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Initial Treatment of Tuberculosis
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International Standards 7, 8, 10, 11, 17
ISTC Training Modules 2008
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 TuberculosisStandards 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
100
120
140
160
180
200
220
1980 1985 1990 1995 2000
Pu
lmo
nar
y T
B c
as
es/1
00,0
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DOTS 1990
PTB falling at 6%/yr
case finding
Effects of Treatment on the Incidence of Tuberculosis in Peru
ISTC Training Modules 2008
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, rifampicin, pyrazinamide and ethambutol.
Standard 8: Initial Phase of Treatment(1 of 4)
ISTC Training Modules 2008
Mixed population (susceptible and resistant)
INH resistant bacilli
Emergence of INH resistant strain because of ineffective treatment (INH monotherapy)
Effective multi-drug therapy
Effect of Treatment on Bacillary Population
Weeks
Log
cfu
0 2 4 6 8 10 12 14 16 18 20 22 24
ISTC Training Modules 2008
Months of Rx 0 5 7 9
INH
RIF
EMB
Smear + + + +
Culture + + + +
Susceptibility
INH R* R R R
RIF S* R R R
EMB S* S S R
* Results not known to clinician
Unintended Monotherapy and Resistance
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
Highest ++++ High +++ Intermediate ++ Low +
DrugEarly
bactericidal activity
Preventing drug
resistance
Sterilizing activity
Isoniazid ++++ +++ ++
Rifampicin ++ +++ ++++
Pyrazinamide + + +++
Streptomycin ++ ++ ++
Ethambutol ++ - +++ ++ +
ISTC Training Modules 2008
Standard 8: Continuation Phase of Treatment
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.
(2 of 4)
ISTC Training Modules 2008
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.
Standard 8: Continuation Phase of Treatment(3 of 4)
ISTC Training Modules 2008
Treatment Recommendations
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.
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.
Optional3 INH, RIF, PZA, EMB daily INH, EMB daily, 6 mos.
ISTC Training Modules 2008
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.
Standard 8: Drug Formulations and Doses(4 of 4)
ISTC Training Modules 2008
Dose Recommendations
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)
EMBchildren: 20 (15-25)*adults: 15 (15-20)*
30 (25-35)
Streptomycin 15 (12-18) 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)
mg/kg (range)
ISTC Training Modules 2008
Treatment of Extrapulmonary TB
ISTC Training Modules 2008
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
Treatment of Extrapulmonary TB
ISTC Training Modules 2008
Treatment Duration and Use of Steroids
Site Length of Rx (mos.) Corticosteroids
Lymph node 6 No
Bone/Joint 6-9 No
Pleural 6 No
Pericarditis 6 Yes
CNS 9-12 Yes
Disseminated 6 No
Genitourinary 6 No
Abd/Peritoneal 6 No
Treatment of Extrapulmonary TB
ISTC Training Modules 2008
Monitoring Treatment for TBand Public HealthReportingStandards 10, 11, & 17
ISTC Training Modules 2008
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.
Standard 10: Monitoring Treatment(1 of 2)
ISTC Training Modules 2008
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
Standard 10: Monitoring Treatment(2 of 2)
ISTC Training Modules 2008
Isoniazid
Rifampicin
Pyrazinamide
Ethambutol
0 1 2 3 4 5 6months
Initial Phase Continuation Phase
Diagnostic
End of intensive phase
Assessment for failure
Completion
Monitoring: Timing of Sputum Specimens
ISTC Training Modules 2008
Treatment Outcomes for Pulmonary TB
98%64%
32%
20%18%
50%
10%
Dead
Sputum negative
Sputum positive
No Chemotherapy
PoorChemotherapy
Good Chemotherapy
0.8%
1.2%
Grzybowski S et al, Bull Int Union Tuberc 1978; (53)2: 70-5
ISTC Training Modules 2008
Monitoring: Adverse Reactions
• 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
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
ISTC Training Modules 2008
Adverse Reactions: Rash
Severe skin rash from thioacetazone
Classic drug-related rash
ISTC Training Modules 2008
Drug-induced HepatotoxicityHepatotoxic 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
A written record of all medications given, bacteriologic response, and adverse reactions should be maintained for all patients
Standard 11: Monitoring Treatment
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
ISTC Training Modules 2008
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.
Initial Treatment of Tuberculosis
ISTC Training Modules 2008
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.
Initial Treatment of Tuberculosis
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
Standard 8: (continued)• EMB may be omitted in the initial phase for non-
HIV 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).
Summary: ISTC Standards Covered*
* Abbreviated versions
ISTC Training Modules 2008
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
Summary: ISTC Standards Covered*
ISTC Training Modules 2008
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
Summary: ISTC Standards Covered*
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
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: Key Points
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 directly-observed 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 Tuberculosis3. 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
Recommended