Initial Treatment of Tuberculosis

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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

Effects of Treatment on the Incidence of Tuberculosis in Peru

220 200 180 160 140 120 100 1980 ISTC TB Training Modules 2009 DOTS 1990 case finding 1985 1990 PTB falling at 6%/yr 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

Emergence of INH resistant strain because of ineffective treatment (INH monotherapy ) Effective multi-drug therapy 0 2 4 6 8 10 12

Weeks

14 16 18 20 22 24 ISTC TB Training Modules 2009

Unintended Monotherapy and Resistance

0 5 7 9 Months of Rx INH RIF Smear EMB Culture Susceptibility INH RIF EMB

+ +

R* S* S*

+ +

R R S

+ +

R R S

+ +

R R R

* 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

Isoniazid Rifampicin Pyrazinamide Streptomycin Ethambutol

Early bactericidal activity ++++ ++ + ++ ++ - +++ Preventing drug resistance +++ +++ + ++ ++ Sterilizing activity ++ ++++ +++ ++ +

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

ISTC TB Training Modules 2009

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 recommended (FDCs) of two (INH and RIF), three (INH, RIF, and PZA), and four (INH, RIF, PZA, and EMB) drugs are highly

ISTC TB Training Modules 2009

Treatment Recommendations

New Patients (not previously treated) Initial Phase (2 months) Continuation Phase (4 months)

INH, RIF, PZA, EMB daily INH, RIF daily INH, RIF, PZA, EMB

1

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

Drug

INH

Adults: mg/kg (range) Daily

5 (4-6), max 300/d

3x Week

10 (8-12), max 900/d RIF PZA 10 (8-12), max 600/d 10 (8-12) max 600/ d 25 (20-30), max 2000/d 35 (30-40), max 3000/d EMB Streptomycin 15 (15-20), max 1600/d 30 (25-35), max 2400/d 15 (12-18) 15 (12-18)

ISTC TB Training Modules 2009

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 Pleural Pericarditis CNS Disseminated Genitourinary Abd/Peritoneal

Length of Rx (mos.) Corticosteroids

6 No 6-9 No 6 6 9-12 6 6 No Yes Yes No No 6 No

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.

2 of 2

ISTC TB Training Modules 2009

Monitoring: Timing of Sputum Specimens

Initial Phase Continuation Phase Isoniazid Rifampicin Pyrazinamide Ethambutol Months 0 1 2 3 4 5 6

Diagnostic End of intensive phase Assessment for failure Completion [*Obtain if smear-positive at month 2]

ISTC TB Training Modules 2009

Treatment Outcomes for Pulmonary TB

10% 1.2% 50% 64% 98% Dead Sputum negative Sputum positive 32% 20% 18%

No Chemotherapy Poor Chemotherapy Good Chemotherapy

0.8% Grzybowski S et al,

Bull Int Union Tuberc

1978; (53)2: 70-5

ISTC TB Training Modules 2009

Monitoring: Adverse Reactions

Adverse Reaction

Rash Gastrointestinal intolerance

Drugs

PZA, INH, RIF, EMB PZA, RIF 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.

Initial Treatment of Tuberculosis

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.

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 follow up 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

ISTC TB Training Modules 2009

Alternate Slides

ISTC TB Training Modules 2009

Purpose of ISTC

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

for Tuberculosis Care Patients’ Charter 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

ISTC TB Training Modules 2009

Questions

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 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 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