TUBERCULOSIS

Infectious disease caused by Mycobacterium tuberculosis Rod 4mm in length

TUBERCULOSIS

Robert Koch (1843 1910) Declared the discovery of Mycobacterium tuberculosis on 24th March, 1882

TUBERCULOSIS

Typical Mycobacteria:

Mycobacterium tuberculosis

Mycobacterium

bovis

TUBERCULOSIS

Atypical Mycobacteria:

Mycobacterium avium Mycobacterium intracellulare Mycobacterium scrofulaceum

Together known as Mycobacterium Avium Complex (MAC)

TUBERCULOSIS

Atypical Mycobacteria:

Mycobacterium kanasaii

Mycobacterium xenopi
Mycobacterium malmonese

TUBERCULOSIS

Characteristics of tubercle bacilli:

Acid Fast Bacilli(AFB) Multiplies slowly Naturally reistant to common antibiotics Cell wall contains mycolic acid Can remain dormant for long period Forms granuloma in infected tissue
(Tiny lesion, about 1mm in diameter composed of predominantly epithelioid cells and rimmed at the periphery by lymphoid cells)

TUBERCULOSIS

Characteristics of tubercle bacilli:

Acquire resistance to the effective drug if given a chance Persists in macrophages & within caseous lesion, which are the main source of relapse

TUBERCULOSIS

Modes of transmission:

Inhalation Intake of infected milk Direct contact with certain articles used by the patients

TUBERCULOSIS

Sterilization of sputum:

Direct sunlight kills bacilli in 5 minutes Heat Distroyed in 20 minutes at 60 C and in 5 minutes at 70C Sodium Hypochlorite (1%) kills rapidly
Resists 5%phenol for several hours

TUBERCULOSIS

Prevention:

BCG (Bacillus Calmette Guerin) Vaccine consisting of live bacilli without virulence. Originally developed from bovine strain grown many years in laboratory 80% protection against TB for 15 Yrs Protection for child esp. against miliary tuberculosis and tuberculous meningitis
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TUBERCULOSIS

Symptoms: IN PTB
Cough

for more than 3 weeks

Coughing

blood

Pain

in the chest >3 weeks loss

Weight

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TUBERCULOSIS

Diagnosis:

Sputum Test
X-ray chest Tuberculin (Mantoux) skin test Injecting PPD intradermally. Not very reliable Culture

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The Course of Tuberculosis

Primary complex Progressive Primary tuberculosis Spread to pleura Acute cavitaion of focus Haematogenous spread

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Infection & patient defences

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Complications of primary complex

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Physiologic population of Mycobacterium

Rapidly multiplying organisms or extracellular organisms or active organisms Intermittently multiplying organisms or Intercaseous organisms or semidormant organisms Slowly multiplying organisms or intracellular organisms Dormant organisms
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Types of tuberculosis
Pulmonary TB Miliary TB
Primary Complex Or Gohns Complex

Progressive Primary TB

Extrapulmonary TB

Pleural effusion Pneumonia Bronchopneumonia

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First Line anti-TB drugs

Isoniazid (INH) Rifampicin Streptomycin Pyrazinamide Ethambutol Thiacetazone H R S Z E T
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Second line anti-TB drugs

Cycloserine PAS Ethionamide Prothionamide Sparfloxacin Ofloxacin Ciprofloxacin Kanamycin Amikacin Capreomycin Viomycin

Etc.
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Isoniazid (INH)
Administration Absorption T max Half-life Distribution Metabolism Excretion Mode of action Usage in pregnancy : Oral : Totally absorbed from GIT : 1-2 hours : 1-3 hours : All body cells & fluid : In liver : In urine : Inhibits the biosynthesis of Mycolic acid : Safe

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Isoniazid (INH)
Dosage : 300 mg/day (Adults) 5 mg/kg/day (Children) : Generalized skin rashes Drug induced hepatitis Peripheral neuropathy, producing tingling and numbness of the hands and feet. It can be treated by giving 100-200 mg pyridoxine daily. It can be prevented by giving 10 mg pyridoxine daily
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Side effects

Rifampicin
Administration Absorption : Oral : Well absorbed when taken in empty stomach. Food delays & reduces absorption : 600 mg 4 : 2-3 hours : 2-3 hours 7-9 mcg/ml

C max T max Half life

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Rifampicin
Distribution : Good penetration to all tissues, due to lipid solubility : In liver : In faeces and urine : Bactericidal. Inhibits an enzyme called DNA dependent RNA polymerase which help in RNA synthesis
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Metabolism Excretion Mode of action

Rifampicin
Dosage : Adults: <50 kg: 450 mg/day >50 kg: 600 mg/day Children: 10 mg/kg/day To be given in empty stomach, half an hour before breakfast : Safe : Liver damage Nausea, anorexia, diarrhoea etc.

Usage in pregnancy Side effects

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Rifampicin

Drug interaction

: Rifampicin stimulates liver enzymes, which may breakdown other drugs more rapidly than normal. So half-life of prednisolone, digoxin, ketoconazole, anticoagulants and oral contraceptives decreased.

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Pyrazinamide
Administration Absorption C max T max Half life : Oral : Well absorbed : 35 mcg/ml : 2 hours : 10 hours

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Pyrazinamide
Distribution : Good distribution in all body tissues & fluids

Metabolism
Excretion

: In liver
: In urine

Mode of action

: Inside the macrophages, in acidic pH it gets converted in to pyrazinoic acid which is bactericidal
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Pyrazinamide
Dosage : < 50 kg body weight : 1.5 gm 50 74 kg : 2 gm >74 kg : 2.5 gm

Usage in pregnancy : Though safety in pregnancy is not yet established, WHO & IUATLD recommends use of Z in a 6 month regimen including R,H & Z. Side effects : Hepatotoxicity Arthralgia Gouty arthritis
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Ethambutol
Advantage : Prevent the emergence of drug resistance when added to main bactericidal drugs

Administration
Absorption

: Oral
: About 80% of the oral dose is absorbed : 15 25 mg/kg 4 2-5 mcg/ml 50 mg/kg 4 10 mcg/ml
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C max

Ethambutol
T max Half life Distribution : 2-4 hours : 5 hours : Distributed in lungs, RBCs and penetrates inflamed meninges

Excretion

: In urine, mostly as unchanged drugs

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Ethambutol
Mode of action : Inhibits synthesis of ribonucleic acid and also inhibits mycolic acid incorporation into bacterial cell wall : 15 mg/kg of body weight/day For resistant cases 25 mg/kg of body weight once daily for 6o days followed by 15 mg/kg once daily

Dosage

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Ethambutol
Side effects : Retrobulbar neuritis leading to blindness Can be reversed, if administration of the drug discontinued in the early stages itself.

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Action of drugs on various physiologic population

Drug
Extracellular

Caseous

Intracellular

H R S Z E

+++ +++

++ +++

+ ++

+++
++

+++ ++
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Chemotherapy
Conventional chemotherapy Short Course Chemotherapy Intermittent Therapy

DOTS
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Short Course Chemotherapy

-Objectives of Intensive Phase To arrest the progress of the disease To prevent complications To make patient noninfectious To prevent development of MDR TB To relieve the disabling symptoms

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Short Course Chemotherapy

-Objectives of Continuation Phase To eradicate pathogen To prevent development of MDR TB

To prevent relapse

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Chemotherapy
Guidelines given by WHO (World Health Organiztion IUATLD (International Union Against Tuberculosis & Lung Disease)

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Chemotherapy
Principles
Must include minimum 2 bactericidal drugs INH for complete regimen if bacillus is not resistent to INH Rifampicin at least in intensive phase Pyrazinamide should be used in intensive phase S & E should not replace Z in intensive phase A single drug should not be added to failing regimen Relapse is suggestive of non-compliance or resistance
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Dosage chart of essential anti-TB drugs

Essential Anti-TB Drugs

Recommended dose (Mg/Kg) Daily 3 days/week 10 (8-12) 10 (8-12) 35 (30-40) 15 (12-18) 30 (25-35) 2 days/week 15 (13-17) 10 (8-12) 50 (40-60) 15 (12-18) 45 (40-50) 5 (4-6) 10 (8-12) 25 (20-30) 15 (12-18) 15 (15-20) 2.5

Isoniazid Rifampicin
Pyrazinamide Streptomycin

Ethambutol Thiacetazone

Not applicable
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WHOs TB treatment categories:

TB Treatment Category
I

Alternative TB treatment regimens

TB patients

Initial phase
2EHRZ(SHRZ)

Continuation phase

New smear-positive PTB;

New smear-negative PTB with extensive parenchymal involvement; New cases of severe forms of extra-pulmonary TB
II

6HE

2EHRZ(SHRZ)
2EHRZ(SHRZ) 2SHRZE/1HRZE 2SHRZE/1HRZE 2HRZ (If the patient is HIV+ add E)

4HR
4H3R3 5HRE 5H3R3E3 6HE 4HR 4H3R3
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Sputum smear-positive; Relapse; Treatment failure;

Treatment after interruption

III

New smear negative PTB (other than category I); new less severe forms of extra-pulmonary TB

Category IV Chronic case : Sputum positive after re-treatment

WHOs TB treatment categories:

TB Treatment Category

Alternative TB treatment regimens

TB patients Initial phase

New smear-positive PTB;
New smear-negative PTB with extensive parenchymal involvement; New cases of severe forms of extra-pulmonary TB

Continuation phase

2 months Tetra-cox or 2 months Roko Kit or 2 months Tricox + Streptomycin Inj. 3 months Tetra-cox or Roko Kit along with Streptomycin Inj. first 2 months 2 months Tricox (If the patient

II

Sputum smear-positive; Relapse; Treatment failure;

Treatment after interruption

6 months Themibutol plus or 4 months Ticinex 5 months Thre

III

New smear negative PTB (other than category I); new less severe forms of extra-pulmonary TB

is HIV+ give Tetracox/Roko Kit)

6 Themibutol plus or 4 Ticinex

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Fixed Dose Combinations

Geneva Workshop 1995 lists advantages: Prevention of acquired drug resistance Elimination of monotherapy Ensuring that R is being taken by the patient Reduction in the number of the tablets Better acceptability Simplifies dosage regimen Improvement in compliance
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Fixed Dose Combinations

According to American Thoracic Society: Enhance patient compliance Reduce the risk of inappropriate monotherapy Prevent secondary drug resistance

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Fixed Dose Combinations

Our FDCs:

Tetracox Thre Tricox

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Our anti-TB brands

Tetracox
Each tablet contains: Rifampicin - 225 mg Isoniazid - 150 mg Pyrazinamide - 750 mg Ethambutol HCl 400 mg For the intensive phase of I & II Category Ensures all 4 cardinal drugs Prevents monotherapy Ensures simplified prescription Prevents relapse

Dosage: 2 tablets per day half an hour before breakfast.

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Our anti-TB brands

Tetracox - Competitors
Forecox - Macleodes R-cinex-EZ Lupin RHZ Plus - Overseas AKT FD Lupin (R-150, H-100, Z-500, E-400)

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Our anti-TB brands

Roko Kit
Each kit contains: One tablet of Rifampicin 450 mg One tablet of ( Ethambutol 800 mg + INH 300mg) Two tablets of pyrazinamide 750 mg each

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Our anti-TB brands

Roko Kit
For the intensive phase in 1st & 2nd Category All four cardinal drugs are ensured Dosage convenience One kit a day

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Our anti-TB brands

Roko Kit Competitors
AKT-4 Lupin R-450 + E-800+H-300 + Z-750 + Z-750

4-D - Novartis R-450+ H-300 + E-800 + Z-750 + Z-750

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Our anti-TB brands

Tricox
Each tablet contains: Rifampicin - 225 mg Isoniazid - 150 mg Pyrazinamide - 500 mg For the intensive phase of III Category Ensures all 3 drugs needed Prevents monotherapy Ensures simplified prescription Prevents relapse

Dosage: 2 tablets per day

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Our anti-TB brands

Tricox - Competitors
Caviter Forte - Merind (Wockhardt) (H-150+Z-750+R-225) 3-FD - Novartis (H-150+Z-750+R-225) RHZ - Overseas (H-150 + Z-500 + R-225)
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Our anti-TB brands

Thre
Each tablet contains: Rifampicin - 450 mg Isoniazid - 300 mg Ethambutol - 800 mg For the continuation phase of Category II Ensures all 3 drugs needed Prevents monotherapy Ensures simplified prescription Prevents relapse Convenient dosage Dosage: 1 tablet per day

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Our anti-TB brands

Thre - Competitors
Monto-3 - Shreya (H-300+E-800+R-450) Rcinex-E - Lupin (H-300+E-800+R-450) AKT-3 - Lupin (1 cap of R450 & 1 tab of E800+H300)
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Our anti-TB brands

Ticinex
Each tablet contains: Rifampicin - 450 mg Isoniazid - 300 mg For the continuation phase of Category I & III Ensures the 2 drugs needed Prevents monotherapy Ensures simplified prescription Prevents relapse Convenient dosage Dosage: 1 tablet per day

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Our anti-TB brands

Ticinex - Competitors
R-Cinex - Lupin Montonex Forte - Shreya Macox Plus - Macleods Rimactazid - Novartis
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Our anti-TB brands

Ticinex Kid
Each tablet contains: Rifampicin - 100 mg Isoniazid - 50 mg Competitors: R-Cinex Kid Tablets - Lupin (R-100 + H-100) Rimactazid DT Tablet - Novartis (R-100 + H-50) Montonex Forte Kid-DT Tablets - Shreya (R-100 + H-50)
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Our anti-TB brands

Themibutol
(Ethambutol)
Strengths: 200 mg 400 mg 600 mg 800 mg 1000 mg Competitors: Combutol Lupin Ecox Macleods Myambutol Wyeth Mycobutol Cadila Pharma Mycostat Overseas
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Our anti-TB brands

Themibutol Plus
(E-800 + H-300) Themibutol Plus 1000 (E-1000 + H-300)
Competitors: Combunex Lupin Coxrid Wyeth Myconex-800 Cadila Pharma Isokoxi-800 Shreya

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Our anti-TB brands

Ticin
(Rifampicin)
Strengths: 150 mg 300 mg 450 mg Competitors: R-cin Lupin Macox Macleods Rimactane - Novartis Montomycin Shreya Monocin Overseas
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Our anti-TB brands

Ticimide
(Pyrazinamide)
Strengths: 500 mg 750 mg Competitors: Pyzina Lupin Macrozide Macleods PZA CIBA - Novartis Montozin Shreya Actizid Overseas
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Multi Drug Resistant Tuberculosis (MDR-TB)

Tuberculosis produced by tubercle bacilli resistant to one or more anti-TB drugs.

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Principles of MDR-TB Treatment

Will require at least some second-line drugs Must use what is likely to be the most effective drugs. Must not aim to keep drugs in reserve. Prefer drugs which the patient has not taken previously. If bacilli remain sensitive to a standard drug, it can be added to the regimen. But do not rely on it.
Continued .

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Principles of MDR-TB Treatment

Initial regimen should consist of at least 3 drugs, preferably 4 or 5 to which the bacilli are likely to be fully sensitive. Adding Z during 3 months is desirable, even if previously used, as resistance is usually unlikely
Continued ..

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Acuspar (Sparfloxacin) ideal drug to treat MDR-TB

Because: 1. Only quinolone showing activity against 17 out of 23 multidrug resistant strains of M. tuberculosis 2. There is no cross-resistance with rifampicin and isoniazid. 3. More potent than ciprofloxacin
Continued
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Principles of MDR-TB Treatment

When the patients sputum has converted to negative, one or more drugs, preferably weaker drugs, which are causing side effects, can be withdrawn.

Other drugs should be continued for at least 18 months after sputum conversion to prevent relapse.
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Ethiocid (Tablets of Ethionamide 250 mg.)

Mode of action: Bactericidal. Acts by inhibiting protein synthesis in the bacterial cell and also inhibits mycolic acid synthesis.

Strains resistant to H, S & PAS remain sensitive to ethionamide.

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Ethiocid (Tablets of Ethionamide 250 mg.)

Pharmacokinetics: Half-life 2 hours T max 3 hours Rapidly and widely distributed Conc. in blood and various organs are approximately equal Significant concentrations become available in CSF Apprx. 50% of the patients do not tolerate single dose larger than 500 mg as it produces severe GI disturbances
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Ethiocid (Tablets of Ethionamide 250 mg.)

Second line drug to treat MDR-TB as part of a regimen Contraindications: Severe hypersensitivity to ethionamide Severe hepatic damage Pregnancy
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Ethiocid (Tablets of Ethionamide 250 mg.)

May intensify the adverse effects of other anti-TB drugs administered concurrently Pyridoxin should be given if neuropathy had developed on previous INH therapy Dosage: Adults: 0.5 to 1 gm daily in divided dosee with meals Children: 12 to 15 mg/kg/day(max. 750mg/day) in divided doses with meals
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Prothicid (Tablets of Prothionamide 250 mg.)

Very similar to ethionamide

Except, prothionamide is much better tolerated Indications, dosage, side effects and precautions same as that of ethionamide
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