Initial Treatment

of Tuberculosis
Makiyatul
BBKPM Surakarta

International Standards 7, 8, 10, 13, 17, 21

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 TB Training Modules 2009

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, 13, 17, and 21
ISTC TB Training Modules 2009

Standards for Treatment

ISTC TB Training Modules 2009

Initial Treatment
of Tuberculosis
Standards 7 & 8

ISTC TB Training Modules 2009

Standard 7: Public Health Responsibility

Any practitioner treating a patient for
tuberculosis is assuming an important
public health responsibility to prevent
ongoing transmission of the infection and
the development of drug resistance. To fulfill
this responsibility the practitioner must not
only prescribe an appropriate regimen, but
also utilize local public health services and
other agencies, when necessary, to assess
the adherence of the patient and to address
poor adherence when it occurs.

ISTC TB Training Modules 2009

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 TB Training Modules 2009

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 TB Training Modules 2009

1985

1990

1995

2000

Standard 8: Initiation of Treatment

(1 of 2)

All patients (including those

with HIV infection) who
have not been treated
previously should receive
an internationally accepted
first-line treatment regimen
using drugs of known
bioavailability. The initial
phase should consist of
two months of isoniazid
(INH), rifampicin (RIF),
pyrazinamide (PZA), and
ethambutol (EMB).

ISTC TB Training Modules 2009

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

10

12

14

Weeks
ISTC TB Training Modules 2009

16

18

20

22

24

Unintended Monotherapy and Resistance

Months of Rx

+
+

+
+

+
+

+
+

R*
S*
S*

R
R
S

R
R
S

R
R
R

INH
RIF
EMB
Smear
Culture
Susceptibility
INH
RIF
EMB

ISTC TB Training Modules 2009

* Results not known to clinician

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 TB Training Modules 2009

Activities of Antituberculosis Drugs

Drug

Early
bactericidal
activity

Preventing
drug
resistance

Sterilizing
activity

Isoniazid

++++

+++

++

Rifampicin

++

+++

++++

Pyrazinamide

+++

Streptomycin

++

++

++

Ethambutol

++ - +++

++

Highest ++++
ISTC TB Training Modules 2009

High +++

Intermediate ++

Low +

Standard 8: Continuation of Treatment

(2 of 2)

The continuation phase

should consist of isoniazid
and rifampicin given for four
months
The doses of antituberculosis
drugs used should conform
to international
recommendations
Fixed-dose combinations (FDCs) of two (INH
and RIF), three (INH, RIF, and PZA), and four
(INH, RIF, PZA, and EMB) drugs are highly
recommended
ISTC TB Training Modules 2009

Treatment Recommendations
New Patients (not previously treated)
Initial Phase

Continuation Phase

(2 months)

(4 months)

INH, RIF, PZA, EMB daily

INH, RIF daily

INH, RIF, PZA, EMB1 3x/wk.

INH, RIF 3x/wk

1. Associated with higher rate of acquired drug resistance and must be

given using directly-observed therapy. Where feasible, daily dosing is
preferred. May consider daily initiation phase, then 3x week
continuation phase. 3x weekly dosing not recommended if living with
HIV or living in an HIV-prevalent setting.
ISTC TB Training Modules 2009

Dose Recommendations
Adults: mg/kg (range)
Drug

Daily

3x Week

INH

5 (4-6), max 300/d

10 (8-12), max 900/d

RIF

10 (8-12), max 600/d

10 (8-12) max 600/ d

PZA

25 (20-30), max 2000/d 35 (30-40), max 3000/d

EMB

15 (15-20), max 1600/d 30 (25-35), max 2400/d

Streptomycin

ISTC TB Training Modules 2009

15 (12-18)

15 (12-18)

Standard 17: Treat Co-morbid Disease

(1 of 2)

All providers should conduct a thorough

assessment for co-morbid conditions that
could affect tuberculosis treatment
response or outcome
At the time the treatment plan is
developed, the provider should identify
additional services that would support an
optimal outcome for each patient and
incorporate these services into an
individualized plan of care
ISTC TB Training Modules 2009

Standard 17: Treat Co-morbid Disease

(2 of 2)

This plan should include

assessment of and referrals
for treatment of other
illnesses with particular
attention to those known
to affect treatment outcome,
for instance care for
diabetes mellitus, drug and
alcohol treatment programs,
tobacco smoking cessation programs, and other
psychosocial support services, or to such services
as antenatal or well baby care
ISTC TB Training Modules 2009

Treatment of
Extrapulmonary
TB

ISTC TB Training Modules 2009

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 TB Training Modules 2009

Treatment of Extrapulmonary TB
Treatment Duration and Use of Steroids
Site
Lymph node
Bone/Joint

Length of Rx (mos.) Corticosteroids

6
No
6-9

No

Pleural

No

Pericarditis

Yes

9-12

Yes

Disseminated

No

Genitourinary

No

Abd/Peritoneal

No

CNS

ISTC TB Training Modules 2009

Monitoring
Treatment for TB
and Public Health
Reporting
Standards 10, 13, & 21
ISTC TB Training Modules 2009

Standard 10: Monitoring Treatment

(1 of 2)

Response to therapy in patients with

pulmonary tuberculosis should be
monitored by follow-up sputum smear
microscopy (2 specimens) at the time of
completion of the initial phase of treatment
(2 months).
If the sputum smear is positive at
completion of the initial phase, sputum
smears should be examined again at 3
months and, if possible, culture and drug
susceptibility testing should be performed. 1 of 2

ISTC TB Training Modules 2009

Standard 10: Monitoring Treatment

(2 of 2)

In patients with
extrapulmonary TB and
in children, the
response to treatment
is best assessed
clinically.

ISTC TB Training Modules 2009

2 of 2

Monitoring: Timing of Sputum Specimens

Initial Phase

Continuation Phase

Isoniazid
Rifampicin
Pyrazinamide
Ethambutol
Months

Diagnostic

End of intensive phase

4
Assessment
for failure

Completion

[*Obtain if smear-positive at month 2]

ISTC TB Training Modules 2009

Treatment Outcomes for Pulmonary TB

1.2%

10%
50%

Dead

64%

98%

Sputum negative
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 TB Training Modules 2009

Monitoring: Adverse Reactions

Adverse Reaction

Drugs

Rash

PZA, INH, RIF, EMB

Gastrointestinal
intolerance

PZA, RIF

Liver toxicity

PZA, INH, RIF

Peripheral neuropathy

INH, (EMB)

EMBlikelihood of causing adverse

Optic
Drugs neuritis
are listed in order of relative
reaction.
Gout
INH/RIF and RIF/PZA appear toPZA
have synergistic effects in
causing hepatitis
ISTC TB Training Modules 2009

Adverse Reactions: Rash

Classic drug-related rash

Severe skin rash from

thioacetazone

ISTC TB Training Modules 2009

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 TB Training Modules 2009

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 TB Training Modules 2009

Standard 13: Monitoring Record

A written record
of all medications
given,
bacteriologic
response, and
adverse
reactions should
be maintained for
all patients
ISTC TB Training Modules 2009

Standard 21: 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
TB Training
Modules
2009

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 TB Training Modules 2009

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.)
Treatment includes assessment and
services for co-morbid conditions that may
effect tuberculosis treatment outcomes
Monitoring for both response to treatment
and for potential adverse events is
essential.
ISTC TB Training Modules 2009

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.

* Abbreviated versions
ISTC TB Training Modules 2009

Summary: ISTC Standards Covered*

Standard 8:
All patients (including those with HIV
infection) who have not been previously
treated should receive an internationally
accepted treatment regimen of known
bioavailability:
Initial phase: 2 months INH, RIF, PZA, and
EMB
Continuation phase: 4 months INH and RIF
The doses of anti-TB drugs used should
conform to international recommendations.
Fixed-dose combinations are highly
recommended.
* Abbreviated versions
ISTC TB Training Modules 2009

Summary: ISTC Standards Covered*

Standard 10:
Response to therapy in patients with
pulmonary TB should be monitored by followup 2 sputum smears at the end of the initial
phase, and if positive, repeated at the end of
3 months (if positive at 3 months, obtain
culture and DST). In extrapulmonary TB and
in children, the response to treatment is best
assessed clinically.
* Abbreviated versions
ISTC TB Training Modules 2009

Summary: ISTC Standards Covered*

Standard 13:
A written record of all medications given,
bacteriologic responses, and adverse reactions
should be maintained for all patients.
Standard 17:
All providers should conduct a thorough
assessment and provide services or referrals for
co-morbid conditions with particular attention to
those known to effect treatment outcome

* Abbreviated versions
ISTC TB Training Modules 2009

Summary: ISTC Standards Covered*

Standard 21:
All providers must report both new and
retreatment TB cases and their treatment
outcomes to local public health authorities

* Abbreviated versions
ISTC TB Training Modules 2009

Alternate Slides

ISTC TB Training Modules 2009

Purpose of ISTC

ISTC TB Training Modules 2009

ISTC: Key Points

21 Standards (revised/renumbered in 2009)
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 TB Training Modules 2009

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 TB Training Modules 2009

Questions

ISTC TB Training Modules 2009

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 TB Training Modules 2009

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 TB Training Modules 2009

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)
TB
ISTC TB Training Modulesextrapulmonary
2009