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Initial Treatment
of Tuberculosis
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International Standards 7, 8, 10, 11, 17
Initial Treatment of Tuberculosis
Objectives: At the end of this presentation,
participants will have an understanding of:
 Drug regimens used in the initial treatment of both
pulmonary and extrapulmonary tuberculosis
 The basis for the public health benefits of treating
tuberculosis
 The clinical and microbiological effects of treatment
 The rationale for patient monitoring and reporting
 The main adverse effects of antituberculosis drugs
ISTC Training Modules 2008
Initial Treatment of Tuberculosis
Overview:
 Effect of appropriate
treatment on public health
 First-line treatment
recommendations
 Treatment of extrapulmonary
tuberculosis
 Monitoring of treatment
 Adverse reactions
 Recording and reporting
International Standards 7, 8, 10, 11, and 17
ISTC Training Modules 2008
Standards for Treatment
ISTC Training Modules 2008
Initial Treatment
of Tuberculosis
Standards 7 & 8
ISTC Training Modules 2008
Standard 7: Public Health Effects of Treatment
Any practitioner treating a patient for
tuberculosis is assuming an important public
health responsibility. To fulfill this
responsibility, the practitioner must not only
prescribe an appropriate regimen, but also
be capable of assessing the adherence of
the patient to the regimen and addressing
poor adherence when it occurs. By so
doing, the provider will be able to ensure
adherence to the regimen until treatment is
completed.
ISTC Training Modules 2008
Effect of Treatment on Public Health
Why is TB Treatment a Public Health Measure?
 Effective treatment rapidly kills organisms, reducing
the bacillary population in respiratory secretions,
thus reducing the potential for transmission.
 Effective multiple-drug treatment greatly reduces
the risk of resistant organisms emerging.
 Effective treatment decreases the duration and
severity of illness and reduces the risk of death.
ISTC Training Modules 2008
Effect of Treatment on Public Health
Pulmonary TB cases/100,000
Effects of Treatment on the Incidence of Tuberculosis in Peru
220
DOTS 1990
200
case finding
180
160
140
120
100
PTB falling at 6%/yr
1980
ISTC Training Modules 2008
1985
1990
1995
2000
Standard 8: Initial Phase of Treatment
(1 of 4)
All patients (including those
with HIV infection) who have
not been treated previously
should receive an
internationally accepted firstline treatment regimen using
drugs of known
bioavailability. The initial
phase should consist of two
months of isoniazid,
rifampicin, pyrazinamide
and ethambutol.
ISTC Training Modules 2008
Effect of Treatment on Bacillary Population
Mixed population (susceptible and resistant)
INH resistant bacilli
Log cfu
Emergence of INH resistant strain because
of ineffective treatment (INH monotherapy)
Effective multi-drug therapy
0
2
4
6
8
10
12
14
Weeks
ISTC Training Modules 2008
16
18
20
22
24
Unintended Monotherapy and Resistance
Months of Rx
0
5
7
9
Smear
+
+
+
+
Culture
+
+
+
+
INH
R*
R
R
R
RIF
S*
R
R
R
EMB
S*
S
S
R
INH
RIF
EMB
Susceptibility
* Results not known to clinician
ISTC Training Modules 2008
Treatment Goals
Microbiological Goals of
Antituberculosis Chemotherapy
 Kill tubercle bacilli rapidly
(early bactericidal effect)
 Prevent the emergence of drug
resistance
 Eliminate persistent bacilli to prevent
relapse (sterilizing effect)
ISTC Training Modules 2008
Activities of Antituberculosis Drugs
Drug
Early
bactericidal
activity
Preventing
drug
resistance
Sterilizing
activity
Isoniazid
++++
+++
++
Rifampicin
++
+++
++++
Pyrazinamide
+
+
+++
Streptomycin
++
++
++
Ethambutol
++ - +++
++
+
Highest ++++
ISTC Training Modules 2008
High +++
Intermediate ++
Low +
Standard 8: Continuation Phase of Treatment
(2 of 4)
 The preferred continuation phase consists of
isoniazid and rifampicin given for four
months.
 Isoniazid and ethambutol given for six
months is an acceptable continuation phase
regimen that may be used when adherence
cannot be assured, but is associated with a
higher rate of failure and relapse, especially
in patients with HIV infection.
ISTC Training Modules 2008
Standard 8: Continuation Phase of Treatment
(3 of 4)
 Ethambutol may be omitted in the initial
phase of treatment for adults and children
who have negative sputum smears, who do
not have extensive pulmonary tuberculosis
or severe forms of extrapulmonary disease,
and who are known to be HIV negative.
ISTC Training Modules 2008
Treatment Recommendations
Ranking
Initial Phase (2 mos.)
Continuation Phase
Preferred
INH, RIF, PZA, EMB1,2 daily
INH, RIF daily, 4 mos.
INH, RIF, PZA, EMB1,2 3x/wk.
INH, RIF 3x/wk, 4 mos.
INH, RIF, PZA, EMB daily
INH, EMB daily, 6 mos.
Optional3
1. Streptomycin may be substituted for EMB
2. Ethambutol may be omitted for adults and children who have negative
sputum smears, do not have extensive pulmonary tuberculosis or severe
forms of extra-pulmonary disease and who are HIV negative
3. Associated with higher rate of treatment failure and relapse; should
generally not be used in patients with HIV infection.
ISTC Training Modules 2008
Standard 8: Drug Formulations and Doses
(4 of 4)
 The doses of antituberculosis drugs used
should conform to international
recommendations.
 Fixed-dose combinations of two (INH and
RIF), three (INH, RIF and PZA), and four
(INH, RIF, PZA, and EMB) drugs are highly
recommended, especially when medication
ingestion cannot be observed.
ISTC Training Modules 2008
Dose Recommendations
mg/kg (range)
Drug
Daily
3x Week
INH
5 (4-6), max 300/d
10
RIF
10 (8-12), max 600/d
10 (8-12) max 600/ d
PZA
25 (20-30)
35 (30-40)
EMB
Streptomycin
children: 20 (15-25)*
adults: 15 (15-20)*
15 (12-18)
30 (25-35)
15 (12-18)
*The recommended daily dose of ethambutol is higher in children (20 mg/kg) than in adults
(15mg/kg), because the pharmacokinetics are different (peak serum ethambutol
concentrations are lower in children than in adults receiving the same mg/kg dose)
ISTC Training Modules 2008
Treatment of
Extrapulmonary
TB
ISTC Training Modules 2008
Treatment of Extrapulmonary TB
 In general, extrapulmonary tuberculosis is
treated the same as pulmonary tuberculosis
 Some experts recommend extending the
duration of therapy in patients with:
• Meningeal tuberculosis
• Bone/joint tuberculosis
 Corticosteroids may be useful adjunctive
treatment in some forms of extrapulmonary
tuberculosis
ISTC Training Modules 2008
Treatment of Extrapulmonary TB
Treatment Duration and Use of Steroids
Site
Lymph node
Length of Rx (mos.) Corticosteroids
6
No
6-9
No
Pleural
6
No
Pericarditis
6
Yes
9-12
Yes
Disseminated
6
No
Genitourinary
6
No
Abd/Peritoneal
6
No
Bone/Joint
CNS
ISTC Training Modules 2008
Monitoring
Treatment for TB
and Public Health
Reporting
Standards 10, 11, & 17
ISTC Training Modules 2008
Standard 10: Monitoring Treatment
(1 of 2)
All patients should be monitored for response
to therapy, best judged in patients with
pulmonary tuberculosis by follow-up sputum
smear microscopy (2 specimens) at least at
the time of completion of the initial phase of
treatment (2 months), at 5 months, and at the
end of treatment.
Patients who have positive smears during the
5th month of treatment should be considered
as treatment failures and have therapy
modified appropriately.
ISTC Training Modules 2008
Standard 10: Monitoring Treatment
(2 of 2)
In patients with
extrapulmonary
tuberculosis and in
children, the response
to treatment is best
assessed clinically.
Follow-up radiographic
examinations are
usually unnecessary
and may be misleading
ISTC Training Modules 2008
Monitoring: Timing of Sputum Specimens
Initial Phase
Continuation Phase
Isoniazid
Rifampicin
Pyrazinamide
Ethambutol
0
1
2
3
4
5
6
months
Diagnostic
End of intensive phase
ISTC Training Modules 2008
Assessment for failure
Completion
Treatment Outcomes for Pulmonary TB
1.2%
10%
50%
Dead
64%
Sputum negative
98%
Sputum positive
32%
18%
20%
0.8%
No
Poor
Good
Chemotherapy Chemotherapy Chemotherapy
Grzybowski S et al, Bull Int Union Tuberc 1978; (53)2: 70-5
ISTC Training Modules 2008
Monitoring: Adverse Reactions
Adverse Reaction
Drugs
Rash
PZA, INH, RIF, EMB
Gastrointestinal
intolerance
PZA, RIF
Liver toxicity
PZA, INH, RIF
Peripheral neuropathy
INH, (EMB)
Optic neuritis
EMB
Gout
PZA
• Drugs are listed in order of relative likelihood of causing adverse
reaction.
• INH/RIF and RIF/PZA appear to have synergistic effects in
causing hepatitis
ISTC Training Modules 2008
Adverse Reactions: Rash
Classic drug-related rash
Severe skin rash from
thioacetazone
ISTC Training Modules 2008
Drug-induced Hepatotoxicity
Hepatotoxic reactions:
 Transaminase elevation age-dependent
with INH
 Transaminase elevation dose-dependent
with PZA
 Cholestasis (increase in bilirubin and
alkaline phosphatase) with RIF
 Symptoms imply significant hepatotoxicity
 (Mild transaminase elevation may not be
clinically significant)
ISTC Training Modules 2008
Managing Hepatotoxicity
Management
 Hold all medications and follow liver
enzymes for significant hepatotoxicity
 Re-challenge depends on circumstances
and severity of liver dysfunction
 In general, patients should be restarted
with EMB (the least hepatotoxic drug) and
RIF, usually followed in several days by
INH if there is no worsening of liver
function
ISTC Training Modules 2008
Standard 11: Monitoring Treatment
A written record
of all medications
given,
bacteriologic
response, and
adverse
reactions should
be maintained for
all patients
ISTC Training Modules 2008
Standard 17: Reporting Cases
All providers must report
both new and retreatment
tuberculosis cases and
their treatment outcomes
to local public health
authorities, in
conformance with
applicable legal
requirements and policies.
ISTC Training Modules 2008
Initial Treatment of Tuberculosis
Summary:
 Appropriate treatment and assessment of
adherence to treatment is an important
public health issue.
 The use of internationally accepted firstline treatment regimens is associated with
a high cure rate and a low risk of acquired
drug resistance.
ISTC Training Modules 2008
Initial Treatment of Tuberculosis
Summary (cont.):
 Pulmonary and extrapulmonary TB are
generally treated with the same regimens.
(Exception: extended duration in
meningeal and bone/joint disease.)
 Monitoring for both response to treatment
and for potential adverse events is
essential.
ISTC Training Modules 2008
Summary: ISTC Standards Covered*
Standard 7:
Practitioners assume an important public health
responsibility in ensuring both appropriate
treatment regimens and assessment of
treatment adherence for their patients.
Standard 8:
All patients who have not been previously
treated should receive an internationally
accepted treatment regimen:
• Initial phase: 2 months INH, RIF, PZA, and EMB
• Continuation phase: 4 months INH and RIF, or
6 months of INH and EMB (higher failure in HIV)
* Abbreviated versions
ISTC Training Modules 2008
Summary: ISTC Standards Covered*
Standard 8: (continued)
• EMB may be omitted in the initial phase for nonHIV smear-negative cases without severe
disease.
• The doses of anti-TB drugs used should conform
to international recommendations. Fixed-dose
combinations are highly recommended.
Standard 10:
All patients should be monitored for response to
therapy, best judged in patients with pulmonary TB
by follow-up sputum smear microscopy (at 2 and 5
months and end of treatment).
* Abbreviated versions
ISTC Training Modules 2008
Summary: ISTC Standards Covered*
Standard 10: (continued)
• Positive smears during the 5th month of
treatment are considered treatment failures
and treatment should be modified
appropriately.
• Response to treatment in extrapulmonary TB
is best assessed clinically.
• Follow-up radiographs are usually
unnecessary and may be misleading.
* Abbreviated versions
ISTC Training Modules 2008
Summary: ISTC Standards Covered*
Standard 11:
A written record of all medications given,
bacteriologic responses, and adverse reactions
should be maintained for all patients.
Standard 17:
All providers must report both new and
retreatment TB cases and their treatment
outcomes to local public health authorities
* Abbreviated versions
ISTC Training Modules 2008
Alternate Slides
ISTC Training Modules 2008
Purpose of ISTC
ISTC Training Modules 2008
ISTC: Key Points
 17 Standards
 Differ from existing guidelines: standards
present what should be done, whereas,
guidelines describe how the action is to be
accomplished
 Evidence-based, living document
 Developed in tandem with Patients’ Charter
for Tuberculosis Care
 Handbook for using the International
Standards for Tuberculosis Care
ISTC Training Modules 2008
ISTC: Key Points
 Audience: all health care practitioners,
public and private
 Scope: diagnosis, treatment, and public
health responsibilities; intended to
complement local and national guidelines
 Rationale: sound tuberculosis control
requires the effective engagement of all
providers in providing high quality care and
in collaborating with TB control programs
ISTC Training Modules 2008
Questions
ISTC Training Modules 2008
Initial Treatment of Tuberculosis
1. A 28 year-old woman taking standard four-drug
treatment for TB for five weeks now complains
of nausea, vomiting, and right upper-quadrant
discomfort. When seen in clinic she is noted to
have scleral icterus and right upper-quadrant
tenderness. Her urine is dark colored. What is
the appropriate action to take at this time?
A. Stop all drugs
B. Stop isoniazid
C. Give pyridoxine (vitamin B6)
D. Replace pyrazinamide with streptomycin
ISTC Training Modules 2008
Initial Treatment of Tuberculosis
2. A 68 year-old woman with smear-positive TB needs to
start treatment. She lives too far to be given directlyobserved treatment (DOT) by your office. Which
treatment regimen is preferred for this patient?
A. Isoniazid and ethambutol for twelve months
B. Isoniazid/rifampicin/ethambutol for the first two months,
followed by isoniazid/rifampicin for an additional four
months
C. Fixed-dose combination of
isoniazid/rifampicin/pyrazinamide for nine months
D. Fixed-dose combinations of
isoniazid/rifampicin/ethambutol/pyrazinamide for the first
two months, followed by isoniazid/rifampicin for an
additional four months
ISTC Training Modules 2008
Initial Treatment of Tuberculosis
3. In considering treatment for extrapulmonary
disease, all of the following statements are correct
except:
A. Extrapulmonary disease is a sign of disseminated
disease, and therefore always requires a longer
duration of treatment
B. Most presentations of extrapulmonary TB can be
treated with the same standard six month regimens
used for pulmonary TB
C. Extending the duration of therapy is recommended by
many experts for central nervous system (CNS) and
bone/joint extrapulmonary TB
D. Corticosteroids are sometimes recommended for
pericardial and central nervous system (CNS)
extrapulmonary TB
ISTC Training Modules 2008