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Interim. Draft Module 6A - July 2008. Treatment of Tuberculosis: New Cases. Project Partners. Collaborative project. Funded by the United States Agency for International Development (USAID). Module Overview. Essential anti-TB drugs Standard Category I regimens (new cases)

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Treatment of tuberculosis new cases

Interim

Draft Module 6A - July 2008

Treatment of Tuberculosis:

New Cases


Project partners

Project Partners

  • Collaborative project

Funded by the United States Agency for International Development (USAID)


Module overview

Module Overview

  • Essential anti-TB drugs

  • Standard Category I regimens (new cases)

  • Management of smear-negative suspect case

  • Treatment of TB in special populations

    • Pregnancy

    • Liver disorders

    • Renal disease

International

Standards

7, 8 & 10


Learning objectives

Learning Objectives

At the end of this presentation, participants will be able to:

  • Describe the drug regimens used in the initial treatment phase of both new pulmonary and extrapulmonary tuberculosis (EPTB)

  • Describe next step if sputum remains smear- positive at the end of 2nd month of Category I treatment

  • Identify treatment and management approaches in TB patients with co-morbid conditions


Lines and regimens defined

Lines and Regimens Defined

  • First-Line Therapy

    • Category I regimen for new patients

    • Category II regimen for re-treatment patients

      • Suspicion of resistance to one anti-TB drug

  • Second-Line Therapy

    • For patients with resistant TB to more than one drug

      • Poly-drug and multi-drug resistance


First line anti tuberculosis drugs

First Line Anti-Tuberculosis Drugs

  • Isoniazid (INH, H)

  • Rifampicin (RIF, R)

  • Pyrazinamide (PZA, Z)

  • Ethambutol (EMB, E)

  • Streptomycin (SM, S)

Plus Pyridoxine


Treatment of tuberculosis new cases

Standards for Treatment


Standard 7 public health effects of treatment

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

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 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

Effect of Treatment on Public Health (2)

Effects of Treatment on the Incidence of Tuberculosis in Peru

220

DOTS 1990

200

case finding

180

Pulmonary TB cases/100,000

160

140

PTB falling at 6%/yr

120

100

2000

1980

1985

1990

1995


Standard 8 initial phase of treatment

Standard 8: Initial Phase of Treatment

All patients (including those with HIV infection) who have not been treated previouslyshould 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.


Modern tb chemotherapy

Modern TB Chemotherapy

  • INH – kills rapidly growing organisms and dormant organisms

  • PZA – kills TB bacilli inside the macrophage and cavities

  • RIF and PZA kill slowly growing organisms

    • sterilizing activity

  • INH, RIF and EMB protect each other from development of resistance

Coombs D et al. Ann Intern Med 1990;112:397-406


Standard 8 initial phase of treatment1

Standard 8: Initial Phase of Treatment

  • Ethambutol may be omitted in the initial phase of treatment for adults and children who:

    • have negative sputum smears

    • do not have extensive PTB or severe forms of EPTB disease, and

    • are known to be HIV negative.


Adequate tb treatment requires

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


Effect of treatment on bacillary population

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)

Log cfu

Effective multi-drug therapy

024681012141618202224

Weeks


Unintended monotherapy and resistance

Unintended Monotherapy and Resistance

* Results not known to clinician


Initial phase of treatment

Initial Phase of Treatment

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

Activities of Antituberculosis Drugs

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


Standard 8 continuation phase of treatment

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 HIVinfection.


Treatment recommendations

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.


Standard 8 drug formulations and doses

Standard 8: Drug Formulations and Doses

  • The doses of antituberculosis 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, especially when medication ingestion cannot be observed.


Adult daily dose of fdc tabs

Adult Daily Dose of FDC Tabs


12 15 pills per day to only 4 5 fdcs

12-15 Pills Per Day to Only 4-5 FDCs

Image source: Jad Davenport

Image source: Pierre Virot


Dose recommendations

Dose Recommendations

mg/kg (range)

*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)


Treatment outcomes for pulmonary tb

Treatment Outcomes for Pulmonary TB

1.2%

50%

10%

98%

64%

Dead

Sputum negative

32%

Sputum positive

20%

18%

0.8%

No

Chemotherapy

Poor

Chemotherapy

Good

Chemotherapy

Grzybowski S et al, Bull Int Union Tuberc1978; (53)2: 70-5


Standard 10

Standard 10

All patients should be monitored for response to therapy, best judged in patients with pulmonary TB by follow-up sputum microscopy (2 specimens):

  • at completion of the initial phase of treatment (2 months)

  • 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.


Required monitoring category i

Required Monitoring – Category I

  • New sputum smear-positive patients should have sputum smear exam:

    • At the end of initial phase (month 2)

    • During continuation phase (month 5)

    • At the end of treatment

       If sputum smear remains positive at the end of month 2:

    • Extend initial phase for additional month after which continuation phase may be initiated

    • Consider collection of sputum after end of 3rd month to evaluate for smear conversion


Case study 1

Case study 1


Case 1

Case 1

  • 29-year-old man

  • Presents with 2-3 years of cough, 2-3 months of night sweats, and 15 lb weight loss

  • HIV negative

  • Past Medical History:

    • TST + in 1991

      Question: What would you do now?


Tb diagnostic algorithm hiv negative or low prevalence area

TB Diagnostic Algorithm:HIV Negative or Low Prevalence Area

All Pulmonary TB Suspects

Sputum AFB Microscopy; Assess for HIV


Case 1 2

Case 1 (2)

  • Three spontaneous sputum specimens were smear negative for AFB

  • Question:How would you manage this patient?


Tb diagnostic algorithm hiv negative or low prevalence area1

TB Diagnostic Algorithm:HIV Negative or Low Prevalence Area

All Pulmonary TB Suspects

Sputum AFB Microscopy

Assess for HIV

2 or 3 smears +

2 or 3 smears -

Only 1 smear +

Rx: Non-anti TB antibiotics

Repeat AFB

  • No improvement after 1 week

    Question:What would you do now?

Yes TB


Case 1 3

Case 1 (3)

  • A repeat sputum specimen was sent using sputum induction

  • Chest X-ray was also obtained

  • The sputum specimen was smear-positive

  • Question:What now?


Case 1 4

Case 1 (4)

  • The patient is started on INH, rifampicin, ethambutol, and pyrazinamide

  • The sputum culture result returns positive for M. tuberculosis complex

  • A sputum specimen is obtained after 2 months of treatment and is smear-positive

    Question:What do we do now?


Case 1 5

Case 1 (5)

  • Continue initial phase for 1 more month

  • Collect sputum prior to completion of month 3 then switch to continuation phase


Treatment of tuberculosis new cases

Treatment of Extrapulmonary TB (EPTB)


Treatment of eptb

Treatment of EPTB

  • In general, EPTB is treated the same as pulmonary tuberculosis

    • Streptomycin replaces EMB when treating CNS TB

  • Some experts recommend extending the duration of therapy in patients with:

    • Meningeal tuberculosis

    • Bone/joint tuberculosis

  • Corticosteroids may be useful in some forms of extrapulmonary tuberculosis


Treatment of eptb 2

Treatment of EPTB (2)

Treatment Duration and Use of Steroids


Treatment of tuberculosis new cases

Treatment Special

Situations


Treatment during pregnancy

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 post-natal transmission


Treatment during pregnancy 2

Treatment During Pregnancy (2)

  • Isoniazid (INH), rifampicin and ethambutol are known to be safe for administration during pregnancy

  • There is insufficient data on the teratogenic effect of PZA

  • Supplement with pyridoxine 25mg/day

  • Streptomycin should be avoided

  • Monitor for signs of hepatotoxicity during pregnancy and immediate post-partem


Breastfeeding

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

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

    • Acute hepatitis

    • Excessive alcohol consumption

  • Use a liver-sparing regimen for patients with established chronic liver disease

    • 2SHRE/6HR or 2SHE/10 HE


Hepatitis

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

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 — rechallenge drugs one-by-one starting with drugs that are not hepatotoxic


The renal impaired tb patient

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

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 25-35mg/kg

    • EMB 15-25mg/kg

  • Include supplemental pyridoxine 25-50mg with the thrice weekly regimen to prevent peripheral neuropathy


Case study 2

Case study 2


Case 2 part 1

Case 2, Part 1

  • A 32-year-old man diagnosed with sputum smear-positive PTB is ready to begin TB treatment under your care. He has never been diagnosed or treated for TB before

  • He reports 4 weeks of a productive cough with fever, sweats and weight loss. He currently weighs 53 kg

  • Two sputum smears are positive on direct microscopy

    Q1:How do you classify this patient?


Case 2 part 1 2

Case 2, Part 1 (2)

Q2:What medications do you start with for the initial phase?

Q3:How many pills per day does he take with FDCs according to his weight?

Q4: Approximately how many pills per day does he take with traditional individual tablets?


Case 2 answer q2

Case 2, Answer Q2

  • What medications do you start for the initial phase?

    • Isoniazid (INH, H)

    • Rifampicin (RIF, R)

    • Pyrazinamide (PZA, Z)

    • Ethambutol (EMB, E)


Case 2 answer q3

Case 2, Answer Q3


Case 2 answer q4

Case 2, Answer Q4

Traditional = 9 or more pills daily (+ pyridoxine)


Case 2 part 1 3

Case 2, Part 1 (3)

Q5: What are the criteria for him to complete the initial phase and change to the continuation phase of therapy?


Case 2 answer q5

Case 2, Answer Q5

  • Sputum smear-negative at month 2

  • Adherent with therapy

  • Clinical improvement on initial complaints

    • Fever

    • Cough

    • Weight gains


Case 2 part 2

Case 2, Part 2

  • The patient has successfully completed the initial 2 months of treatment and had 2 negative sputum smears at week 8

  • He is ready to start the continuation phase

  • He now weighs 55 kg


Case 2 part 2 2

Case 2, Part 2 (2)

Q6:What medications and dosages does the patient take in the continuation phase?

  • How many pills per day does he take with FDCs (Fixed Dose Combination pills)?

  • How many pills per day does he take with traditional individual tablets?


Case 2 answer q6

Case 2, Answer Q6

  • Isoniazid and rifampicin

  • FDCs = 4 pills daily (plus pyridoxine)

    • He gained weight and now has an increased dose


Case 2 answer q6 2

Case 2, Answer Q6 (2)

Traditional = 3 pills daily (+ pyridoxine)


Summary

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 and bone/joint disease.)

  • Monitoring for both response to treatment and for potential adverse events is essential


Summary istc standards covered

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


Summary istc standards covered1

Summary: ISTC Standards Covered*

Standard 8:(continued)

  • EMB may be omitted in the initial phase for non-HIV smear-negative cases without severe disease.

  • The doses of anti-tuberculosis 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 tuberculosis by follow-up sputum smear microscopy (at 2 and 5 months and end of treatment).

* Abbreviated versions


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