Unit 7: Treatment of TB Botswana National Tuberculosis Programme Manual Training for Medical Officers.

Unit 7: Treatment of TBUnit 7: Treatment of TB

Botswana National Tuberculosis Programme Manual Training for Medical Officers

Slide 7-2Unit 7: Treatment of TB

ObjectivesObjectives

At the end of this unit, participants will be able to:

• Explain the principles of TB treatment

• Use the category regimens appropriately

• Properly monitor treatment, follow-up, and end of treatment

• Discuss side effects of drugs and their management


Admission PolicyAdmission Policy

• Admit patients who present with the following: • TB meningitis and miliary TB, until ambulatory • Danger signs (e.g., respiratory distress,

temperature of 39º C or more, inability to walk unaided)

• Spinal TB • Severe adverse events (e.g. hepatitis)

• Observe strict infection control and isolation procedures


Aims of TB Treatment Aims of TB Treatment

• Cure the patient of TB

• Prevent death from active TB or its latent effects

• Prevent relapse of TB

• Prevent the development of acquired resistance

• Prevent transmission of TB to others


Importance of Follow-upImportance of Follow-up

Retrospective analysis in 1997 in Gaborone with 127 patients:• 11.8% had treatment delay• 10.2% had incomplete workup (one smear

performed) & were not registered• 4.5% had 2 or more positive smears and were not

registered for treatment

Source: Creek T, et al., Int J Tuberc Lung Dis, 2000.


Treatment Regimens Treatment Regimens

• Category I regimen for new patients

• Category II regimen for re-treatment patients

• Category III regimen for children with less severe cases of TB

• Category IV for chronic and MDR-TB cases


First-Line Anti-TB Drugs (1)First-Line Anti-TB Drugs (1)

Essential Drug (abbreviation)

Recommended Daily Dose in mg/kg body weight (range)

Isoniazid (H) Adults: 5 mg (4-6) kg/d, 300mg/d maximumChildren: 10-15 mg/kg/d, 300 mg/d maximum

Rifampicin (R) Adults: 10 mg (8-12), 600mg/d maximumChildren: 10-20 mg/kg/d, 600 mg/d maximum


Essential Drug (abbreviation)

Recommended Daily Dose in mg/kg body weight (range)

Pyrazinamide (Z) 25 mg (20-30), 2000 mg/d maximum

Ethambutol (E) Adults: 15 mg (15-25), 1600 mg/d maximumChildren: 20 mg/kg (range 15-25 mg/kg) daily

Streptomycin (S) 15 mg (12-18) Maximum for <40 years = 1g Maximum for ≥ 40 years = 0.75g

First-Line Anti-TB Drugs (2)First-Line Anti-TB Drugs (2)


Mode of Action: Mode of Action: Special Population HypothesisSpecial Population Hypothesis

Continuous Growth

Dormant

In Acid environment

Spurts Of

Metabolism

Speed of bacterial growth

High

Low

INH (RMP, SM)

PZA RMP

Source: Mitchison DA, Tubercle, 1985.


Extent of activity

Prevention of resistance

Early bactericidal activity

Sterilising activity

High Isoniazid Isoniazid Rifampicin

Low

Rifampicin Pyrazinamide

Ethambutol

Ethambutol Rifampicin Isoniazid

Streptomycin

Streptomycin Streptomycin

Pyrazinamide Pyrazinamide Ethambutol

Source: Mitchinson DA, Tubercle , © 1985.

The Action of The Action of Anti-tuberculosis DrugsAnti-tuberculosis Drugs


Modern TB Chemotherapy (1)Modern TB Chemotherapy (1)

• INH – kills rapidly growing organisms (early bactericidal activity)

• INH and RMP protect each other from development of resistance

• Rifampicin and pyrazinamide kill slowly growing organisms• Sterilising activity

Source: Combs D et al., Ann Intern Med., 1990.


History of TB Treatment History of TB Treatment

TB Drug Development Milestones

• 1944 | Streptomycin• 1949 | P-Aminosalicylic Acid• 1952 | Isoniazid• 1954 | Pyrazinamide• 1955 | Cycloserine• 1962 | Ethambutol• 1963 | RifampicinC

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History of TB History of TB Treatment in BotswanaTreatment in Botswana

• 1975-1986: 2STH/16TH

• 1986-1993: 2SHRZ/4HR

• 1993-present: 2HRZE/4HR

• S= streptomycin

• T= thiacetazone

• H= isoniazid

• R= rifampicin

• Z= pyrazinamide

• E=ethambutol


Modern TB Chemotherapy (2)Modern TB Chemotherapy (2)

British Thoracic Society

No. 2; 1982• Initial 2 months

• HRZE

• Continuation 4 months• HR

• 97% cure rate

US Public Health Service

No. 21; 1990• Initial 2 months

• HRZ+/-E

• Continuation 4 months• HR

• 97% cure rate

Source: Iseman, MD. A Clinician’s Guide to Tuberculosis. 2000.British Thoracic Society, 1982.


Category I RegimenCategory I Regimen

Initial Phase• Normally two months• 4 drugs: 2HRZE

• Isoniazid (H)• Rifampicin (R)• Pyrazinamide (Z)• Ethambutol (E)

• Daily and observed

Continuation Phase• Normally four months• 2 drugs: 4HR

• Isoniazid (H)• Rifampicin (R)

• Daily and observed


Category I Regimen EligibilityCategory I Regimen Eligibility

• New Patients• Sputum smear + PTB• Sputum smear – PTB• Extra-pulmonary TB

• TB Meningitis: streptomycin substitutes for ethambutol

• Streptomycin should not be used if pregnant


Category I:Category I:Adult Daily Dose of Single DrugsAdult Daily Dose of Single Drugs

>70 kg 51-70kg 33-50 kg <33 kg

RIF 600mg 600mg 450-600mg

10-20mg/kg/d

INH 300mg 300mg 200-300mg

5-10 mg/kg/d

PZA 2000-2500mg

1750-2000mg

1000-1750 mg

30-40 mg/kg/d

EMB 1600-2000mg

1200-1600mg

800-1200mg

25mg/kg/d

Source: BNTP, 2007.


FDC: Fixed DoseFDC: Fixed DoseCombination Tabs (1)Combination Tabs (1)

Courtesy of: STOP TB Partnership


FDC: Fixed Dose FDC: Fixed Dose Combination Tabs (2)Combination Tabs (2)

• Fixed Dose Combination pills include two, three or even four drugs in one pill

• Advantages of FDCs • Reduces the number of pills patients must take• Minimises errors in dosing• Simplifies distribution of pills to patients• Simplifies monitoring adherence


Category I:Category I:Adult Daily Dose FDCsAdult Daily Dose FDCs

>70 kg 55-70 kg 40-54 kg 30-39 kg

HRZE

(H75mg + R150mg + Z400mg +

E275mg)

5 tabs 4 tabs 3 tabs 2 tabs


Treatment Follow-upTreatment Follow-up

• Patients should be assessed monthly during treatment (more frequently, if needed) • Symptoms: cough, weight loss, fever, adverse

effects• Adherence: review the treatment card• Adverse events: enquire about any side effects• Weight measurement: adjust dosages to account

for any weight change• Sputum smear: obtain at 2 and at 5-6 months


The Role of CXR in Follow-UpThe Role of CXR in Follow-Up

• There is no need for routine CXR in follow-up of PTB patients• CXR can be useful for the follow-up of some EPTB

patients (e.g., pleural effusion)

• Treatment decisions in PTB (switching to continuation phase, ending treatment) should generally be based upon sputum smear exams at stated intervals and clinical monitoring


Monitoring Treatment ResponseMonitoring Treatment Response

• Important to tuberculosis control• Allows assessment of

• Infectivity of a patient• Response to treatment• Outcome of treatment

• Assessed through clinical, laboratory and radiological methods

• Relies primarily on sputum conversion • X-rays are not part of routine follow-up of TB cases in

Botswana


Category I: Category I: End of 2 Months of TreatmentEnd of 2 Months of Treatment

Conduct sputum smear microscopy at end of two months

AFB positive AFB negative

Stop intensive phase Begin continuation phase

Three month smears remain positive

Stop intensive phase and begin continuation phase pending DST results*

Prolong intensive phase for third month Repeat smear at end of three months

Submit additional specimens for culture and drug susceptibility


Category I: Category I: 5-6 Months of Treatment5-6 Months of Treatment

Conduct sputum smear microscopy at 5-6 months


(and was negative at the end of the intensive phase)

Treatment outcome: “Cured”

•Stop Category I treatment•Re-register the patient as “Retreatment after failure”•Send sputum for culture and drug sensitivity testing•Start Category II treatment

Treatment outcome: “Treatment Failure”


Introduction to Introduction to Category II RegimenCategory II Regimen

• Adds a fifth drug, streptomycin, to the other first-line medications

• Prolongs treatment to 8 months in total

• Initiated and managed by the same clinicians and nurses as category I

• Requires two months of injections (given daily)


Category II RegimenCategory II Regimen

Adults

• Intensive phase • 2 months SHRZE• 1 month HRZE

• Continuation phase • 5 months HRE

Courtesy of: WHO, 2008.

Children

• Intensive phase• 2 months SHRZ• 1 month HRZ

• Continuation phase• 5 months HR


Category II Regimen EligibilityCategory II Regimen Eligibility

For smear-positive or culture-positive retreatment cases after• Relapse

• Default

• Treatment failure


Category II:Category II:Adult Daily Dose of Single DrugsAdult Daily Dose of Single Drugs

>70 kg 51-70kg 33-50 kg <33 kg

RIF 600mg 600mg 450-600mg 10-20mg/kg/d

INH 300mg 300mg 200-300mg 5-10 mg/kg/d

PZA 2000-2500mg

1750-2000mg

1000-1750 mg

30-40 mg/kg/d

EMB 1600-2000mg

1200-1600mg

800-1200mg

25mg/kg/d

STREP 1000mg 1000mg 500-750mg 15-20mg/d

Source: BNTP, 2007.


Category II:Category II:Adult Daily Dose FDCsAdult Daily Dose FDCs

>70 kg 55-70 kg 40-54 kg 30-39 kg

HRZE

(H75mg + R150mg + Z400mg +

E275mg)

5 tabs 4 tabs 3 tabs 2 tabs

S 1.0g 1.0g 0.75g 0.5g

Source: BNTP, 2007.


Category II Regimen: PregnancyCategory II Regimen: Pregnancy

• Streptomycin should be avoided in pregnancy if possible• Due to possible foetal ear damage and

nephrotoxicity

• Women of childbearing age should have a pregnancy test prior to starting category II

• If not pregnant, advise contraception


Category II: Category II: End of 3 Months of RetreatmentEnd of 3 Months of Retreatment

Conduct sputum smear microscopy at the end of three months of retreatment


Proceed with continuation phase as planned

Positive result at the end of four months

Continue with remaining four drugs for one month Repeat smear at the end of four months

Start patient on continuation phase Repeat smear at five months

Positive results indicate failure of treatment

Repeat sputum for culture and drug sensitivity testing


Category II: Category II: End of 8 months of TreatmentEnd of 8 months of Treatment

Conduct sputum smear microscopy at the end of 8 months of treatment


Treatment outcome: “Cured”•Treatment outcome: failure of re-treatment regimen•Send sputum for culture and sensitivity testing•Refer patient to a specialist physician


Treating Mono- Treating Mono- and Poly-resistant TBand Poly-resistant TB

Drug Resistance Pattern

Suggested Regimen Minimum Trtmt Duration (months)

H (+ S) R, Z, E 6-9

H and Z R, E, fluoroquinolones 9-12

H and E R, Z, fluoroquinolones 9-12

R H, E, fluoroquinolones + at least 2 months of Z 12-18

R and E (+ S) H, Z, fluoroquinolones + injectable agent for at least first 2-3 months

18

R and Z (+ S) H, E, fluoroquinolones + injectable agent for at least first 2-3 months

18

H, E, Z (+ S) R, fluoroquinolones + oral second-line agent + injectable agent first 2-3 months

18


Category III RegimenCategory III Regimen

• This is the recommended regimen for most children with TB in Botswana

• Intensive phase• 2 months HRZ

• Continuation phase• 4 months HR


Category IV Category IV Regimen and EligibilityRegimen and Eligibility• Specially-designed standardised or

individualised regimens are recommended

• For all patients who remain or become smear positive after completing a fully supervised retreatment regimen

• For chronic and MDR-TB cases

• Second line TB drugs include amikacin, ethionamide, ciprofloxacin and first line drugs with continued activity against M. tuberculosis


Treatment of Severe Forms of TBTreatment of Severe Forms of TB

• Prolong the continuation phase to 6 months for the following sites of disease:• Tuberculous meningitis*• TB percardiditis• Disseminated TB• Spinal disease with neurologic complications

*For tuberculous meningitis: substitute streptomycin for ethambutol during the initial phase of treatment

Source: Basquoz N, 2007.


Treatment of Severe TB: Treatment of Severe TB: Adjuvant CorticosteroidAdjuvant Corticosteroid• Indications:

• TB meningitis, TB pericarditis, Massive lymphadenopathy with airway obstruction

• Recommended dose: usually prednisolone • TB meningitis: 2mg/kg/day up to 60mg/day for 4 weeks,

then taper over several weeks• TB pericarditis: 2mg/kg/day up to 60mg/day for 4 weeks,

then 30mg/day for 4 weeks, then taper over several weeks

• In patients that cannot tolerate oral medication, IV dexamethasone is recommended


Side EffectsSide Effects

• Each TB medication has potential side effects and drug interactions

• Patients should be educated on particulars of potential side effects Courtesy of: Virot P, Lung Health Image Library, 2004.


Clinical Monitoring for ToxicityClinical Monitoring for Toxicity

Symptoms• Nausea• Vomiting• Right upper quadrant

pain• Burning in feet• Change in vision• Joint pain• Dizziness

Signs• Fever• Rash• Jaundice• Pallor

• Other signs of anaemia

• Confusion, psychosis• Seizures


Paradoxical ReactionsParadoxical Reactions

• Apparent clinical worsening of TB on appropriate therapy• Caused by an immunologic reaction to TB as patient improves• Common with TB adenitis

• Also occurs with brain tuberculomas and other manifestations

• Monitor for bacteriologic relapse/failure• Continue TB treatment• Steroid therapy may be helpful for severe paradoxical

reaction, after excluding TB treatment failure and other etiologies of apparent clinical worsening


Common Adverse Drug Reactions (1)Common Adverse Drug Reactions (1)

Caused by Adverse Reaction Signs and Symptoms

Any drug Allergy Skin rash

Ethambutol Optic Neuritis Blurred or changed vision

Changed color vision

Isoniazid,

Pyrazinamide or

Rifampicin

Hepatitis Abdominal pain

Abnormal liver function test results

Fatigue

Lack of appetite

Nausea

Vomiting

Yellowish skin or eyes

Dark urine




Isoniazid Peripheral neuropathy

Tingling sensation in hands and feet

Pyrazinamide Gastrointestinalintolerance

Arthralgia

Arthritis

Upset stomach, vomiting, lack of appetite

Joint aches

Gout (rare)

Streptomycin Ototoxicity

Renal toxicity

Balance problems

Hearing loss

Ringing in the ears

Abnormal kidney function test results




Rifampicin Thrombocytopenia

Gastrointestinal intolerance

Drug interactions

Easy bruising

Slow blood clotting

Upset stomach

Interferes with certain medications, such as oestrogen-containing contraceptives


Shared Side Effects of TB and ARV Therapy

Side Effect ARV TB Medication

nausea didanosine, zidovudine, ritonavir,

saquinavir

pyrazinamide

hepatitis nevirapine, efavirenz rifampicin, isoniazid, pyrazinamide

peripheral neuropathy

stavudine, didanosine

isoniazid

rash nevirapine, efavirenz rifampicin, isoniazid, pyrazinamide


Managing Minor Side EffectsManaging Minor Side Effects

• Loss of appetite, nausea, abdominal pain• Provide anti-emetics such as promethazine or

metoclopromide• Check liver function tests or ALT, especially if symptoms

persist• Joint pains

• Aspirin or Non-Steroidal Anti-Inflammatory Drugs (NSAID)• Peripheral Neuropathy

• Give pyridoxine 100-200 mg daily until symptoms disappear and then decrease to preventive dose

• Orange/red urine• Reassurance

Source: WHO, 2004.


Managing Major Side EffectsManaging Major Side Effects

• Severe rash• Stop all drugs; see Unit 8

• Jaundice, vomiting and abdominal pain, confusion• Stop all drugs; see Unit 8

• Visual changes• Stop ethambutol and revise treatment

• Generalised reaction, shock, purpura• Stop all drugs until stable


Serial Drug ChallengeSerial Drug Challenge

• When symptoms of a major side effect have subsided, wait two weeks

• Reintroduce TB medicines as described in Table 6.7 in the Botswana National Tuberculosis Programme Manual


Schedule for Schedule for Reintroduction of Anti-TB DrugsReintroduction of Anti-TB Drugs

Day Drug and dose 1 INH 25 mg

2 INH 50 mg

3 INH 100 mg

4 INH 200 mg

5 INH 300 mg*

6 INH 300 mg + R 150 mg

7 INH 300 mg + R 300 mg

8 INH 300 mg + R 450 mg

9 INH 300 mg + R 600 mg*

10 INH 300 mg + R 600 mg + E 400 mg

11 INH 300 mg + R 600 mg + E 800 mg

12 INH 300 mg + R 600 mg + E 1200 mg*

13 INH 300 mg + R 600 mg + E 1200 mg + Z 500 mg

14 INH 300 mg + R 600 mg + E 1200 mg + Z 1000 mg

15 INH 300 mg + R 600 mg + E 1200 mg + Z 1500 mg

16 INH 300 mg + R 600 mg + E 1200 mg + Z 2000 mg*


Drug Interactions Drug Interactions

• With many patients on ARVs also taking ATT, quite common for drug levels to be altered to some degree

• Antituberculosis drugs sometimes change concentrations of other drugs

• Rifampicin can decrease serum concentrations of many drugs (e.g., most of the HIV-1 protease inhibitors) to subtherapeutic levels

• Isoniazid increases concentrations of some drugs (e.g., phenytoin) to toxic levels


Cytochrome P450 CYP3ACytochrome P450 CYP3A

SUBSTRATE INHIBITOR INDUCER

amitriptyline antidepressants carbamazapine

benzodiazapines azole antifungals dexamethasone

calcium blockers cimetidine phenobarbital

dexamethasone clarithromycin phenytoin

erythromyocin erythromycin rifampicin

ethinyl estradiol protease inhibitors

ketoconazole

protease inhibitorsSource: Cupp M, et al., American Family Physician, 1998.


Treatment of MOTTTreatment of MOTT

• The most common non-tuberculous mycobacteria that cause disease in the US are• MAC, M.kansasii, M.fortuitum

• MAC is treated with clarithromycin, rifampicin, and ethambutol for 18-24 months

• M. kansasii is treated for 1 year after culture conversion with rifampicin, ethambutol and INH

Source: American Thoracic Society, 2007.


MOTT ManagementMOTT Management

• Patients with MOTT are generally not isolated

• These bacteria are widespread in the environment and are typically not spread person-to-person

• MOTT is not MDR TB

• MOTT may be present on culture but not cause disease


Key Points (1)Key Points (1)

• TB treatment rapidly kills growing bacteria, prevents the emergence of drug resistance, and kills persistent organisms to avoid relapse

• Treatment renders adherent and drug-sensitive patients non-infectious, usually within several days to several weeks

• Modern chemotherapy can cure 97% of persons with drug susceptible TB


Key Points (2)Key Points (2)

• There are 4 treatment categories of anti-TB medicines

• First-line anti-TB medicines are isoniazid, rifampicin, pyrazinamide, ethambutol, and streptomycin

• TB treatment should be monitored monthly

• Side effects should be addressed as they occur

Unit 7: Treatment of TB Botswana National Tuberculosis Programme Manual Training for Medical Officers.

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