The Treatmentof Tuberculosis

Treating TB

• Old concepts Nutritional support Fresh Air, elevation, caves

• Sanatoriums– Weimar

Exercise Surgical Death rate in 1900 was 194/100K

British Sanatorium 1880s

a Denver sanatoriumin the 1920s

Treatment

• Before 1940s: open air(sanatorium)

• 1946: streptomycin• 1952: isoniazid• 1970: rifampin

The aims of treatment of TB are:• to cure the patient

• to prevent death from active TB or its late effects

• to prevent relapse of TB

• to decrease transmission of TB to others

• to prevent the development of acquired drugresistance

It is vital to achieve these aims while preventing theselection of resistant bacilli in infectious patients.

First Line Anti-Tuberculosis Drugs

• Isoniazid (INH, H)

• Rifampicin (RIF, R)

• Pyrazinamide (PZA, Z)

• Ethambutol (EMB, E)

• Streptomycin (SM, S)

Modern TB Chemotherapy

• INH – kills rapidly growing organisms anddormant organisms

• PZA – kills TB bacilli inside themacrophage and cavities

• RIF and PZA kill slowly growing organisms sterilizing activity

• INH, RIF and EMB protect each other fromdevelopment of resistance

Activities of Antituberculosis Drugs

DrugEarly

bactericidalactivity

Preventingdrug

resistance

Sterilizingactivity

Isoniazid ++++ +++ ++Rifampicin ++ +++ ++++

Pyrazinamide + + +++Streptomycin ++ ++ ++Ethambutol ++ - +++ ++ +

Highest ++++ High +++ Intermediate ++ Low +

Group 1. First-line oral antituberculosis drugs

• Isoniazid - H• Rifampicin - R• Ethambutol - E• Pyrazinamide - Z• Rifabutin - Rfb• Rifapentine - Rpt

• Group 1 anti-TB drugs, the most potent and best tolerated,should be used if there is good laboratory evidence andclinical history that suggests that a drug from this group iseffective. For patients with strains resistant to lowconcentrations of isoniazid but susceptible to higherconcentrations, the use of high-dose isoniazid may havesome benefit

• Rifabutin and Rifapentine have similar microbiological activityas rifampicin

Group 2. Injectable anti-TB drugs(injectable agents or parental agents)

• Streptomycin - S• Kanamycin - Km• Amikacin - Am• Capreomycin – Cm

• All patients should receive a second-line Group 2 injectableagent in the intensive phase of MDR-TB treatment unlessresistance is documented or highly suspected. Eitherkanamycin, amikacin or capreomycin can be used as a firstchoice if all meet the criteria of “likely to be effective”

• There are high rates of streptomycin resistance in strains ofMDR-TB; therefore, streptomycin is not considered asecond-line anti-TB injectable agent

Group 3. Fluoroquinolones

• Levofloxacin - Lfx• Moxifloxacin - Mfx• Gatifloxacin - Gfx

• Fluoroquinolones are often the most effective anti-TB drugs in an MDR-TB regimen

• All MDR-TB patients should be treated using “later-generation” fluoroquinolones – levofloxacin ormoxifloxacin

Group 4. Oral bacteriostatic second-lineantituberculosis drugs

• Ethionamide - Eto• Prothionamide - Pto• Cycloserine - Cs• Terizidone - Trd• Para-aminosalicylic acid - PAS• Para-aminosalicylate sodium - PAS-Na

• Group 4 drugs are added on the basis of estimatedsusceptibility, drug history, efficacy, adverse effectsprofile and cost

Group 5. Group 5 drugs are not recommended byWHO for routine use in MDR-TB treatment

• Bedaquiline - Bdq• Delamanid - Dlm• Linezolid - Lzd• Clofazimine - Cfz• Amoxicillin/clavulanate - Amx/Clv• Imipenem/cilastatin - Ipm/Cln• Meropenem - Mpm• High-dose isoniazid - High dose H• Thioacetazone - T• Clarithromycin - Clr

Group 5

• Group 5 drugs are not recommended by WHO for routineuse in MDR-TB treatment

• Although all of them have demonstrated some activity atleast in vitro or in animal models, the quality of the evidenceof their efficacy and safety in humans for the treatment ofdrug-resistant TB varies

• Most of these drugs are, with the exception of bedaquilineand delamanid, not registered for treatment of MDR-TBmaking their use “off-label”

• However, they remain as options in cases where adequateregimens are impossible to design with medications fromGroups 1–4

• If a situation requires the use of Group 5 drugs, often expertswill recommend using two to three drugs from the groupgiven the limited knowledge of efficacy

New Drugs in TB Treatment

• Bedaquiline, formerly TMC207, is a newdiarylquinoline antibiotic with specific activityagainst Mycobacterium tuberculosis and severalnontuberculous mycobacteria

• It acts by inhibiting ATP synthase, interfering withthe energy generation needed by the bacterial cell

• Based on clinical evaluations for safety, tolerabilityand efficacy, bedaquiline has recently receivedaccelerated approval for the treatment of pulmonarymultidrug-resistant TB in adults

New Drugs in TB Treatment

• Delamanid (OPC-67683), a nitro-dihydro-imidazooxazole derivative, is a new antituberculosismedication that inhibits mycolic acid synthesis andhas shown potent in vitro and in vivo activity againstdrug-resistant strains of Mycobacteriumtuberculosis

• Delamanid was associated with an increase insputum-culture conversion at 2 months amongpatients with multidrug-resistant tuberculosis

Second-line Drugs

• Increased treatmentdifficulties Expensive,unavailable More side effects Difficult Ab penetration Longer treatment

• Controversy Standard treatments Everything it takes

Determining the Case Definition

TB CASES

Severity of Disease

Extra-pulmonary

Smear-negative

Pulmonary

Smear-positive

NO

YES

New

Return afterdefault

Relapse

Failure

BacteriologySite of Disease

History of TB

New case

• new, smear-positive tuberculosis cases• new smear-negative cases with extensive

parenchymal lesions• new cases with severe extrapulmonary tuberculosis

(disseminated, meningeal, pericardial, peritoneal,bilateral pleural, spinal, intestinal and genito-urinary)

! A new case is defined as a patient who has neverpreviously been treated for tuberculosis or who hasreceived treatment for less than one month.

• smear-positive cases who have already receivedtreatment for at least one month in the past whoneed to receive re-treatment. Among these patientsthree groups can be distinguished:“Relapses” — patients who have been treated and

declared cured, but whose smear examinations areonce again positive“Failures” — patients whose smear examinations

have remained positive or have once again becomepositive 5 or more months after starting treatment“Return after interruption” — patients who return

to the health centre smear-positive after interruptingtreatment for more than two consecutive months

Retreatment

Chronic cases

• chronic cases defined as smear-positive cases of pulmonary tuberculosiswho have already received a supervisedre-treatment regimen

• Resistant form of TB

Treatment regimens

• initial intensive phase, which rapidly reduces thebacterial population

• the initial intensive phase consists of at least fourdrugs

• continuation phase, which destroys those bacteriathat remain

• the continuation phase is given for 4 months if thetwo most bactericidal drugs, isoniazid andrifampicin, are used, and for 6 months if isoniazidand a bacteriostatic drug are used

Treatment schedulesrecommended by tuberculosis case

Tuberculosis case Recommended treatmentschedule

Initial phase Continuationphase

- New case of smear-positive PTB- Severe forms of smear-negative PTB- Severe extra-pulmonary tuberculosis

2 EHRZ(SHRZ)2 EHRZ(SHRZ)2 EHRZ(SHRZ)

6 HE or 6 TH4 HR4 HR

Treatment of Active TB

• Four drug regimen for first 2 months:• INH 300 mg• Rifampin 600 mg• PZA 15-30 mg/kg• Ethambutol 15-25 mg/kg or streptomycin 15

mg/kg• Two drug regimen for next 4 months:

• INH and rifampin

Treatment schedulesrecommended by tuberculosis case

Tuberculosis case Recommended treatmentschedule

Initial phase Continuationphase

Smear-positive pulmonarytuberculosis:•Relapse•Failure•Return after interruption

2 SHRZE/1HRZE

5 HRE

Ongoing Diagnostic Monitoring

• Monthly sputum collection (until twonegative smears)

• Look for smear positive cases afterinitial two months of therapy

• Liver function tests if abnormalitieson screening or risk factors forhepatitis

Monitoring the efficacy of treatmentwith bacteriological examinations

• At the end of the initial phase sputum conversionis observed in most cases. If the patient is stillsmear-positive the initial phase should be prolongedby 1 month

• At the end of the 4th month for 6-month regimens,and at the end of the 5th month for 8-monthregimens

• During the last month (at the 6th or 8th month,depending on the regimen). These smearexaminations confirm the success or failure of thetreatment

• In the case of extrapulmonary tuberculosis, follow-up is essentially clinical

Treatment outcome

• Cured: at least two negative examinations (oneafter the end of the initial intensive phase oftreatment and another during the last month oftreatment).

• Treatment completed: the patient has received afull course of treatment but has not undergone thenecessary bacteriological examinations.

• Failure: still positive or positive once again after the5th month of treatment.

Treatment outcome

• Died: whatever the cause of death.

• Transferred out: the patient has been transferredto another health centre while on treatment but thefinal outcome of the treatment is not known at thecentre where the patient was registered. Where thefinal outcome is known, this should be recorded,rather than “transferred out”.

• Defaulted: the patient has not turned up to collectdrugs for more than 2 months since the last visit.

Problems of TB therapy

• Toxicity e.g. liver• Multiple therapy• Prolonged treatment• Drug interactions e.g. anti HIV drugs

Directly observed treatment

means that an observer watches thepatient swallowing their tablets, in a waythat is sensitive and supportive to thepatient's needs. This ensures that a TBpatient takes the right antituberculosisdrugs, in the right doses, at the rightintervals

Directly Observed Therapy (DOT)

• Health care worker watches patient swalloweach

-Dose of medication-Every pill, every day-Self-administered is NOT DOT

REMEMBER

DOT for all patients on all regimens

NO exceptions

Directly Observed Therapy (DOT)

• DOT can lead to reductions inrelapse and acquired drugresistance

• Use DOT with other measures topromote adherence

• DOT is the key to CURE

Directly Observed Therapy (DOT)

What is DOTS?

• D.O.T.S stands for Directly-ObservedTreatment Short Course

• It is a comprehensive strategy endorsedby the World Health Organization (WHO)and International Union AgainstTuberculosis and Lung Diseases(IUATLD) to detect and cure TB patients

DOTS PLUS

• A case management strategy underdevelopment, designed to manage MDR-TB using second line drugs within theDOTS strategy in low – and middle –income countries.

To prevent further developmentand spread of MDR-TB.

Drug Resistance

Definition of Drug Resistant TB

• Confirmed mono-resistance:tuberculosis in patients whose infectingisolates of M. tuberculosis are confirmedto be resistant in vitro to one first-lineantituberculosis drug

Definition of Drug Resistant TB

• Confirmed poly-resistance:tuberculosis in patients whose infectingisolates are resistant in vitro to morethan one first-line antituberculosis drug,other than both isoniazid and rifampicin

Definition of Drug Resistant TB

• Multi-Drug Resistance (MDR):resistance to at least both isoniazid andrifampicin

• eXtensive-Drug Resistance (XDR):resistance to any fluoroquinolone, and atleast one of three second-line injectabledrugs (capreomycin, kanamycin andamikacin), in addition to multidrug resistance

• Treatment based on susceptibilities• Higher risk of mortality

Drug Resistance Definitions

• Primary drug resistance Applies to previously untreated patients who

are found to have drug- resistant organisms,presumably because they have been infectedfrom an outside source of resistantMycobacterium tuberculosis.

• Acquired drug resistance Applies to patients who initially have drug-

susceptible bacteria that become drug-resistant due to inadequate, inappropriate, orirregular treatment or, more importantly,because of non-adherence in drug taking.

Causes of Resistance

• Irregular Self Administration with Failureto closely supervise

• Care of patients by non specialists• Increased immigration

Persons at Increased Riskfor Drug Resistance

• History of treatment with TB drugs• Contacts of persons with drug resistant

TB• Smears or cultures remain positive

despite 2 months of TB treatment• Received inadequate treatment regimens

for >2 weeks

“Inadequate Treatment”

• Multi-factorial Lack of adherence/intermittent or

interrupted therapy Malabsorption Inappropriate regimens; to properly treat

TB one must always add at least two drugsto a failing regimen Sub-therapeutic dosing Expired or substandard drugs

Standardized treatment

• Regimens are designed on the basis ofrepresentative DRS data of specifictreatment categories

• However, suspected MDR-TB should alwaysbe confirmed by DST results wheneverpossible. All patients in a defined group orcategory receive the same treatmentregimen

Empirical treatment

• Each regimen is individually designed on thebasis of the previous history ofantituberculosis treatment and with the helpof representative DRS survey data

• Commonly, an empirical treatment is adjustedin each patient when his or her DST resultsbecome available

Individualized treatment

• Each regimen is designed based on thepatient’s past history of TB treatmentand individual DST results

The basic principles

• Regimens should be based on the history of drugstaken by the patient

• Regimens should consist of at least four drugswith either certain, or almost certain,effectiveness

• Drugs are administered at least six days a week• An injectable agent (an aminoglycoside or

capreomycin) is used for a minimum of 6 months• Treatment is for a minimum duration of 18 months

beyond conversion• Each dose is given as DOT throughout the

treatment

Step 1Use anyavailable

Begin with anyFirst line agents toWhich the isolate isSusceptible

Add aFluoroquinoloneAnd an injectableDrug based onsusceptibilities

Fluoroquinolones

LevofloxacinMoxifloxacin

Injectable agentsAmikacinCapreomycinStreptomycinKanamycin

PLUSOne ofthese

One ofthese

First-line drugs

Pyrazinamide

Ethambutol

PLUS

BS

Step 1Use anyavailable

Begin with anyFirst line agents toWhich the isolate isSusceptible

Add aFluoroquinoloneAnd an injectableDrug based onsusceptibilities

Fluoroquinolones

LevofloxacinMoxifloxacin

Injectable agentsAmikacinCapreomycinStreptomycinKanamycin

PLUSOne ofthese

One ofthese

First-line drugs

Pyrazinamide

Ethambutol

PLUS

Step 2 Pick one or more of these

Oral second line drugsCycloserineEthionamidePAS

Add 2nd line drugs untilyou have 4-6 drugs towhich isolate issusceptible (which havenot been used previously)

Step 3

Third line drugsImipenem Linezolid MacrolidesAmoxicillin/Clavulanate

Consider use of these

If there are not4-6 drugsavailableconsider 3rd linein consult withMDRTB experts

Step 1Use anyavailable

Begin with anyFirst line agents toWhich the isolate isSusceptible

Add aFluoroquinoloneAnd an injectableDrug based onsusceptibilities

Fluoroquinolones

LevofloxacinMoxifloxacin

Injectable agentsAmikacinCapreomycinStreptomycinKanamycin

PLUSOne ofthese

One ofthese

First-line drugs

Pyrazinamide

Ethambutol

PLUS

Step 2 Pick one or more of these

Oral second line drugsCycloserineEthionamidePAS

Add 2nd line drugs untilyou have 4-6 drugs towhich isolate issusceptible (which havenot been used previously)

BS

Treatment of Active TB

• INH resistant TB: Rifampin, PZA, and ethambutol for 6 months

• Rifampin resistant TB: INH, PZA, and streptomycin for 9 months or INH

and ethambutol for 18 months• MDR/XDR TB: Based on susceptibility patterns

Treatment of MDR TB in RM

• Standardized treatment (WHO):• Initial phase - 6 months:

Cm, Eth, Z, Lfx, Cs,(PAS)• Continuation phase – 18 months:

Eth, Z, Lfx, Cs,(PAS)• DOT

Consequences of MDR

• Delay in diagnosis• Treatment duration extended 18 to 24 mo.

• Second line drugs Effectiveness decreases Toxicity increases

• Expensive to treat• Community transmission

How we can prevent MDR TB

• Initial treatment with standardizedregimens (HRZE)

• Directly observed therapy (DOT)• Drug susceptibility testing for all

retreatment cases• Infection control precautions• Monitor drug resistance through surveys• Effective contact management

Interventions to prevent drug-resistant TB

1. Early detection and high quality treatment ofdrug-susceptible TB

2. Early detection and high quality treatment ofdrug-resistant TB

3. Effective implementation of infection controlmeasures

4. Strengthening and regulation of healthsystems

5. Addressing underlying risk factors and socialdeterminants

59

1st-lineoral

•INH

•RIF

•PZA

•EMB

•(Rfb)

Injectables

•SM

•KM

•AMK

•CM

Fluoroquinolones

•Cipro

•Oflox

•Levo

•Moxi

•(Gati)

Oral bacteriostatic 2nd line

Unclear efficacy•ETA/PTA

•PASA

•CYS

Not routinely recommended,efficacy unknown, e.g.,amoxacillin/clavulanic acid,clarithromycin, clofazamine,linezolid, inmipenem/cilastatin,high dose isonizid

XDR= HR + 1 FQ + 1 Injectable (KM or AMK or CM)

Drug treatment of sensitive TB

Drug treatment of MDR TB

Drug treatment of XDRTB

Treatment options for XDR?

www.cdc.gov/tb/xdrtb/

Tuberculosisanywhere

is

Tuberculosiseverywhere

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