Unit 7: Treatment of TB
Botswana National Tuberculosis Programme
Manual Training for Medical Officers
Objectives
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
Unit 7: Treatment of TB
Slide 7-2
Admission 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
Unit 7: Treatment of TB
Slide 7-3
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
Unit 7: Treatment of TB
Slide 7-4
Importance 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.
Unit 7: Treatment of TB
Slide 7-5
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
Unit 7: Treatment of TB
Slide 7-6
First-Line Anti-TB Drugs (1)
Essential Drug
(abbreviation)
Isoniazid (H)
Rifampicin (R)
Unit 7: Treatment of TB
Recommended Daily Dose in mg/kg body weight
(range)
Adults: 5 mg (4-6) kg/d, 300mg/d maximum
Children: 10-15 mg/kg/d, 300 mg/d maximum
Adults: 10 mg (8-12), 600mg/d maximum
Children: 10-20 mg/kg/d, 600 mg/d maximum
Slide 7-7
First-Line Anti-TB Drugs (2)
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 maximum
Children: 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
Unit 7: Treatment of TB
Slide 7-8
Mode of Action:
Special Population Hypothesis
High
Speed of
bacterial
growth
INH (RMP, SM)
Continuous
Growth
PZA
In Acid
environment
RMP
Spurts
Of
Metabolism
Dormant
Low
Unit 7: Treatment of TB
Source: Mitchison DA, Tubercle, 1985.
Slide 7-9
The Action of
Anti-tuberculosis Drugs
Extent of
activity
High
Prevention of
resistance
Isoniazid
Early bactericidal
activity
Isoniazid
Rifampicin
Sterilising activity
Rifampicin
Pyrazinamide
Ethambutol
Ethambutol
Rifampicin
Isoniazid
Streptomycin
Streptomycin
Pyrazinamide
Ethambutol
Streptomycin
Low
Pyrazinamide
Source: Mitchinson DA, Tubercle , © 1985.
Unit 7: Treatment of TB
Slide 7-10
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
Unit 7: Treatment of TB
Source: Combs D et al., Ann Intern Med., 1990.
Slide 7-11
Courtesy of: Global Alliance for TB Drug Development, 2007.
History of TB Treatment
Unit 7: Treatment of TB
TB Drug Development
Milestones
•
•
•
•
•
•
•
1944 | Streptomycin
1949 | P-Aminosalicylic Acid
1952 | Isoniazid
1954 | Pyrazinamide
1955 | Cycloserine
1962 | Ethambutol
1963 | Rifampicin
Slide 7-12
History of TB
Treatment in Botswana
• 1975-1986:
2STH/16TH
• 1986-1993:
2SHRZ/4HR
• 1993-present:
2HRZE/4HR
Unit 7: Treatment of TB
•
•
•
•
•
•
S= streptomycin
T= thiacetazone
H= isoniazid
R= rifampicin
Z= pyrazinamide
E=ethambutol
Slide 7-13
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.
Unit 7: Treatment of TB
Slide 7-14
Category I Regimen
Initial Phase
• Normally two months
• 4 drugs: 2HRZE
•
•
•
•
Isoniazid (H)
Rifampicin (R)
Pyrazinamide (Z)
Ethambutol (E)
Continuation Phase
• Normally four months
• 2 drugs: 4HR
• Isoniazid (H)
• Rifampicin (R)
• Daily and observed
• Daily and observed
Unit 7: Treatment of TB
Slide 7-15
Category 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
Unit 7: Treatment of TB
Slide 7-16
Category I:
Adult Daily Dose of Single Drugs
>70 kg
51-70kg
33-50 kg
<33 kg
RIF
600mg
600mg
INH
300mg
300mg
PZA
20002500mg
16002000mg
17502000mg
12001600mg
450600mg
200300mg
10001750 mg
8001200mg
1020mg/kg/d
5-10
mg/kg/d
30-40
mg/kg/d
25mg/kg/d
EMB
Unit 7: Treatment of TB
Source: BNTP, 2007.
Slide 7-17
FDC: Fixed Dose
Combination Tabs (1)
Courtesy of: STOP TB Partnership
Unit 7: Treatment of TB
Slide 7-18
FDC: Fixed Dose
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
Unit 7: Treatment of TB
Slide 7-19
Category I:
Adult Daily Dose FDCs
>70 kg
HRZE
(H75mg +
R150mg +
Z400mg +
E275mg)
Unit 7: Treatment of TB
5 tabs
55-70 kg 40-54 kg 30-39 kg
4 tabs
3 tabs
2 tabs
Slide 7-20
Treatment 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
Unit 7: Treatment of TB
Slide 7-21
The 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
Unit 7: Treatment of TB
Slide 7-22
Monitoring 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
Unit 7: Treatment of TB
Slide 7-23
Category I:
End of 2 Months of Treatment
Conduct sputum smear
microscopy at end of two months
AFB positive
Submit additional specimens for
culture and drug susceptibility
AFB negative
Stop intensive phase
Begin continuation phase
Prolong intensive phase for third month
Repeat smear at end of three months
Three month smears remain positive
Stop intensive phase and begin
continuation phase pending
DST results*
Unit 7: Treatment of TB
Slide 7-24
Category I:
5-6 Months of Treatment
Conduct sputum smear
microscopy at 5-6 months
AFB positive
AFB negative
(and was negative at the end
of the intensive phase)
Treatment outcome: “Treatment Failure”
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
Unit 7: Treatment of TB
Slide 7-25
Introduction to
Category 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)
Unit 7: Treatment of TB
Slide 7-26
Category II Regimen
Children
• Intensive phase
Adults
• Intensive phase
• 2 months SHRZ
• 1 month HRZ
• 2 months SHRZE
• 1 month HRZE
• Continuation phase
• Continuation phase
• 5 months HR
• 5 months HRE
Unit 7: Treatment of TB
Slide 7-27
Courtesy of: WHO, 2008.
Category II Regimen Eligibility
For smear-positive or culture-positive
retreatment cases after
• Relapse
• Default
• Treatment failure
Unit 7: Treatment of TB
Slide 7-28
Category II:
Adult 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
20002500mg
17502000mg
1000-1750
mg
30-40 mg/kg/d
EMB
16002000mg
12001600mg
8001200mg
25mg/kg/d
STREP
1000mg
1000mg
500-750mg
15-20mg/d
Unit 7: Treatment of TB
Source: BNTP, 2007.
Slide 7-29
Category II:
Adult 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.
Unit 7: Treatment of TB
Slide 7-30
Category 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
Unit 7: Treatment of TB
Slide 7-31
Category II:
End of 3 Months of Retreatment
Conduct sputum smear microscopy
at the end of three months of retreatment
AFB positive
AFB negative
Repeat sputum for culture
and drug sensitivity testing
Continue with remaining four drugs for one month
Repeat smear at the end of four months
Proceed with continuation
phase as planned
Positive result at the end of four months
Start patient on continuation phase
Repeat smear at five months
Positive results indicate failure of treatment
Unit 7: Treatment of TB
Slide 7-32
Category II:
End of 8 months of Treatment
Conduct sputum smear
microscopy at the end of 8 months of treatment
AFB positive
•Treatment outcome: failure of
re-treatment regimen
•Send sputum for culture and
sensitivity testing
•Refer patient to a specialist physician
Unit 7: Treatment of TB
AFB negative
Treatment outcome: “Cured”
Slide 7-33
Treating Monoand Poly-resistant TB
Drug Resistance
Pattern
Suggested Regimen
Minimum Trtmt
Duration (months)
H (+ S)
R, Z, E
H and Z
R, E, fluoroquinolones
9-12
H and E
R, Z, fluoroquinolones
9-12
6-9
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
Unit 7: Treatment of TB
Slide 7-34
Category III Regimen
• This is the recommended regimen for most
children with TB in Botswana
• Intensive phase
• 2 months HRZ
• Continuation phase
• 4 months HR
Unit 7: Treatment of TB
Slide 7-35
Category IV
Regimen 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
Unit 7: Treatment of TB
Slide 7-36
Treatment 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.
Unit 7: Treatment of TB
Slide 7-37
Treatment of Severe TB:
Adjuvant 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
Unit 7: Treatment of TB
Slide 7-38
Side Effects
Courtesy of: Virot P, Lung Health Image Library, 2004.
Unit 7: Treatment of TB
• Each TB medication
has potential side
effects and drug
interactions
• Patients should be
educated on particulars
of potential side effects
Slide 7-39
Clinical Monitoring for Toxicity
Symptoms
Signs
• Nausea
• Vomiting
• Right upper quadrant
pain
• Burning in feet
• Change in vision
• Joint pain
• Dizziness
•
•
•
•
Unit 7: Treatment of TB
Fever
Rash
Jaundice
Pallor
• Other signs of anaemia
• Confusion, psychosis
• Seizures
Slide 7-40
Paradoxical 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
Unit 7: Treatment of TB
Slide 7-41
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
Unit 7: Treatment of TB
Slide 7-42
Common Adverse Drug Reactions
(2)
Caused by
Adverse Reaction
Signs and Symptoms
Isoniazid
Peripheral
neuropathy
Tingling sensation in hands and feet
Pyrazinamide
Gastrointestinal
intolerance
Upset stomach, vomiting, lack of
appetite
Arthralgia
Joint aches
Arthritis
Gout (rare)
Ototoxicity
Balance problems
Streptomycin
Hearing loss
Ringing in the ears
Renal toxicity
Unit 7: Treatment of TB
Abnormal kidney function test results
Slide 7-43
Common Adverse Drug Reactions
(3)
Caused by
Rifampicin
Adverse Reaction
Thrombocytopenia
Signs and Symptoms
Easy bruising
Slow blood clotting
Unit 7: Treatment of TB
Gastrointestinal
intolerance
Upset stomach
Drug interactions
Interferes with certain medications,
such as oestrogen-containing
contraceptives
Slide 7-44
Shared Side Effects
of TB and ARV Therapy
Side Effect
ARV
TB Medication
nausea
didanosine,
zidovudine, ritonavir,
saquinavir
pyrazinamide
hepatitis
nevirapine, efavirenz
peripheral
neuropathy
rash
stavudine,
didanosine
rifampicin, isoniazid,
pyrazinamide
isoniazid
Unit 7: Treatment of TB
nevirapine, efavirenz
rifampicin, isoniazid,
pyrazinamide
Slide 7-45
Managing 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
Unit 7: Treatment of TB
Source: WHO, 2004.
Slide 7-46
Managing 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
Unit 7: Treatment of TB
Slide 7-47
Serial 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
Unit 7: Treatment of TB
Slide 7-48
Schedule for
Reintroduction 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*
Unit 7: Treatment of TB
Slide 7-49
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
Unit 7: Treatment of TB
Slide 7-50
Cytochrome P450 CYP3A
SUBSTRATE
amitriptyline
benzodiazapines
calcium blockers
dexamethasone
erythromyocin
ethinyl estradiol
ketoconazole
protease inhibitors
Unit 7: Treatment of TB
INHIBITOR
antidepressants
azole antifungals
cimetidine
clarithromycin
erythromycin
protease inhibitors
INDUCER
carbamazapine
dexamethasone
phenobarbital
phenytoin
rifampicin
Source: Cupp M, et al., American
Family Physician, 1998.
Slide 7-51
Treatment 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.
Unit 7: Treatment of TB
Slide 7-52
MOTT 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
Unit 7: Treatment of TB
Slide 7-53
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 drugsensitive patients non-infectious, usually
within several days to several weeks
• Modern chemotherapy can cure 97% of
persons with drug susceptible TB
Unit 7: Treatment of TB
Slide 7-54
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
Slide 7-55