TB and LTBI Treatment

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Treatment of Tuberculosis andLatent TB Infection

Division of TB ControlVirginia Department of Health


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TB Diagnosis

The first rule of TB diagnosis: is tothink TB.

Include TB in your differential diagnosis whenhistory, symptoms are consistent with TBdiagnosis

Order the appropriate diagnostic tests


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TB Diagnosis

Symptoms: persistent cough, fever, nightsweats, weight loss

Risk factors for exposure to TB: close contactof case, residence/travel in high prevalencecountry, congregate living with other high riskindividualsRisk factors for development of activedisease if infected: recent infection,HIV/AIDS, other underlying medical condition


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Diagnosis of Pulmonary TB(80-85% of TB Cases)

Chest x-rayStandard PA and lateral films; apical lordotic views may behelpful

Infiltrates, nodular densities, cavities, +/- hilar adenopathy Abnormalities may be subtle in immunocompromisedpatientsPrevious x-rays for comparison may be useful

CT scansOften obtainedNice to have but rarely critical to diagnosisExpensive


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Diagnosis of Pulmonary TB

TSTPositive supports but does not make diagnosis

Negative does not exclude TB as possiblediagnosis

QuantiferonScreening test only, not diagnostic


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Mycobacteriology laboratory tests AFB smear

CultureID of isolate confirm M.tb

Antimicrobial susceptibility testing

Rapid, direct tests


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Coughed sputumBest specimen when available

Early AM best, supervise collection AFB smear best available tool for assessinginfectiousnessMost likely to yield positive culture

Multiple specimens recommended to maximizechances for +AFB/culture


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Induced sputumUseful if no/non-productive cough

Unpleasant but safe, well tolerated, efficient wayto quickly collect specimensSpecimen may be scant, difficult to interpretsmears to assess infectiousness

Multiple specimens recommended to maximizechances for +AFB/culture


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Y ield of smear and culture from repeated sputuminduction for the diagnosis of pulmonary

tuberculosis

specimen one two three four

AFB smear 64 81 91 98

AFB culture 70 91 99 100

Int J Tuberc Lung Dis. 2001 Sep;5(90:855-60. Al Zahrani K, et al.

Induced sputum (% yield)


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Bronchoscopy (+/- transbronchial biopsy)Specimen dilute (saline lavage)Cannot compare AFB + or to sputum

Only one specimen availableMay result in increased cough

Collect coughed or induced sputum x3 after bronchoscopy; use AFB smear results to assessinfectiousness

Must collect sputum (coughed or induced) x3 to assessinfectiousness after bronch culture result reported

Lung biopsyMust culture as well as send for pathologyStill need sputum for smear, culture


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Laboratory Tests for M.tb

AFB smear Available in 24-48 hours

Simple test; requires skilled technologist to readNot diagnostic for M.tb : All AFB look alike

Assess infectiousnessNeed for isolation, contact investigation

Monitor response to treatmentDecrease in AFB on smear correlates witheffectiveness of treatment


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Laboratory Tests for M.tbCulture and Identification of Isolate

Gold standard for TB diagnosisUsually complete in 2-4 weeks

Not signed out as negative until 8 weeksTraditional identification based on growthcharacteristics, biochemical testsID by probe now standard

Requires isolate (2-4 weeks)

Tests DNA can ID M.tb complex , M.avium , +/-othersMore rapid than chemicals, just as accurateCannot distinguish among M.tb complex species(M.tb vs. M.bovis)


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Laboratory Tests for M.tb

Antimicrobial susceptibility testingRequires isolate

2-4 weeks after isolate availableIREZ +/- S testing standardSecond line drug testing only on request

Discuss w/ DTC

3-10% of VA TB isolates resistant to > 1 first lineTB drug

Continue IREZ until susceptibility results available


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Other Laboratory Tests for M.tb

Direct/rapid tests for M.tb in sputumNucleic acid amplificationResults in 3-5 days

Limited experience, generally reliableMay help with decisions on isolation, contactinvestigationsNot useful for follow-up

Genotyping

New technique; limited field experienceMay be useful epi toolNo role in patient management


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Diagnosis/Follow-up of Pulmonary vs.Extra-Pulmonary TB

PulmonarySputum for AFB smear and culture

Chest x-ray helpfulFollow-up sputum smearsand cultures useful tomonitor treatment

Extra-pulmonaryMore variability inpresentation; may be

more difficult to diagnose AFB smear and culturedone on tissue or fluidFollow-upsmears/cultures may notbe possible

Must evaluate for pulmonary diseaseChest x-ray may benormal; x-rays/scans maybe helpful


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Diagnosis and Treatment of Pulmonary vs.Extra-Pulmonary TB

AFB smears, culture and antimicrobial sensitivity testscritical

Antimicrobial drug resistance rates similar

Same drugs, same doses, duration of treatment may varyProspects for survival, cure similar; permanent damagedepends on location of infectionRapidly progressive and/or disseminated TB more likely invery young, immunocompromised patients

Guidelines for monitoring (drug side effects/toxicity) similar Guidelines for supervision of treatment (DOT) similar less strict for extra-pulmonary because usually notinfectious


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Treatment of TB Disease

The first rules of TB treatment are:Enough drugs (4 to start)

The right drugs (antimicrobial sensitivities)Enough milligrams of each drug (patient weight)Enough doses (count doses)

Enough attention to detail (monitoring of laboratory studies and clinical course)


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Antituberculosis Drugs Currently in Usein the US

First-line DrugsIsoniazidRifampin

RifapentineRifabutinEthambutolPyrazinamide

Second-line DrugsCycloserineEthionamide

LevofloxacinMoxifloxacinGatifloxacinP -Aminosalicylic acidStreptomycin

Amikacin/kanamycinCapreomycinLinezolid


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Standard regimenIREZ x 8 weeks, then IR x 18+ weeks5 days/week x 8 weeks, then 2x/week for remainder of treatmentTreatment extended if necessary to achieve requirednumber of dosesDoses based on patients weight

Standard regimen ok for ~75% of patients90+% of eligible patients complete standardcourse of treatment within 12 months


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Patients who require non-standard regimensDrug resistant TBDrug side effects/toxicity

Other medical conditionsHIVRenal failureLiver diseaseConditions causing malabsorption

Children (sometimes)Elderly (sometimes)Pregnant women


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Drug resistant TBChoice of drugs depends on resistancepattern

May require second line drug(s)Requires DOTRequires >26 weeks of treatment

Usually requires daily therapyMonitoring for culture conversion, clinicalimprovement, side effects/toxicity critical


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Resistance to First Line Antimicrobial AgentsTreatment of Cases and Contacts

Drug(s) # Resistant Isolates Treatment Modifications

I 169 (6%) R for contacts

R 11 (


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Drug Side Effects/ToxicitySome side effects (e.g., nausea) almost universal; do notrequire modifications in treatmentSome adverse events uncommon but serious, reversible if identified early; require monitoring

HepatitisHearing lossVisual acuity, color vision

Selection of drugs and dosage based on weight, liver functionand renal function can prevent toxicity

Limit use of hepatotoxic drugs in patients with liver diseaseChange dosing frequency in patients with renal disease

Some adverse effects cannot be accurately predictedHepatitis in patients without known liver diseaseBone marrow suppression or destruction of red blood cells,white blood cells, platelets


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TB Treatment in Patients with Other Medical Conditions

Common co-existing conditionsHIV

Interactions with anti-retroviral agentsTB may be disseminated and/or slow to respond;require longer treatment

Renal failureLiver disease (alcohol, hepatitis B, hepatitis C)

Conditions causing malabsorptionHIV, severe debility, malnutrition


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TB Treatment in Patients with Other Medical Conditions

Careful monitoring criticalSputum for smears, cultures

Monitor for signs of drug toxicityClinical improvement (weight gain, feeling better)LFTs, renal function testsConsider drug levels


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TB treatment in special populations

ChildrenSame as adults

Dosage based on weightFewer problems with toxicityHarder to administer Harder to monitor

Pills (crushed) vs. liquid preparationsSome clinicians reluctant to use ethambutol


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TB treatment in special populations

ElderlySame as younger adultsDosage based on weight

Can be difficult to monitor for side effectsMay not tolerate 2 or 3 x per week dosing

Pregnant women Avoid aminoglycosides, PZA


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Treatment of Latent TB Infection

Recommended regimenIsoniazid for 9 months is optimal, 6 months

acceptableFour month course of rifamycin acceptable

Recommendation for PZA/rifamycin has beenwithdrawn

Problems with liver toxicityExtremely close monitoring required if usedRemember its still efficacious !


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Treatment of Latent TB Infection

Monthly clinical monitoring requiredMonthly Clinical Assessment form

AST or ALT and serum bilirubin in selected casesBaseline

HIV infectionHistory of liver disease

AlcoholismPregnancy

RepeatBaseline results abnormalPregnancy, immediate postpartum (first 3 months), or athigh risk for adverse reactionsSymptoms of adverse reactions


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References

Radiographic Manifestations of Tuberculosis: A Primer for Clinicians Frances J. Curry National Tuberculosis Center,20032003 ATS TB Treatment StatementPediatric Redbook 2003 EditionDrug-Resistant Tuberculosis A Survival Guide for Clinicians(Frances J. Curry National Tuberculosis Center, 2004PDR or package insertLaboratory Diagnosis call DTC for referencesDrug Side Effects, Toxicity call DTC for referencesTargeted Tuberculin Testing and Treatment of LatentTuberculosis Infection MMWR 2000;49 (No. RR-6)


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VDH/DTC

Phone: 804 864 7906Fax: 804 371 0248

www.vdh.virginia.gov


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TB and LTBI Treatment

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