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Management of Tuberculosis

Dr. Uttam Kumar Dasgupta

MBBS (Cal) MD (Cal, Chest)

Introduction

Commonest cause of death due to a single inf. agent.

1882 – Discovery of TB bacilli.

1944 – First Anti – TB drug, Streptomycin

discovered.

1963 – Efficacy of domiciliary treatment established.

1993 – WHO declares TB a global emergency.

Statistics Total no. of pts. infected with TB = 2 bi. (0.3 bi.) Total no. of active TB pts. = 20 mi. (12 mi.) Total no. of pts. dying of TB / year = 3 mi. (5 lakhs) Total no. of NSSP pts. / year = 8 mi. (1.5 mi.)

Principle of standard short course therapy

Mycobacterial population divided into 4 groups

(Mitchison’s Theory)1. Grp. A – EC Bacilli in liq. caseous material (H, R)

2. Grp. B – Slow growing in macrophage (Z)

3. Grp. C – Small no. of EC Bacilli in solid caseations exhibiting brief spurts of metabolism

( R)

4. Grp. D – Dormant bacilli (nil)

Aims of treatment

1. To cure pts. with least interference to their lives.

2. To prevent death from active TB or its effects.

3. To avoid relapse / recurrence.

4. To prevent development of drug resistance.

5. To decrease transmission to others.

Protocol of treatment with dose

a. 2 RHEZ / 4 RH

b. 2 SRHEZ / 1 RHEZ / 5 RH

c. 2RHZ / 4 RH

R = 10 mg / kg H = 5 mg / kg

E = 25 mg / kg 15 mg / kg Z = 25 – 35 mg / kg

S = 15 mg / kg

Side effect profile

Rifampicin Common

GI toxicity (nausea, anorexia, abd. pain). Uncommon

Cut. reactions (flushing, itchiness, rash). Hepatitis. Reduced effectiveness of oral contraceptives. Pseudomembranous colitis, gynaecomastia. ARF, thrombocytopenia, flu syndrome, shock, haemolytic

anaemia.

Contd…

INH

1. Peripheral neuropathy.

2. Hepatitis.

3. Rarely, giddiness, convulsion, optic neuritis, psychosis.

Contd…

Ethambutol

1. Progressive loss of vision due to retrobulbar neuritis.

2. Rarely peripheral neuropathy, joint pain, skin rash.

Contd…

Pyrazinamide

1. Hepatitis (Bilirubin, SGPT x3 – stop)

2. Arthralgia – mild but common. Gout.

3. Rarely – GI symptoms, rash, sideroblastic anemia.

Contd…

Streptomycin

1. Auditory & vestibular nerve damage.

2. Renal damage.

3. Rarely skin rash & anaphylaxis.

Adverse effects with management

Adverse effect Drugs responsible Management

Seizures Cs

H, FQ

1. Suspend Tt.

2. Anticonvulsant

3. Pyridoxine

Peripheral neuropathy

Cs, H

AG, FQ, Eto, Pto

1. Pyridoxine

2. Change to Cm

3. Amitryptiline

Contd…

Adverse effects Drugs responsible Management

Psychotic reactions Cs, H

FQ, Eto, Pto

1. Stop drugs – 1 to 4 weeks

2. Antipsychotics

3. Reduced dosage / stop

Depression Cs

FQ, H, Eto, Pto

1. Antipsychotics

Contd…

Adverse effects Drugs responsible Management

Hearing loss AG

Clr

Change to Cm

Hypothyroidsm PAS, Eto, Pto Thyroxine

Gastritis Eto, Pto, PAS

R

PPI / Antiemetics

Contd…

Adverse effects Drugs responsible

Management

Renal toxicity AG Use Cm

Give bi / tri wkly.

Electrolyte disturbances (K, Mg )

Cm

AG

Replace

Optic neuritis E Stop

Arthralgia Z NSAID

Dose / Stop

Revised National Tuberculosis Control Programme (RNTCP)

1963 – Launching of NTP.

1993 – NTP declared a failure.

1993 – 1996 – Pilot Programme

1997 – Formal Launching Of RNTCP

2007 – 632 districts – 1114 million people covered

Setup

S T S S T LS T B H V L T

T U (M O T C )

D T C (D T O )

S ta te H e a lth D e p a rtm e nt, T B S e c tio n (S T O )

M in is try O f H e a lth , C e n tra l T B S e c tion (D D C en tra l T B )

Categorization of TB pts. for registration on diagnosis

1. New – Never ATD / < 1 month2. Relapse – Declared Cured / TC, again Sp. +ve3. Failure – Failed with previous treatment now Sp.

+ve, also initially Sp. –ve now +ve4. TAD – ATD > 1 month anywhere, then

defaulted, now Sp. +ve 5. Chronic – Sp. +ve after completing rett. Regime.6. Others – Not in the above categories

Standardized treatment protocol

1. Cat I – [2 (RHEZ)3 / 4 (RH)3]

2. Cat II – [2 (SRHEZ)3 / 1 (RHEZ)3 / 5 (RHE)3]

3. Cat III – [2 (RHZ)3 / 4 (RH)3]

4. Cat IV - Individualised

DOTS

1. Aim

A. Cure at least 85% of NSSP pts.

B. Detect 70% of NSSP pts.

Contd…

2. Components:A. Political & Administrative commitment.

B. Good quality diagnosis.

C. Good quality drugs.

D. Short course chemotherapy under direct supervision.

E. Systemic monitoring & accountability.

Sputum Categorization

If slide has Results Grading No. of fields

>10

AFB / OIFPOS 3+ 20

1 – 10

AFB / OIFPOS 2+ 50

10 – 99

AFB / 100 OIFPOS 1+ 100

1 – 9

AFB / 100 OIFScanty No / 200 200

Nil NEG - 100

Outcome

1. Cured

2. TC

3. Died

4. Failure

5. Defaulter

6. Transferred Out

Debates

1. Cat II

2. Cat III

3. Is it only Cat I & Cat IV

TB & Diabetes Mellitus

Fact Sheet:1. TB is 2 to 7 times more common in diabetics.2. 30% of DM have TB which is the commonest

complicating illness (5.9%).3. Management of TB in DM is no different than in

non DM patients.4. Complication of TB in DM as in non – DM but

MDR TB & mortality is more.

Points to remember in TB + DM

1. Prompt initiation of Pharmacotherapy.

2. Adequate diet prescription.

3. Possible failure of sulphonylureas with Rifampicin co-administration.

4. Augmentation of hepatotoxicity of ATT (esp. with Thiazolidindiones but less with biguanides).

5. Insulin is always a good option.

TB & HIV (The Deadly Duo)

Estimates in 2000:1. Globally no. of people with TB + HIV = 11.4 mi.

(2 mi.).2. 8.3 million new cases of TB (3.7 mi. is Sp. +ve).

Most live in SSA, WP & S.E. Asia where 34 mi. (85%) of estimated 40 mi. people with HIV also live.

3. 9% of 8.3 mi. new TB cases were due to HIV.

Contd…

4. 12% of 1.84 mi. deaths due to TB were due to HIV.

5. 11 % of all adult AIDS deaths were due to TB.

6. HIV infected pts. has a five time risk of developing TB than non – HIV pts.

7. TB & HIV interaction is bi-directional.

Issues in HAART – ATD

1. When to start HAART‘Virologic, immunologic & clinical responses to HAART of HIV – 1 TB patients treated concurrently with antitubercular therapy & HAART was similar to those of non TB patients’

Hung C. C. et. al AIDS 2003; 17: 2615 - 2622

Contd…

Proposal:1. CD 4 < 100 / µL or in advanced AIDS –

concurrent HAART as early as possible.2. CD 4 100 – 200 / µL – Start HAART 4 – 8 weeks after

ATD initiation.3. CD 4 > 200 / µL – initiation of HAART based on

a) Further AIDS defining condition.b) CD 4 counts & rate of decline.c) Drug toxicity & interactions.

Contd…

2. Optimal duration of therapy6 months but prolonged to 9 months in delayed

clinical (sym.) / microbiologic response (culture +ve at 2 months)

Treatment failure & relapse is related to:1. Advanced immuno deficiency.2. Acquired Rifamycin resistance (common in intt. ATD).

So daily ATD.

Overlapping adverse event profileAdverse Effects Possible Causes

ATT HIV Medication other than ARV

ARV drugs IRS

Skin Rash ZRH, RBT Folliculitis CTMX NVP, EVP, ABC

-

Nausea Vomiting

- Do - Other opp infections

- Do - ZDV, r, IDV +

Pancreatitis or Intra – abd. Adenitis

Ocular Effects E, RBT - - Ddl -

Hepatitis ZRH, RBT - CTMX NVP, all PI + in pts. With chr. Viral hepatitis

Peripheral neuropathy

H & E - - d4T, ddl & ddc -

Pancytopenia RBT, R Bone marrow dysplasia

CTMX

Valganciclovir

ZDV -

Drug – drug interaction

1. R reduces PI & NNRTI by increasing CYP3A which metabolises PI & NNRTI. So R never with PI & NNRTI.

2. RBT also increases CYP3A but less so, so can be used with PI.

3. PI & NNRTI alters R level by increasing or decreasing CYP3A. PI can increase levels of RBT & it’s metabolites.

4. So when using NNRTI with RBT, increase dose of RBT & while using PI reduce dose of RBT

5. H inhibits CYP3A thus increasing levels of PI & NNRTI.

IRS

Definition: Restoration of immunity by ARV therapy leading to increased inflammation in TB resulting in significant worsening of S / S (Paradoxical reactions)

Onset – Within days of ARV therapy or months after ARV initiation.

Symptoms: Fever, adenopathy, increased pulmonary infiltrates, serositis. Less common features are worsening of meningitis, increased CNS tuberculomas, soft tissue & bone abscess & diffuse skin lesions.

Diagnosis: Difficult.

BCG & HIV

Role of BCG in preventing TB in HIV +ve pts. is not known.

Conversion to +ve MT after BCG is less frequent but significant

BCG is safe in HIV

WHO recommendation:

In high prevalence – BCG except in children with S / S of HIV / AIDS

In low prevalence – no BCG

MDR TB

Definition: Resistance to H + R + / - other drugs.

Causes:

1. Inadequate & inappropiate previous treatment with ATD.

2. Patients with extensive cavitary disease.

3. Addition syndrome

4. Ineffectual & irrational drug schedule.

5. Contact with a known MDR patient.

Basic principles of Tt. Of MDR TB

1. Tt. should be in a specialised centre with C / S facilities.

2. Careful analysis of past drug history.3. Never to add a single to a failing regimen.4. Never combine two drugs of the same group or a

drug with known cross resistance. (eg. Thioamides / TZN, Km or Am / Sm, R / RBT)

5. Intt. therapy is not effective in MDR TB

Contd…6. Regimen should contain >= 4 drugs with certain (or nearly so)

effectiveness.7. No drug should be kept in reserve & the most powerful

bactericidal drugs should be used initially in maximum combination.

8. Tt. should be under direct observation throughout or at least till sputum conversion.

9. Surgical treatment may be an adjunct.10. Injectable drugs for a min. of 6 months. Total duration 18 – 24

months after smear conversion or 12 months after culture becomes negative. Z throughout.

Drugs used in MDR TB

1. Group 1 – 1st line oral ATD2. Group 2 – Injectable ATD (Cm in cross resistance)3. Group 3 – Fluoroquinolones (Mx = Gx > Lx > Ox > Cx)4. Group 4 - Oral bacteriostatic drug

a) Eto / Pto – start with small dose.b) PAS – Combine if imperative.c) Csd) Cs + (Eto / Pto or PAS)

5. Group 5 – Cfz, Amx / Clv, Clr, LzdRegimen

Group 2 + 3 + two to three Group 4 + / - Group 5 + Z

Doses

Drugs < 33 Kg. 33–50 Kg. 51-70 Kg. > 70 Kg.

AG 15–20m/k - - -

Ofx 15–20m/k 800 mg. 800 mg. 800-1000 mg.

Lfx 7.5–10m/k 750 mg. 750 mg. 750-1000 mg.

Mfx / Gfx 7.5–10m/k 400 mg. 400 mg. 400 mg.

Eto / Pto 15-20m/K 500 mg. 750 mg. 750-1000 mg.

Cs 15-20m/K 500 mg. 750 mg. 750-1000 mg.

PAS 150 m/K 8 g. 10 g. 10 – 12 g.

Case 1

42 year old male, in whom Cat I / Cat II has failed. DST done. Non diabetic. HIV –ve.

Resistant to – S R HSensitive to – E Km Ofx Eto Cs PASOn RHE since DST has been sent. Sensitivity to Z

was not possible.

What would you give?

KM

Ofx

Eto

Cs

+ / - PAS

Case 2

36 year old female in whom Cat I / Cat II has failed. Non diabetic. HIV –ve. DST sent for.

Resistant to – S R H E Z Km

Sensitive to – Cm Ofx Pto Cs PAS

Not on any drugs since DST was sent.

What would you give?

Option 1 – Cm Ofx Pto Cs

Option 2 – Cm Ofx Pto Cs + / - PAS

Case 3

35 year old male on Km Ofx Eto Z remains sputum +ve after eight months of treatment. DST done four months ago.

Resistant to – R H E Z Eto

Sensitive to – Km Cm Ofx Cs PAS

What would you give?

Cm

Ofx

Cs

PAS

one of Group 5 drugs

Management of contacts of MDR TB patients

1. Identify & Evaluate2. If contact Sp. +ve / CXR +ve – DST3. If DST NA – Protocol of the index case.4. If contact Sp. –ve (but symptomatic) & CXR –ve

Antibiotics

If symptoms persist

FOB / CT5. If all NA – rpt. work-up monthly if patients remains symptomatic.6. Chemoprophylaxis – 2nd line not recommended – close FU.

XDR TB (Extensively drug resistant TB)

Defintion: MDR TB + resistance to any FQ + resistance to at least one of three injectables ( Cm Am Km.) 1 to 2 % of MDR TB in India are XDR TB. This figure is 4% in the US, 19% in Latavia.

Causes:1. Incorrect drug prescription by doctors.2. Poor quality drugs.3. Erratic supply of drugs.4. Patient non – adherence.

Actions to prevent XDR TB

1. Strengthen basic TB care to prevent emergence of drug resistance.

2. Ensure prompt diag. & Tt. of DR TB to cure existing cases & prevent further transmission.

3. Increase HIV TB control programme collaboration.

4. Increase investment in lab. infrastrutures to enable better detection & management.

DOTS PLUS & Green Light Committee

DOTS PLUS is a comprehensive management strategy that includes five tenets of DOTS strategy. It considers specific issues (eg. use of reserve drugs) that needs to be addressed in high MDR TB areas.

Green Light Committee is a working group that has made arrangement with the pharmaceutical industry to provide concessionally - priced 2nd line anti TB drugs to DOTS PLUS pilot projects for management of MDR TB.

TB & Pregnancy1. Avoid.2. No adverse effect of pregnancy on TB & vice – versa.3. Effect of maternal TB on baby. Examine placenta.4. Treatment is the same (avoid Sm Eto Pto).5. Management of new born

a) Don’t separate (unless mother is desperately ill)b) If mother Sp. –ve give BCGc) If mother is / was Sp. +ve during pregnancy / delivery

i. If baby ill & TB suspected – full ATDii. If baby well - give INH 5 mg. / Kg. X2 months. Then MT done. If MT –ve –

stop INH. Give BCG. If MT +ve – give INH upto 6 months.

6. If mother MDR – start Tt. in 2nd trimester with 3 – 4 oral drugs (except Am, Eto, Pto)

Management of latent TB – Indications of Tt.

5 mm. induration 10 mm. induration 15 mm. induration

HIV +ve Immigration No risk persons

Recent contact Residents & employees of high risk setup.

Prior TB (fiibrosis) Lab personnel

Chr. immunosupression

Silicosis / DN / malignancy

Treatment of latent TB

1. HIV –ve – INH 9 months2. HIV +ve

a) MT +ve – INH 9 months.b) MT –ve – no INH

3. Shorter alternativesa) RZ x2 months – not givenb) RH x3 months – not givenc) R x4months – exclude active TB 1st

Toxicity with Tt. of latent TB

1. HIV -ve – Low risk. Hepatitis (fatal), PN (use B6)

2. HIV +ve – Toxicity > that of HIV –ve pts.

Problems with treatment of latent TB1. Low rate of Tt. inititation.2. Low Tt. completion rates.3. Monitoring for toxicity is a must.4. Logistic difficulties.

Future protocol1. RPT + INH x3 months2. Mx

Special situations1. Pregnant / breast feeding females – INH 2. Children – INH3. Contacts with MDR – Z + E / Z + FQ x6 – 12 months

Newer drugs in TB

Why is it required?

1. To improve current Tt. Of active TB byi. Shortening duration of treatment

ii. Providing more widely spaced intt. therapy.

2. To improve MDR TB Tt.

3. To provide more effective Tt. of latent TB.

The Drugs

1. Rifabutinea) First used in MAC prophylaxis.

b) Now, used as a substitute for R & for patients who can’t be given R for drug drug interaction.

c) Given twice weekly, it increases acquired drug resistance.

2. Rifalazina) Acts by reducing enzyme induction.

b) Reduces drug drug interaction

c) Flu like syndrome

3. Rifapentinea) It is not indicated in advanced TB & HIV infection

(acquired Rifamycin resistance)

b) It’s chief indication is LTBI where it is combined with H.

c) Dose is 900 mg. / day.

4. Moxifloxacina) It’s bactericidal activity is better than R but = H

Contd…

5. Diarylquinoline (R 207910)a) Effective against drug sensitive bacilli & strains resistant to

SRHEZFQ.b) It is effective against other myco bacteria. It may be combined

with any standard ATD (RHZ).c) It’s ability to shorten duration is under trial.

6. Pyrrole (LL 3858) – It’s a good steriliser.7. Dihydroimidazo – oxazoles (OPC – 67683)

a) No cross resistance or antagonistic action against other ATD.b) Better than the first line drugs.

Contd…

8. Nitroimidazopyrans (PA – 824)a) Effective against sensitive & resistant TB.

b) It is highly selective.

c) Active against non replicating bacilli (cf ‘H’).

d) Active against MDR TB.

e) Does not demonstrate mutagenicity.

f) Min. effective dose is 12.5 mg. / day.

g) It is not genotoxic.

9. SQ 109 – Active against MDR TB

Contd…

10. Oxazolidinonesa) It is very active against MDR TB

b) May rarely cause peripheral & optic neuropathy.

Where youth grows pale, and spectre-thin, and dies;         Where but to think is to be full of sorrow                 And leaden-eyed despairs,     Where Beauty cannot keep her lustrous eyes,         Or new Love pine at them beyond to-morrow.

- John Keats (Ode To A Nightingale)

Thank You!