Training on Tuberculosis & Its Treatment

Dr Anshu P GokarnDr Anshu P Gokarn


MycobacteriaThree major groups

• Tubercular complex: Causes TB

e.g. M.tuberculosis, M.bovis. M.africanum, M.microti

• Non tubercular or atypical mycobacteria

e.g.: MAC (Mycobacterium Avium Complex)

• M.leprae : Causes leprosy

Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New York:Churchill Livingstone;1995.


Mycobacterium tuberculosis


Properties of Mycobacteria• Acid fast bacilli

• Gram positive

• Obligate Aerobe ( organisms that strictly require oxygen for survival)

• Non-spore forming

• Nonmotile bacillus

• Unique Cell wall content-Mycolic acids (high molecular weight lipids)

• Generation time: 15-20 hoursHaas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New York:Churchill Livingstone;1995.


Morphology of M.tuberculosis

• Very slender

• Occur singly,in pairs joined at an angle

• Clumps with individual cells



Nontuberculous or atypical mycobacteria (NTM )

• Mycobacterial species that may cause human disease but not tuberculosis.

• NTM infections are not contagious unlike tuberculosis.

• Risk groups:People with emphysema, bronchiectasis or previous tuberculosis infection,AIDS.

E.g: Mycobacterium kansasii

Mycobacterium avium



Tuberculosis A chronic, contagious bacterial infection caused by Mycobacterium

tuberculosis.

Primararily affects the LUNGS

In one –third of cases it spreads to other organs like lymph nodes, kidneys, pleura, bones and joints genitourinary tract by the bloodstream or lymphatic system.

Granulomatous lesions characteristic of active disease.

Dissemination of bacilli takes place to many organs and tissues.

With appearance of immunity ,delayed hypersensitivity (DTH) develops to M.tuberculosis.

Raviglione CM et al.Tuberculosis.In: Braunwald E et al.,editors.Harrison’s Principles of Internal Medicine.15th ed.New York:McGraw Hill;2001.


Types of Tuberculosis

Pulmonary

Extrapulmonary

• Braunwald E et al. HArrisons Principles of Internal Medicine Vol.1, 15 th ed. Mc Graw Hill: New York, 2001: 1027-1029

• WeatherHall DJ et al. Oxford Text Book of Medicine, vol 1 3 rd ed; Oxford University Press: Oxford,1996: 652-654

• Tuberculosis- Types- Pulmonology. http://www.pulmonologychannel.com/tuberculosis/types.shtml


Pulmonary Tuberculosis

• Primary Tuberculosis Pneumonia

• Tuberculosis Pleurisy

• Cavitary Tuberculosis

• Miliary TB

• Laryngeal Tuberculosis • Braunwald E et al. HArrisons Principles of Internal Medicine Vol.1, 15 th ed. Mc Graw Hill: New York, 2001: 1027-1029

• WeatherHall DJ et al. Oxford Text Book of Medicine, vol 1 3rd ed; Oxford University Press: Oxford,1996: 652-654



Extrapulmonary Tuberculosis

• Lymph Node Disease

• Tuberculosis Peritonitis

• Tuberculosis Pericarditis

• Osteal Tuberculosis• Braunwald E et al. HArrisons Principles of Internal Medicine Vol.1, 15 th ed. Mc Graw Hill: New York, 2001: 1027-1029



Occurs primarily in immunocompromised patients

• Renal Tuberculosis

• Adrenal Tuberculosis

• Tuberculosis

Meningitis




Primary Tuberculosis Pneumonia

• This uncommon type of TB presents as pneumonia and is very infectious.

• Patients have a high fever and productive cough.

• It occurs most often in extremely young children and the elderly.

• It is also seen in patients with immunosuppression, such as HIV-infected and AIDS patients, and in patients on long term corticosteroid therapy.

• Braunwald E et al. Harrisons Principles of Internal Medicine Vol.1, 15 th ed. Mc Graw Hill: New York, 2001: 1027-1029




Tuberculosis pleurisy• This usually develops soon after initial infection.

• A granuloma located at the edge of the lung ruptures into the pleural space, the space between the lungs and the chest wall

• Once the bacteria invade the space, the amount of fluid increases dramatically and compresses the lung, causing shortness of breath (dyspnea) and sharp chest pain that worsens with a deep breath (pleurisy).

• Mild- or low-grade fever commonly is present.

• Generally resolves without treatment

• 2/3rd patients with tuberculosis pleurisy develop active pulmonary TB within 5 years.





Cavitary TB• Cavitary TB involves the upper lobes of the lung.

• Progressive lung destruction by forming cavities, or enlarged air spaces.

• Symptoms include productive cough, night sweats, fever, weight loss, and weakness. There may be hemoptysis (coughing up blood).

• Highly contagious. • Occasionally, disease spreads into the

pleural space and causes TB empyema (pus in the pleural fluid).

• Braunwald E et al. Harrisons Principles of Internal Medicine Vol.1, 15th ed. Mc Graw Hill: New York, 2001: 1027-1029




Miliary TB• Miliary TB is disseminated TB.

• "Miliary" describes the appearance on chest x-ray of very small nodules throughout the lungs that look like millet seeds.

• Miliary TB can occur shortly after primary infection.

• The patient becomes acutely ill with high fever and is in danger of dying. The disease also may lead to chronic illness and slow decline.

• Symptoms may include fever, night sweats, and weight loss.

• Patients who are immunosuppressed and children who have been exposed to the bacteria are at high risk for developing miliary TB.

• Braunwald E et al. Harrisons Principles of Internal Medicine Vol.1, 15th ed. Mc Graw Hill: New York, 2001: 1027-1029




Miliary tuberculosis


Laryngeal TB

• TB can infect the larynx, or the vocal

chord area.

• It is extremely infectious.






Lymph node disease• Lymph nodes contain macrophages that capture the

bacteria.

• Any lymph node can harbor uncontrolled replication

of bacteria, causing the lymph node to become

enlarged.

• The infection can develop a fistula (passageway)

from the lymph node to the skin. • Braunwald E et al. Harrisons Principles of Internal Medicine Vol.1, 15 th ed. Mc Graw Hill: New York, 2001: 1027-1029




Tuberculosis peritonitis• M. tuberculosis can involve the outer linings of

the intestines and the linings inside the abdominal wall, producing increased fluid, as in tuberculosis pleuritis.

• Increased fluid leads to abdominal distention and pain.

• Patients are moderately ill and have fever.





Tuberculosis pericarditis• The membrane surrounding the heart (the

pericardium) is affected in this condition.

• This causes the space between the pericardium and

the heart to fill with fluid, impeding the heart's ability

to fill with blood and beat efficiently.





Osteal Tuberculosis

• Infection of any bone can occur, but one of

the most common sites is the spine.

• Spinal infection can lead to compression

fractures and deformity of the back. • Braunwald E et al. Harrisons Principles of Internal Medicine Vol.1, 15 th ed. Mc Graw Hill: New York, 2001: 1027-1029




Renal Tuberculosis• This can cause asymptomatic

pyuria (white blood cells in the

urine) and can spread to the

reproductive organs and

affect reproduction.

• In men, epididymitis

(inflammation of the

epididymis) may occur. • Braunwald E et al. Harrisons Principles of Internal Medicine Vol.1, 15 th ed. Mc Graw Hill: New York, 2001: 1027-1029




Gastrointestinal tuberculosis• Manifestation of primary tuberculosis

• Caused by consuming unpastuerized milk containing M.bovis

• Occurs in patients with post primary pulmonary tuberculosis who have swallowed infected sputum.

• Symptoms: Recurrent abdominal pain and constipation with weight loss

• Clinical finding: Non healing ulcers of the tongue, oropharynx, esophageal disease and duodenal disease

• Standard chemotherapy is used•Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New York:Churchill Livingstone;1995.

•WeatherHall DJ et al. Oxford Text Book of Medicine, vol 1 3rd ed; Oxford University Press: Oxford,1996: 652-654


Adrenal Tuberculosis

• TB of the adrenal glands can lead to adrenal

insufficiency.

• Adrenal insufficiency is the inability to

increase steroid production in times of

stress, causing weakness and collapse. • Braunwald E et al. Harrisons Principles of Internal Medicine Vol.1, 15 th ed. Mc Graw Hill: New York, 2001: 1027-1029




TB meningitis• M. tuberculosis can infect the meninges (the main

membrane surrounding the brain and spinal cord).

• This can be devastating, leading to permanent impairment and death.

• TB can be difficult to discern from a brain tumor because it may present as a focal mass in the brain with focal neurological signs.

• Headache, sleepiness, and coma are typical symptoms.

• The patient may appear to have had a stroke.





Symptoms of Tuberculosis

• Coughing, general fatigue, loss of appetite, chest

pain, night sweats, and low-grade fever.

• The cough is at first not too productive, but later

increasing amounts of phlegm are coughed up.

• The person loses weight and the sputum becomes

bloody.





MDR -TB• A form of tuberculosis that is resistant to two or more of

the primary drugs used for the treatment of tuberculosis.

• Resistance to one or several forms of treatment occurs when the bacteria develops the ability to withstand antibiotic attack and relay that ability to their progeny.

• Since that entire strain of bacteria inherits this capacity to resist the effects of the various treatments, resistance can spread from one person to another.

• On an individual basis, however, inadequate treatment or improper use of the anti-tuberculosis medications remains an important cause of drug-resistant tuberculosis.

Braunwald E et al. HArrisons Principles of Internal Medicine Vol.1, 15th ed. Mc Graw Hill: New York, 2001: 1027-1029WeatherHall DJ et al. Oxford Text Book of Medicine, vol 1 3rd ed; Oxford University Press: Oxford,1996: 652-654


MDRTB: Treatment• Standardized regimens cannot be developed for MDRTB,

and good data are lacking on the efficacy of non-standard

regimens.

• If a person has MDRTB, a longer course of treatment (up

to 2 years) with more drugs is necessary.

• Some drugs used include aminoglycosides (e.g.,

amikacin, capreomycin, kanamycin), fluoroquinolones

(e.g., ciprofloxacin, ofloxacin), cycloserine, and

ethionamide.

• In some advanced, treatment-resistant cases, surgery

may be done to remove infected lung tissue.Rrecommendations on treatment of patients with MDRTB, NYC Department of Health, TB Control Program, Clinical Policies and Protocols, 3rd edition, 1999.


General rules of MDRTB treatment

• Program of daily DOT (directly observed therapy) to ensure adherence.

• At least two -- and preferably three to five -- medications to which the mycobacterial strain is reported to be susceptible should be used.

Rrecommendations on treatment of patients with MDRTB, NYC Department of Health, TB Control Program, Clinical Policies and Protocols, 3rd edition, 1999.


• Treatment to be continued for a minimum of 18 months after culture conversion to negative

• Patients with HIV infection or cavitary disease : treatment to be continued for 24 months after culture conversion.

• Treatment must be daily, not intermittent.

• An aminoglycoside (e.g., streptomycin, kanamycin, amikacin) or capreomycin should be prescribed from the start of therapy and for at least 6 months after cultures convert to negative.

General rules of MDRTB treatment contd…

Rrecommendations on treatment of patients with MDRTB, NYC Department of Health, TB Control Program, Clinical Policies and Protocols, 3rd edition, 1999.



Risk of progression from Infection to active disease

• 5-15% of infected individuals will develop active tuberculosis.

• Likelihood of developing active disease varies with the intensity and duration of exposure.

• Strongest risk factor- AIDS

• Other factors: malnutrition,renal failure,immunosuppressed.

1. Raviglione CM et al.Tuberculosis.In: Braunwald E et al.,editors.Harrison’s Principles of Internal Medicine.15th ed.New York:McGraw Hill;2001.

2. Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New York:Churchill Livingstone;1995.


Transmission of the tubercle bacilli

Transmission is by airborne droplet infection:Coughing, sneezing, speaking can transmit TB.

Contrary to popular myth, fomites (ie countertops) do not spread TB

50% of those exposed are usually infected

10-15 % of those who are infected after exposure go on to develop disease




How Tuberculosis DevelopsInhalation of M.tuberculosis

Dormant inside macrophages for years or get activated to cause infection

Pathogen reaches lungs where multiplication begins

Destroys alveolar macrophages,monocytes

Infected macrophages are carried by lyphatics,,spreads throughoout the body bvia bloodstream


Extrapulmonary Tuberculosis




Granulomatous Lesions: Typical of Tuberculosis


Complications of TuberculosisToxicity of drugs– Rifampin and isoniazid may both cause a

non-infectious hepatitis.

Other complications include:– drug resistance – relapse of the disease – tuberculous meningitis – respiratory failure – adult respiratory distress syndrome (ARDS)




Secondary or Reactivated Tuberculosis

• Secondary tuberculosis is usually due to the reactivation of old lesions or gradual progression of primary tuberculosis into chronic form

• The characteristics of secondary tuberculosis include extensive tissue damages due to immunologic reactions of the host to tubercle bacilli and their products.




TB and HIV infectionTB is an opportunistic infection in HIV-infected patients.

HIV patients show increased susceptibility to tuberculosis due to weakened immune system

In early HIV infection,pulmonary tuberculosis is most common infection.

In advanced HIV infection, the following diseases are most common

Extrapulmonary tuberculosis-

disseminated,lymphatic,pleural and pericardial

Mycobacteremmia

Meningitis.• Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious

Diseases.4th Ed.New York:Churchill Livingstone;1995.


Diagnosis of tuberculosis Microscopy (Ziehl Neelson Method)

Culture

o Identification of cultural properties

Animal inoculation

Typing

o to trace the source of infection

Tuberculin tests

Chest X-rays

Lung biopsy




Microscopy

Films of sputum ,pus can be stained by

• Ziehl Neelson

• Fluorescent (Auramine – Rhodamine)

method.




Acid fastness of mycobacteria

• A distinguishing feature

• Acid fastness is due to high molecular weight lipids- Mycolic acids

• Since mycobacteria grow slowly ,acid fast smear play an important role in early diagnosis of mycobacterial infections.




Importance of Acid fast Stained Smears It provides a presumptive diagnosis of

mycobacterial disease.

Most infectious cases are rapidly identified.

Used to follow-up the success of chemotherapy of tuberculosis patients.

Vitally important to the patient's discharge from the hospital, or return to employment.

It can confirm that cultures growing on media are indeed acid-fast.




Staining of Mycobacteria

Their lipid-rich cell walls of Mycobacteria

are relatively impermeable to various basic

dyes unless the dyes are combined with

phenol.

Once stained the cells resist

decolonization with acidified organic

solvents and are therefore called ACID

FAST. 1. Raviglione CM et al.Tuberculosis.In: Braunwald E et al.,editors.Harrison’s Principles of Internal Medicine.15th ed.New York:McGraw

Hill;2001.2. Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th

Ed.New York:Churchill Livingstone;1995.


Fluorescent staining• Smears are flooded

with Auramine

Rhodamine stain.

• Decolorize by 0.5% of

Acid Alcohol.

• Acceptable result:

Orange to yellow

flourescence1. Raviglione CM et al.Tuberculosis.In: Braunwald E et al.,editors.Harrison’s Principles of Internal Medicine.15th ed.New York:McGraw




Disadvantages of Fluorescent Staining

• Dead, or organisms rendered non-

cultivable by chemotherapy may still

fluoresce positive (stained)

• Therefore more bacilli are stained than by

the Ziehl-Neelsen method – Count error in

microscopy.1. Raviglione CM et al.Tuberculosis.In: Braunwald E et al.,editors.Harrison’s Principles of Internal Medicine.15th ed.New York:McGraw Hill;2001.2. Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New

York:Churchill Livingstone;1995.


Ziehl Neelson Method• Requires 105 AFB per

mL of sputum for recognition.

• Heat fixed Smears are flooded with Carbol fuchsin and steamed for 5 minutes.

• Decolorized with 3% acid-alcohol

• Counterstained with methylene blue

Acceptable result: Red bacilli against blue background




Mycobacterial Culture• Definitive diagnosis depends on isolation and

identification of M.tuberculosis from diagnostic specimen.

• Culture detects as few as 10 to 100 CFU/mL of sputum

• Cultured on Lowenstein-Jenson media

• Media Selective for M.tuberculosis and M.bovis

• Colonies confirmed by Ziehl Neelson staining and biochemical identification tests.




Tuberculin Skin test (PPD Testing) Used to measure hypersensitivity. Tuberculin, a protein extracted from M.

tuberculosis, is injected into an individual. A localized immune reaction elicited within 1-3

days:- tuberculin-positive. Indurations (hardening) and edema :- Previous

exposure but may not have the disease. For most individuals, immune protection gained

from previous exposure is lifelong.1. Raviglione CM et al.Tuberculosis.In: Braunwald E et al.,editors.Harrison’s Principles of Internal Medicine.15th ed.New York:McGraw




Nucleic acid amplification:Rapid diagnosis

PCR, DNA probes specific against 16S ribosomal RNA of mycobacterial species can

Facilitates rapid detection of mycobacteria in culture media

Rapid differentiaton of pathogenic

M.tuberculosis from other mycobacteria from a positive culture.

1. Raviglione CM et al.Tuberculosis.In: Braunwald E et al.,editors.Harrison’s Principles of Internal Medicine.15th ed.New York:McGraw Hill;2001.2. Haas W D et al.Mycobacterium Tuberculosis.In:Mandell LG and Bennett EJ,editors.Principles and practice of infectious Diseases.4th Ed.New

York:Churchill Livingstone;1995.



HistoryUntil the late 1940's no drugs were available to

treat tuberculosis.

Treatment was directed toward lessening the

symptoms, identifying environmental factors,

and enhancing general physical health.

Many prescribed substances to be taken were

actually lethal, such as a kerosene and whiskey

concoction. Shikes, R.H. (1986) Rocky Mountain Medicine: Doctors, Drugs, and Disease in Early Colorado. Boulder, Johnson Books. http://www.uccs.edu/~cragmor/tuber.html


Need for Sanatoriums??

• Sanatorias are essentially

large treatment centres

that specialized in the

diagnosis and recovery of

patients with tuberculosis

• Demonstrate the value of

rest, fresh air, good

nutrition and isolation to

prevent the spread of

infection.

Simple Bed Rest


Anti tuberculosis drugs

• Three key first line drugs used for previously

untreated patients are:

Isoniazid

Rifampicin

Pyrazinamide

• Ethambutol and streptomycin are valuable

additional drugs.

• In some countries thiacetazone and p-

aminosalicylic acid are still usedOxford textbook of medicine. Third edition. Vol 1. Oxford medical publications, page no.655


• Reserve drugs which may be used when first line

drugs have failed are:

Ethionamide

Prothionamide

Amikacin

Kanamycin

Capreomycin

Viomycin

Cycloserine

Quinolones (ofloxacin, ciprofloxacin,

sparfloxacin)Oxford textbook of medicine. Third edition. Vol 1. Oxford medical publications, page no.655


Principles of anti tuberculosis therapy.

• Large number of actively multiplying bacilli must be killed :

isoniazid achieves this.

• Treat semi dormant bacilli that metabolizes slowly or

intermittently: rifampicin and pyrazinamide are the most

efficacious.

• Prevent emergence of resistance by multiple therapy to

suppress drug-resistant mutants : isoniazid and rifampicin are

best.

• Combined formulations are used to ensure that poor compliance

does not result in monotherapy with consequent drug

resistance.

Laurence DR, Bennett PN, Brown MJ, Clinical pharmacology. 8 th edition. Churchill Livingstone publications. Page 225-27


Older treatment regimensAll TB cases or suspects were started on a 4

drug treatment regimen of isoniazid, rifampicin,

pyrazinamide, ethambutol.

This can be given in three ways:

Daily

Bi-weekly :4-drug therapy-daily for 2 weeks

and 2 times a week for 6 weeks.

Thrice weekly 4 drug therapy –6 monthsWorld health organization. Essential drugs. WHO Model List (revised in December 1997). WHO Drug information 1998; 12:22-25


Classification of agents.

Drugs used in the treatment of

tuberculosis can be divided into two

major categories.

First line agents

Second line agentsGoodman and Gilman’s The pharmacological basis of therapeutics. Ninth edition, page:1155-1174.


First line drugsThese combine the greatest level of efficacy with an acceptable degree of toxicity.

These include:

Isoniazid

Rifampin / Rifampicin

Ethambutol

Streptomycin

Pyrazinamide

A large majority of patients can be treated successfully these agents.

Goodman and Gilman’s The pharmacological basis of therapeutics. Ninth edition, page:1155-1174.


Because of microbial resistance or factors

such as HIV infection or AIDS, it may be

necessary to resort to second-line drugs in

addition, so that treatment may be initiated

with 5-6 drugs.

Second line drugs



The drugs in this class include:

Ofloxacin

Ciprofloxacin

Ethionamide

Aminosalicylic acid

Cycloserine

Amikacin

Kanamycin

CapreomycinGoodman and Gilman’s The pharmacological basis of therapeutics. Ninth edition, page:1155-1174.

Second line drugs


Isoniazid

Group- Tuberculocidal (Antimycobacterial agent )

Synonyms - INH; INAH; Isoniazidium; Isonicotinic acid

hydrazide; Isonicotinyl hydrazide; Isonicotino-

hydrazide; Pycazide; Tubazid

Origin-. synthetic pyridine derivative of nicotinamide

Chemical name- isonicotinic acid hydrazide

Molecular formula- C6H7N3O

Molecular weight - 137.14 Goodman and Gilman’s The pharmacological basis of therapeutics. Ninth edition, page:1155-1174.


Mechanism of action (MOA)

• Inhibitory action on the

biosynthesis of mycolic

acid, an important

constituent of the

mycobacterial cell wall.

• High degree of

mycobacterial selectivity.


Mycolic acid

Lipid bilayer

Porin

INH


Bacterial resistanceDue to missense mutation within the mycobacterial inhA gene involved in mycolic acid biosynthesis.

Cross-resistance between INH and other anti TB drugs (except ethionamide, which is structurally related to INH) does not occur.

Shift from primary sensitive to mainly insensitive microorganisms occasionally occurs within a few weeks after therapy is started.

The time of appearance of resistance may vary considerably from one case to another.



Pharmacokinetics

Rapidly and completely (90-95%) absorbed both

orally and parenterally.

Cmax= 3 to 5µg/ml

Tmax= 1 to 2 hours after oral administration.

Diffuses readily into all body fluids and cells.

Drug detected in the pleural and ascitic fluids.

Concentration in the CSF similar to plasma.Goodman and Gilman’s The pharmacological basis of therapeutics. Ninth edition, page:1155-1174.


Main biotransformation mechanisms involve

acetylaytion and hydrolysis.

Human populations show genetic heterogeneity with

regard to rate of acetylation of INH. Based on that the

two classes are:

Fast acetylators (rapid metabolism-short half life)

Slow acetylators (slow metabolism-longer half life)

The half life of the drug may be prolonged in the

presence of hepatic insufficiency.

75% to 95 % of drug is excreted in urine within 24 hours

mostly as metabolites.Goodman and Gilman’s The pharmacological basis of therapeutics. Ninth edition, page:1155-1174.


Dosage of Isoniazid

Daily dose Twice daily dose Thrice weekly dose

Children Adults Children Adults Children Adults

10-20 < 300mg

5 < 300mg

20-40 < 900mg

15 < 900mg

20-40 < 900mg

15 <900mg


RifampinGroup- Antimycobacterial agent

Synonyms - Rifampin Rifaldazine Rifamycin

Origin-. semisynthetic derivative of rifamycin antibiotics

Molecular formula- C43H58N4O12

Molecular weight – 822.96




10-20

< 600mg

10

< 600mg

10-20

< 600mg

10

< 600mg

10-20

< 600mg

10

<600mg


Mechanism of action

• It inhibits DNA-dependent RNA polymerase and

mycobacteria and other microorganisms by

forming a stable drug-enzyme complex , leading to

suppression of initiation of chain formation (but

not chain elongation) in RNA synthesis.

• More specifically, the ß subunit of this complex

enzyme is the site of action of the drug, although

rifampin binds only to the holoenzyme.



PharmacokineticsReadily absorbed from the GI tract (90%).

Peak plasma concentration occurs at 1.5 to 4 hours after an oral dose.

89(+/- 1) % of rifampicin in circulation is bound to plasma proteins.

When the meninges are inflamed, rifampicin enters the cerebrospinal fluid

It reaches therapeutic levels in the lungs, bronchial secretions, pleural fluid, other cavity fluid, liver, bile, and urine.



Approximately 85% of rifampicin is metabolised by

the liver microsomal enzymes to its main and active

metabolite - deacetylrifampicin.

Rifampicin undergoes enterohepatic recirculation

but not the deacetylated form.

Rifampicin metabolite deacetylrifampicin is excreted

in the bile and also in the urine.

Approximately 50% of the rifampicin dose is

eliminated within 24 hours and 6 to 30% of the drug

is excreted unchanged in the urine, while 15% is

excreted as active metabolite. Goodman and Gilman’s The pharmacological basis of therapeutics. Ninth edition, page:1155-1174.


EthambutolGroup- Antimycobacterial agent

Origin-. synthetic oral antibiotic derivative of ethylenediamine which contains two imine radicals and two butanol radicals.

Molecular formula- C10H24N2O2

Molecular weight – 204.3

Chemical structure:


CH3CH2CH(CH2OH)NHCH2CH2NHCH(CH2OH)CH2CH3



15-25

mg

15-25 mg 50mg 50mg 25-30

mg

25-30 mg


Mechanism of action

Ethambutol is bacteriostatic and appears to

inhibit the synthesis of one or more

metabolites, thus causing impairment of cell

metabolism, arrest of multiplication, and cell

death. Goodman and Gilman’s The pharmacological basis of therapeutics. Ninth edition, page:1155-1174.


Pharmacokinetics

• Following a single oral dose of 25 mg/kg of body

weight, attains a peak of up to 5 œg/mL in serum

within 4 hours after administration and is less than 1

ug/ml by 24 hours.

• About 80% of an oral dose of ethambutol is

absorbed from the gastro-intestinal tract.

• Ethambutol diffuses readily into red blood cells and

into the cerebrospinal fluid when the meninges are

inflamed.



• The main path of metabolism appears to be an initial

oxidation of the alcohol to an aldehydic intermediate,

followed by conversion to a dicarboxylic acid

• During the 24-hour period following oral

administration of ethambutol, approximately 50% of

the initial dose is excreted unchanged in the urine,

while an additional 8% to 15% appears in the form of

metabolites.

• From 20 to 22% of the initial dose is excreted in the

faeces as unchanged drug



Pyrazinamide

• Synthetic pyrazine analog of nicotinamide.

• Bactericidal

• Well absorbed orally

• Widely distributed.

• Metabolized by hydroxylation

• Primary excretion by glomerular filtration.




15-30

< 2 g

15-30

< 2 g

50-70

< 4 g

50-70

< 4 g

50-70

< 3 g

50-70

< 3 g


Streptomycin• Aminoglycoside.

• Not absorbed by mouth,is given by i.m. inj.

• Serum half life may be prolonged during renal impairment.

• Half life prolonged in new born babies and adults over 40 years, thereby increasing risk of toxicity.

• Leads to ototoxicity.

• Since it crosses placental barrier, should not be used in pregnant women.

Oxford textbook of medicine. Third edition. Vol 1. Oxford medical publications, page no.638-64



20-40

< 1.0g

15

< 1.0g

25-30

< 1.5g

25-30

< 1.5 g

25-30

< 1.5g

25-30

< 1.5g


Thiacetazone

• A thio semi carbazone

• Bacteriostatic

• Widely used in combination with other

agents in developing countries due to

cheapness

• Should not be given to patients with liver

disease due to hepatotoxic effects.Oxford textbook of medicine. Third edition. Vol 1. Oxford medical publications, page no.638-64


Para-amino salicylic acid

• Bacteriostatic

• Either used in combination with isoniazid or

as a reserve drug when it has not already

been used.

• Due to GI reactions it has been replaced by

other drugs

• Should not be given to patients with impaired

renal function.Oxford textbook of medicine. Third edition. Vol 1. Oxford medical publications, page no.638-64


Ethionamide and Prothionamide

• Derivative of thioisonicotinamide

• Secondary agent- to be used concurrently with other

drugs only when therapy with primary agents is

ineffective or contraindicated

• It acts by inhibition of oxygen dependant of mycolic

acid synthesis

• Used limited by their adverse effects.

• Adverse reactions less severe in children and with

prothionamide.

Ethionamide and Prothionamide

Oxford textbook of medicine. Third edition. Vol 1. Oxford medical publications, page no.638-64



Cycloserine

Acts by inhibiting cell wall synthesis

One of the several alternatives for retreatment regimen or for the treatment primary drug resistant M. tuberculosis

Low level of activity against MDR TB strains

Used as a reserve drug

Use limited by mental disturbances.



Role of quinolones

• Of the quinolones ciprofloxacin, ofloxacin,

flerofloxacin, and sparfloxacin all have inhibitory

activity against M. tuberculosis and MAC

bacteria, in vitro.

• Used in combination with second line agents in

the treatment of MDR TB and in patients with

HIV.Goodman and Gilman’s The pharmacological basis of therapeutics. Ninth edition, page:1155-1174.


WHO recommended Alternative Treatment regimens(1997)

• INH + RIF for 9 months

• RIF + EMB for 12-18 months:Can be used in

disease caused by INH –resistant organism.

• RIF,EMB and PZA for 6-9 months.

• INH + EMB for 18-24 months:Can be used in

disease caused by RIF resistant organismWorld health organization. Essential drugs. WHO Model List (revised in December 1997). WHO Drug information 1998; 12:22-25


Treatment regimen in Pregnancy-WHO recommended (1997)

• 3 drug regimen with INH,RIF and EMB

• PYZ not approved

• No harm to the breast-fed infant due to anti-

TB drugs.World health organization. Essential drugs. WHO Model List (revised in December 1997). WHO Drug information 1998; 12:22-25


TUBERCULOSIS CONTROL - INDIA

India now has the second-largest DOTS (Directly

Observed Treatment, Short-course) programme

in the world, placing about 40,000 patients on

treatment every month.

World health organization. Essential drugs. WHO Model List (revised in December 1997). WHO Drug information 1998; 12:22-25


Short course treatment

Prolonged therapy leads to poor patient

compliance and hence short course

regimens were developed.

To be effective the therapy must continue for

at least 6 months, or longer if isoniazid and

rifampicin are not given throughout.

Martindale-the extra pharmacology, 31st edition.


Treatment of choice for pulmonary

tuberculosis.

Recommended by the International Union

Against Tuberculosis and Lung Disease

(IUAT- LD).



The IUAT-LD regimens combine drugs

with potent bactericidal activity (Isoniazid,

Rifampicin)

with sterilizing activity against semi dormant

bacilli (Rifampicin, Pyrazinamide)

with the ability to suppress drug resistant

mutants (Isoniazid, Rifampicin) and

which may be administered 2 or 3 times

weekly (Isoniazid, rifampicin, pyrazimamide,

ethambutol)Martindale-the extra pharmacology, 31st edition.


The IUAT regimen for newly diagnosed

adults and children with pulmonary and extra

pulmonary disease consist of concurrent

adninisteration of isoniazid and rifimpicin for

6 months with pyrazinamide given with

isoniazid and rifampicin in the 8 week initial

phase.



Prevention and Control: BCG vaccination

Derived from attenuated strain of M.bovis.Safe Recommended for routine use at birth in

high tuberculosis prevalence countries, healthcares workers.

WHO recommends vaccination in asymptomatic HIV-infected children from endemic areas.




Treatment of Latent tuberculosis Patients are identified by PPD testing from high

risk groups.

INH at a dose of 15 mg/kg twice weekly for 6 months recommended in PPD positive –HIV negative patients

Alternative regimens for adults:

– 2-months daily rifampin+ PYR

– 4-months daily rifampin.




Zucox Range

• Zucox-2 Captabs: (R 450 mg+ H 300 mg)

• Zucox-3 Kit (R 450 mg+ H 300 mg, E 800 mg)

• Zucox-4 Kit (R 450 mg+ H 300 mg, E 800 mg, Z

1500 mg

• Zucox Kit (R 450 + H 300, Z1500 mg)


Recommended Daily Dosage Regimen for Adults (wt. 33-50 kg)

Treatment Category

Description

Zucox Range

Daily Regimen

Initial phase Continuation phase

I New smear positive pulmonary TBNew cases of smear negative severe Pulmonary/ Extrapulmonary TB

Zucox -4(For 2 months)

Zucox-2 (For 4

months)

II Smear PositiveRelapseTreatment failureTreatment after interruption

Zucox -4(For 3 months)Streptomycin

inj(for 2 months)

Zucox-3(For 5

months)

III New smear negative Pulmonary TB other than Category I and less severe forms of Extrapulmonary TB

Zucox Kit (For 2 months)

Zucox-2(For 4

months)


Training on Tuberculosis & Its Treatment

Documents

tuberculosis types

extrapulmonary tuberculosis

new york

oxford text book of

rd ed oxford university

churchill livingstone1995

mandell lg

bennett ej