Initial Treatment of Tuberculosis Your name Institution/organization Meeting Date International Standards 7, 8, 10, 11, 17.

Initial Treatment of Tuberculosis

Your name Institution/organizationMeetingDate

International Standards 7, 8, 10, 11, 17

ISTC Training Modules 2008


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



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


Standards for Treatment


Initial Treatment of TuberculosisStandards 7 & 8


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.


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.


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

00

DOTS 1990

PTB falling at 6%/yr

case finding

Effects of Treatment on the Incidence of Tuberculosis in Peru


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)


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


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


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)


Activities of Antituberculosis Drugs

Highest ++++ High +++ Intermediate ++ Low +

DrugEarly

bactericidal activity

Preventing drug

resistance

Sterilizing activity

Isoniazid ++++ +++ ++

Rifampicin ++ +++ ++++

Pyrazinamide + + +++

Streptomycin ++ ++ ++

Ethambutol ++ - +++ ++ +


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)


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)


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.


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)


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)


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



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



Monitoring Treatment for TBand Public HealthReportingStandards 10, 11, & 17


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)


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)


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


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


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


Adverse Reactions: Rash

Severe skin rash from thioacetazone

Classic drug-related rash


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)


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


A written record of all medications given, bacteriologic response, and adverse reactions should be maintained for all patients

Standard 11: Monitoring Treatment


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.



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.



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.



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


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).




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.




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




Alternate Slides


Purpose of ISTC


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


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


Questions



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



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


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

Initial Treatment of Tuberculosis Your name Institution/organization Meeting Date International Standards 7, 8, 10, 11, 17.

Documents

treatment slide

tb treatment

initial phase of treatment

istc training modules

line treatment regimen

resistance slide

peru slide

incidence of tuberculosis