECRETARIATHealthTechnologyAssessmentSection

MedicalDevelopmentDivisionMinistryofHealthMalaysia

4thFloor,BlockE1,ParcelE,62590PutrajayaTel:603-88831246E-mail:htamalaysia@moh.gov.my

Management of Tuberculosis (Third Edition)

3

HIGH RISK GROUPS

• CloseTBcontactsespeciallyinfants&childrenunder5yearsofage• Immunocompromised patients such as those with diabetes mellitus, HIV

infection, end-stage renal disease,malnutrition, use of immunosuppressantdrugs,etc.

• Intravenousdrugusers• Peoplelivinginovercrowdedconditions

INVESTIGATIONS • PTB

o CXR (PA) should be taken in symptomatic & high risk patients. Anyabnormalitywarrantsfurtherdiagnosticinvestigation.

o A minimum of 2 sputum samples (including 1 early morning sample)shouldbesentforTBmicroscopy.OnesampleshouldbesubjectedtoM. tuberculosisC&Stesting.

o Spontaneously produced sputum is generally used for laboratory testing;however sputum induction could be carried out if patient is unable toexpectorate.

o NAAT can be carried out for the rapid identification of M. tuberculosis anddetectionofMDR-TB.ThistestcanbecarriedoutinaTBrisklevel2laboratory.

• EPTBo Patient with EPTB should have aCXR to exclude or confirm co-existing

PTB.Imaging(ultrasound,computerisedtomography&magneticresonanceimaging)may be carried on the area of interest to demonstrate featuressuggestiveofTB.

o Bodyfluidsor tissuesamplessuspectedofTBshouldbesubjectedtoTBC&S.

o NAATtestingcanbecarriedoutonpositiveTBcultures.

TREATMENT FOR NEW TB CASES

• Fornewly-diagnosedPTB,thestandardantiTBtreatmentisa6-monthregimenconsistingofdaily2-monthofEHRZfollowedbydaily4-monthofHR.

Dosages of First-Line AntiTB Drugs

Drug

Recommended doseDaily 3 times per week

Dose (range) in mg/kg

body weight

Maximum in mg

Dose (range)in mg/kg

body weight

Daily maximum

in mg

Isoniazid(H)* 5(4-6) 300 10(8-12) 900Rifampicin(R) 10(8-12) 600 10(8-12) 600Pyrazinamide(Z) 25(20-30) 2000 35(30-40)** 3000**Ethambutol(E) 15(15-20) 1600 30(25-35)** 2400**Streptomycin(S) 15(12-18) 1000 15(12-18)** 1500**

*Pyridoxine10-50mgdailyneedstobeadded.**Dailytreatmentisthepreferredregimen.Fixed-Dose Combination Dosing

Drug Body weight Dose

Akurit-430-37kg 2tabletsdaily38-54kg 3tabletsdaily55-70kg 4tabletsdaily

Morethan70kg 5tabletsdaily

Management of Tuberculosis (Third Edition)

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• Any deviation from the standard regimen or previously treated TB should bereferredtospecialistwithexperienceinTBmanagement.

• Durationoftreatmentmaybeprolongedincertaincircumstances:-o PersistentlyAFBsmearpositiveafter2months o EPTBo ExtensivecavitationonCXR

LATENT TB INFECTION• Only individuals who are at high risk of acquiring LTBI or developing TB

reactivationshouldbeinvestigated.TreatmentmightbeconsideredforthosewhoarepositiveforLTBI.

Positive TST for LTBI

Positive TST Reaction Types of Individual≥5mm •HIV-infectedpersons

•Organtransplantrecipients•Personswhoareimmunosuppressedforotherreasons

≥15mm •IndividualsfromcountrieswithlowincidenceofTB≥10mm •Closecontacts

•Recentimmigrants•Injectingdrugusers•Residents&employeesofhighriskcongregatesettings(suchascorrectionalfacilities,nursinghomes,homelessshelters,hospitals&otherhealthcarefacilities)

•PersonswithfibroticchangesonCXR

TB IN CHILDREN• Recommendedtreatmentregimens&dosagesforTBinchildrenareasthefollowing:-

TB casesRegimen

Intensive phase Maintenance phase•NewsmearpositiveornegativePTB•LesssevereEPTB 2HRZ 4HR

•SevereconcomitantHIVdisease 2HRZE 4HR•SevereformofEPTB•TBmeningitis/spine/bone 2HRZE 10HR

•PreviouslytreatedsmearpositivePTBincluding relapse & treatment afterinterruption

3HRZE 5HRE

Drug Dose (range) in mg/kg Maximum doseIsoniazid* 10(10-15) 300mgRifampicin 15(10-20) 600mgPyrazinamide 35(30-40) 2gEthambutol 20(15-25) 1g*Pyridoxine5-10mgdailyneedstobeaddedifisoniazidisprescribed.• For asymptomatic children with history of TB contact, CXR & TST should be

performed.• Treatment for LTBI in children is either daily 6months of isoniazid or daily 3

monthsofisoniazid+rifampicin

TB IN PREGNANCY, LACTATION & USE OF ORAL CONTRACEPTIVE• First-lineantiTBdrugsexceptstreptomycinaresafeforpregnancy&breastfeeding.• DeferBCGatbirthfornewbornsofmotherswithactiveTB<2monthsbeforedelivery.• Patientsonrifampicinshoulduseanalternativecontraceptivemethodotherthan

oralcontraceptivepills.

Management of Tuberculosis (Third Edition)

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TB-HIV CO-INFECTION• Isoniazidprophylaxistherapyfor6monthsshouldbeofferedtoallHIVpatients

afteractive TB is ruled out.• Highly Active Antiretroviral Therapy (HAART) during TB treatment reduces

mortality&resultsinearliersputumsmear/cultureconversion.

CD4 count (cells/µl) Timing of HAART initiation

<50 2weeksafterstartingintensivephaseofantiTBtreatment

>50 AftercompletionofintensivephaseofantiTBtreatment

>350 ContinueantiTBtreatment&monitorCD4.CommenceHAARTifCD4drops<350cells/µl.

• Efavirenz is the preferred Non-Nucleoside Reverse Transcriptase Inhibitor(NNRTI) incombinationwith2NucleosideReverseTranscriptase Inhibitors forHIV-TBco-infection.

• ImmuneReconstitution Inflammatory Syndrome (IRIS) usually occurs within 3monthsofantiTBtreatment,typicallywithin2-12weeksafterstartingHAART:o EspeciallyinpatientswithCD4<50cells/µl,anaemiaorEPTBo Majormanifestationsarefeverorlymphadenitis

• Co-trimoxazoleprophylaxisshouldbegivenforTB-HIVco-infection&throughoutantiTBtreatment.

FLOW CHART FOR THE RECOMMENDED 6-MONTHS TREATMENT OF PTB

Visit Duration Regimen Investigations1.

2.

3.

4.

5.

Startoftreatment

2-4weeks

2months

4months

6months

HR

HR

Completionof6monthstreatment

H3R3

H3R3

EHRZ/SHRZ

EHRZ/SHRZ

FBC,RBS,RP,LFT,HIVSputumAFBdirectsmearSputumMTBC&S,CXR

LFTifnecessarySputumAFBdirectsmear*SputumMTBC&Sifsmearremainspositive,CXR

LFT

SputumAFBdirectsmear&CXRonlyifthereisnoclinicalimprovement

SputumAFBdirectsmearCXR

Patients with initial sputum smear negative should have repeat sputum smear at 2monthsofantiTBtreatment.Ifstillnegative,nofurthersputumsampleisrequired.*IfsmearAFBremainspositiveat2months,refertospecialistswithexperienceinTBmanagement,&repeatsputumAFB&sputumMTBC&Sat3months.H3R3=thriceweeklyofisoniazid&rifampicin

E-Ethambutol FBC-Fullbloodcount,RBS-RandombloodsugarH-Isoniazid RP-Renalprofile,CXR-Chestx-rayR-Rifampicin LFT-LiverfunctionTest,HIV-HIVscreeningtestZ-Pyrazinamide MTBC&S-Mycobacterium tuberculosisculture&sensitivity

• Follow-upmaynotbeconductedroutinelyaftercompletionofantiTBtreatment.Patientsshouldbewell-informedonsymptomsofTBrecurrence.

Management of Tuberculosis (Third Edition)

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FIR

ST-L

INE

AN

TITB

MED

ICAT

ION

S: C

OM

MO

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IDE

EFFE

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, DR

UG

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omm

on S

ide

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g-D

rug

Inte

ract

ions

Ant

iTB

& H

AA

RT

Con

cern

Isoniazid

Skin

rash,

jaundice,

hepatitis,

drow

siness,

anorexia,

nausea,

abdominalpain,burning,n

umbnessor

tinglingsensationinthehandsorfeet

•R

eductioninphenytoin&diazepamlevel

•Increaseinthe

toxicityofanticonvulsa

nts,

benzodiazepines,

paracetamol,

serotonergic

antidepressants,w

arfarin&theophylline

Careis

neededw

hentakin

gitwithH

AART

medica

tionsthatcan

cause

peripheral

neuropathy,particularlystavudine

(d4T)&

didanosin

e(ddI)

Rifampicin

Skinrash,jaundice

,hepatitis,anorexia

,nausea,abdominalpain,orangeor

redurine&flusyndrom

e(fever,chills,

malaise,headache,bonepain)

Reductioninplasm

alevelofanti-infectives,hormone

therapy

(inclu

dingethinylestradiol,norethindrone,

tamoxifen,levothyroxine),

methadone,

warfarin,

cyclo

sporine,

corticosteroid,

anticonvulsa

nts,

cardiovascularagents,theophylline,sulfonylurea,

HMG-CoAreductase

inhibitors,

antipsychotics,

benzodiazepines&possiblere

ductioninefficacyof

azoleantifungaldrug

Reduceslevelsofproteaseinhibitors&NNRT

Is

Pyrazin

amide

Skinrash,jaundice

,hepatitis,anorexia

,nausea,abdom

inalpain&jointpain

Excretionmaybeblockedbyprobenecid

Shouldbetaken2hoursbeforedidanosine

(ddI)

Ethambutol

Visualim

pairm

ent

Absorption

delayed

orreduced

byalum

inium

hydroxide

-

Streptom

ycin

Skinrash,

deafness(no

waxon

otoscopy),

dizziness

(vertigo

&nystagmus),decreasedurineoutput

Mayincreaseototoxicity&nephrotoxicitywhenuse

witham

inoglycoside,am

photericinB

,cephalosporins,

cyclo

sporin,cisp

latin,frusemide&vancom

ycin

-

Management of Tuberculosis (Third Edition)

7

ALG

OR

ITH

M O

N M

AN

AG

EMEN

T O

F C

HIL

DR

EN W

ITH

PO

SITI

VE H

ISTO

RY O

F C

ON

TAC

T W

ITH

TB

Note:

•Mantouxtestmaybenegativeinchildrenwhoaremalnourishedandimmunocom

prom

ised.

•Contacttracingandinvestigationsinchildrenaretobedonew

ithin

6 w

eeksofdiagnosisoftheindexpatient.

Management of Tuberculosis (Third Edition)

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PTB Close Contact*

Symptomatic

Asymptomatic

Mantoux test

10 mm <10 mm

CXR Discharge with advice**

Normal – manage as LTBI

Abnormal – evaluate for active TB

Evaluate for active TB • CXR • Sputum AFB • Mantoux test

(optional)

"

Diagnosis confirmed – treat

Diagnosis inconclusive – refer specialist

ALGORITHM ON INVESTIGATIONS FOR TB CONTACT TRACING IN ADULTS

*Immunocompetentclosecontacts**ToseekmedicaladviceifpatienthassymptomssuggestiveofTBsuchasfever,coughetc.formorethan2weeks.

• ThefollowingconditionsshouldbereferredtospecialistswithexperienceinTBmanagement:-o UnsureofTBdiagnosiso RetreatmentofTBo AdverseeventsfollowingantiTBdrugso MDR-TB&extensivelydrug-resistantTBo EPTBexceptfortuberculouslymphadenitiso Renal&/orliverimpairmentwithTBo HIV-TBco-infectiono SmearnegativeTBo Smearpositiveafter2monthsoftreatmento AllchildrendiagnosedwithTBo MaternalTBo ComplexTBcasesrequiringsurgicalintervention

REFERRAL CRITERIA