Download New Patient

Module 7A – March 2010
Treatment of
Tuberculosis:
New Case
Project Partners
Funded by the Health Resources and Services Administration (HRSA)
Module Overview
 Drugs and treatment
standards
 Standard new case
regimens and dosages
 Treatment of EPTB and
in special situations
International
Standards
7, 8 & 10
•
•
•
•
Smear-negative PTB
Pregnancy
Liver disorders
Renal disease
Learning Objectives
At the end of this presentation, participants
will be able to:
 Describe the drug regimens used to treat new
TB cases (pulmonary and extrapulmonary)
 Identify treatment and management approaches
in special situations (e.g., smear-negative PTB,
pregnancy, presence of co-morbidities)
 Describe the essential monitoring based on site
of disease, bacteriological status, and in special
populations
First Line Anti-Tuberculosis Drugs
 Isoniazid (INH, H)
 Rifampicin (RIF, R)
 Pyrazinamide (PZA, Z)
 Ethambutol (EMB, E)
 Streptomycin (SM, S)
Standards for Treatment
Standard 7: Public Health Effects of
Treatment
Practitioners assume an important public
health responsibility in ensuring both
appropriate treatment regimens and
assessment of treatment adherence for their
patients.
Effect of Treatment on Public Health
Why is TB Treatment a Public Health Measure?
 Providing the patient with an effective treatment that
kills the organisms will rapidly reduce and ultimately
eliminate the bacillary population in respiratory
secretions, thus reducing the potential for
transmission
 Effective multiple-drug treatment, using fixed-dose
combination tablets, greatly reduces the risk of
resistant organisms emerging
 Effective treatment decreases the duration and
severity of illness and reduces the risk of death
Effect of Treatment on Public Health (2)
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
1985
1990
1995
2000
Standard 8: Treatment New Cases
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 2 months of
isoniazid, rifampicin,
pyrazinamide and ethambutol
 The continuation phase should consist of
isoniazid and rifampicin given for four months
Antituberculosis Drug Activity
Drug
Early
bactericidal
activity
Preventing
drug resistance
Sterilizing
activity
Isoniazid
++++
+++
++
Rifampicin
++
+++
++++
Pyrazinamide
+
++ - +++
+
++
+++
+
Ethambutol
Highest ++++
High +++
Intermediate ++
Low +
Microbiological Goals - Anti-TB Drugs
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)
Adequate TB treatment requires:
 An appropriate combination of anti-TB
medications to prevent resistance
 Correctly prescribed dosage
 Taken regularly by the patient
 Treatment for a sufficient period of time to
prevent relapse
 All doses directly observed (DOT)
 Never add a single drug to a failing
regimen
Treatment Effect 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
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
Standard Regimens by Patient Group
 New Patient – factors influencing regimen:
• Presumed to have drug susceptible TB
• Patient also HIV co-infected
• Setting known to have high prevalence of INH
resistance in new patients
 Previously Treated Patient – regimen is
based on:
• Availability of drug sensitivity testing
• Likelihood of multi-drug resistance (MDR)
Benefits of Standard Regimens
 Reduces errors in prescriptions
 Facilitates estimates of drug need,
purchasing, distribution and monitoring
 Facilitates staff training
 Reduces cost
 Facilitates regular drug supply
 Makes outcome evaluation convenient
and comparable
Treatment Recommendations
New Patient
Groups
Presumed or
known drug
susceptible
TB treatment regimens
Initial phase
(2 mos.)
Continuation
phase
Optimal
HRZEa
Optimal
HR, 4 mos.
Acceptable
HRZEa or
HRZEa, b, 3x/wk
Acceptable
HR 3x/wk, 4 mos.
H = Isoniazid; R = Rifampicin; Z = Pyrazinamide; E = Ethambutol
Twice weekly dosing for full course of treatment should
not occur unless done in context of formal research
Treatment Recommendations (2)
New Patient
Groups
Presumed or
known drugsusceptible
and living
with HIV or in
a high HIV
prevalence
setting
TB treatment regimens
Initial phase
(2 mos.)
Continuation
phase
Optimal
HRZEa
Optimal
HR, 4 mos.
Acceptable
HRZEa
Acceptable
HRc 7 mos.
Treatment Recommendations (3)
TB treatment regimens
New Patient Groups
Setting with high
levels of INH
resistance where DST
at start of treatment is
not universal
Settings where >3%
of new patients have
MDR
Initial phase
(2 mos.)
Continuation
phase
Acceptable
HRZEa daily
Acceptable
HRE, 4 mos.
Obtain DST at the start if therapy
DST = drug susceptibility testing
Standard 8: Drug Formulations and Doses
 The doses of
anti-tuberculosis drugs
used should conform
to international
recommendations
 Fixed-dose combinations
(FDC) of two (INH and RIF), three (INH,
RIF, and PZA), and four (INH, RIF, PZA,
and EMB) drugs are highly recommended
Adult Daily Dose of FDC Tabs
Body Weight
KG
Initial Phase
[RHZE]
Continuation
Phase [RH]
30-37
2
2
38-54
3
3
55-74
4
4
≥75
5
5
12-15 Pills Per Day to Only 4-5 FDCs
Image source: Pierre Virot
Image source: Jad Davenport
Dose Recommendations
Doses of First-line Anti-TB Drugs in Adults
Drugs
Recommended dose in mg/kg body weight
Daily (mg/kg range)
3 x weekly
Isoniazid (INH, H)
5 (4-6),
max 300mg/day
10 (8-12)
max 900/dose
Rifampicin (RIF, R)
10 (8-12),
max 600mg/day
10 (8-12)
max 600/dose
Pyrazinamide (PZA, Z)
25 (20-30),
max 2000mg/day
35 (30-40)
max 3000/dose
Ethambutol (EMB, E)
15 (15-20),
max 1600mg/day
30 (25-35)
max 2400/dose
Streptomycind (SM, S)
15 (12-18),
max 1000mg/day
15 (12-18)
Treatment Outcomes for Pulmonary TB
1.2%
10%
50%
Dead
64%
98%
Sputum positive
32%
18%
Sputum negative
20%
0.8%
No
Poor
Good
Chemotherapy Chemotherapy Chemotherapy
Grzybowski S et al, Bull Int Union Tuberc 1978; (53)2: 70-5
ISTC Standard 10
 Response to therapy in patients with
pulmonary tuberculosis should be monitored
by follow-up sputum microscopy (two
specimens) at the time of completion of the
initial phase of treatment (two months)
 If the sputum smear is positive at completion
of the initial phase, sputum smears should
be examined again at 3 months and, if
positive, culture and drug susceptibility
testing should be performed
ISTC Standard 10 (2)
In patients with
extrapulmonary
tuberculosis and in
children, the response
to treatment is best
assessed clinically.
Required Monitoring
 New sputum smear-positive patients should
have sputum smear exams monthly
 Other clinical markers of treatment response
to monitor:
• Weight at initiation of treatment, then monthly
until weight is stable
• Review of TB symptoms present at time of
diagnosis and documentation when symptoms
resolve
 With the RIF-based regimen throughout,
WHO no longer recommends extending
initial phase if smear-positive at 2 months
Treatment of
Extrapulmonary
TB (EPTB) and
Special
Situations
Treatment: Extrapulmonary TB
 In general, EPTB is treated the same as
PTB except:
• Streptomycin replaces EMB when treating CNS
TB
• Corticosteroids may be useful in some forms of
EPTB
• Some experts recommend extending the duration
of therapy in patients with:
– CNS tuberculosis
– Bone/joint tuberculosis
 WHO no longer recommends option to omit
EMB during initial phase in HIV-negative
EPTB patients
Treatment: Extrapulmonary TB (2)
Treatment Duration and Use of Steroids
Site
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
Lymph node
Bone/Joint
CNS
ATS/CDC/IDSA 2003
New Sputum Smear-Negative PTB
 If also HIV-positive and/or severely ill:
• Obtain CXR and sputum TB culture
• Start antibiotic treatment for pneumonia (nonFQN) and if CXR findings suggest that TB is
likely (positive or negative TB smear) then
register as a new TB case and initiate TB
treatment
 If HIV-negative and/or mild/moderate illness:
• Obtain CXR and sputum TB culture
• If CXR findings suggest that TB is likely or TB
culture is positive then register as a new case
and initiate TB treatment
Treatment During Pregnancy
Risk to mother and fetus is far greater
from untreated TB than from the drugs
used to treat TB:






Increased risk of spontaneous abortion
Increase in perinatal mortality
Small for gestational age births
Increased maternal morbidity
Congenital TB
Increased risk of perinatal and early
postnatal transmission
Treatment During Pregnancy (2)
 Isoniazid (INH), rifampicin (RIF) and
ethambutol (EMB) are known to be safe
for administration during pregnancy
 Supplement with pyridoxine 25mg/day
 Streptomycin should be avoided
 Monitor for signs of hepatotoxicity during
pregnancy and immediate post-partum
Breastfeeding
 Most of the TB
medications are
secreted into
breast milk but
not in significant
concentrations
(usually <1-12%
of levels
measured in the
serum)
 Levels are not likely
to lead to toxicity in
the infant
 Levels will not be
sufficient to protect
the infant – infant
should receive IPT
 Supplement Mom
with B6 while
breastfeeding
TB Treatment and Liver Disease
 Use standard short-course regimen for
patients without clinical evidence of
chronic liver disease but history of:
• Hepatitis virus carriage
• Past history of acute hepatitis
• Current excessive alcohol consumption
 Hepatotoxic reactions are more common
in these patients and should therefore be
anticipated
TB Treatment and Liver Disease
 Use a liver sparing regimen for patients
with established chronic liver disease:
• Two hepatotoxic drugs
– 9HR+E (until or unless INH susceptibility
documented)
– 2HRSE/6HR
– 6-9RZE
• One hepatotoxic drug
– 2HES/10HE
• No hepatotoxic drugs
– 18-24SE+Fluoroquinolone
Hepatitis
 Hepatitis (asymptomatic elevation
AST/ALT occurs in 20% patients on 4
drugs)
• Drug induced hepatitis =  AST or ALT ≥3
times upper limits of normal in the presence
of symptoms OR  >5 times if asymptomatic
• INH, PZA and RIF can all cause
hepatotoxicity
– Hepatitis from INH is age related, from PZA is dose
related, and RIF is unpredictable and less common
TB Treatment and Hepatitis
 If  >3x normal with symptoms or > 5x
normal without symptoms:
• stop all anti-TB medications and evaluate
patient
• refer patient to doctor for clinical evaluation
• try to rule out other causes of acute liver
disease
• if severely ill, may start 3 non-hepatotoxic drugs
• after AST < 2 times upper limit of normal —
re-challenge drugs one-by-one starting with
drugs that are not hepatotoxic
The Renal Impaired TB Patient
 Patients with end stage renal disease
(ESRD) have increased risk for
progression to active TB disease
• Risk is 10 – 25 times greater for persons with
ESRD than in the general population
The Renal Impaired TB Patient (2)
 If CrCl <30ml/min., including hemodialysis
patients, administer anti-TB treatment
thrice weekly after dialysis at the following
doses:
• Isoniazid and rifampicin 10mg/kg
• PZA 25-mg/kg
• EMB 15-mg/kg
 Include supplemental pyridoxine 25-50mg
with the thrice weekly regimen to prevent
peripheral neuropathy
Summary
 Appropriate treatment and assessment of
adherence to treatment is an important public
health issue
 The use of internationally accepted first-line
treatment regimens is associated with a high
cure rate and a low risk of acquired drug
resistance
 Pulmonary and EPTB are generally treated with
the same regimens (Exception: extended
duration in meningeal/CNS and bone/joint
disease)
 Monitoring for both response to treatment and
for potential adverse events is essential
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
* Abbreviated versions
Summary: ISTC Standards Covered*
Standard 8: (continued)
 The doses of anti-tuberculosis drugs used
should conform to international
recommendations. Fixed-dose combinations
are highly recommended.
Standard 10: Response to therapy in patients
with pulmonary TB should be monitored by
follow-up sputum microscopy (2 specimens),
if positive, sputum smears should be
examined again at 3 months. If positive,
culture and DST should be performed.
* Abbreviated versions