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Initial Treatment
of Tuberculosis
Your name
Institution/organization
Meeting
Date
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
0
2
4
6
8
10
12
14
Weeks
ISTC TB Training Modules 2009
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 TB Training Modules 2009
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
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 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.
ISTC TB Training Modules 2009
1 of 2
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 0
Diagnostic
1
2
3
End of intensive phase
4
5
Assessment
for failure
6
Completion
[*Obtain if smear-positive at month 2]
ISTC TB Training Modules 2009
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 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)
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 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
TB Training
Modules
Modules
2008
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)
extrapulmonary TB
ISTC TB Training Modules 2009