Training on Tuberculosis & Its Treatment

Mycobacteria
Three 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.

Dr Anshu P Gokarn

Mycobacterium tuberculosis

Dr Anshu P Gokarn

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 hours
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.

Dr Anshu P Gokarn

Morphology of M.tuberculosis
• Very slender

• Occur singly,in pairs joined at an angle

• Clumps with individual cells

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.

Dr Anshu P Gokarn

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

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.

Dr Anshu P Gokarn

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.

Dr Anshu P Gokarn

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

Dr Anshu P Gokarn

Pulmonary Tuberculosis
• Primary Tuberculosis Pneumonia

• Tuberculosis Pleurisy

• Cavitary Tuberculosis

• Miliary TB

• Laryngeal Tuberculosis
• Braunwald E et al. HArrisons Principles of Internal Medicine Vol.1, 15th 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

Dr Anshu P Gokarn

Extrapulmonary Tuberculosis
Occurs primarily in immunocompromised
patients

• Lymph Node Disease • Renal Tuberculosis
• Adrenal Tuberculosis
• Tuberculosis Peritonitis
• Tuberculosis
• Tuberculosis Pericarditis
Meningitis
• Osteal Tuberculosis
• Braunwald E et al. HArrisons Principles of Internal Medicine Vol.1, 15th ed. Mc Graw Hill: New York, 2001: 1027-1029

Dr Anshu P Gokarn

Pulmonary Tuberculosis

Dr Anshu P Gokarn

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

Dr Anshu P Gokarn

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

Dr Anshu P Gokarn

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).


Dr Anshu P Gokarn

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.

Dr Anshu P Gokarn

Miliary tuberculosis

Dr Anshu P Gokarn

Laryngeal TB

• TB can infect the larynx, or the vocal

chord area.

• It is extremely infectious.

Dr Anshu P Gokarn

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.

Dr Anshu P Gokarn

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.

Dr Anshu P Gokarn

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.


Dr Anshu P Gokarn

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.

Dr Anshu P Gokarn

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.

Dr Anshu P Gokarn

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

Dr Anshu P Gokarn

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.

Dr Anshu P Gokarn

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.

Dr Anshu P Gokarn

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.


Dr Anshu P Gokarn

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: 1027-1029
WeatherHall DJ et al. Oxford Text Book of Medicine, vol 1 3rd ed; Oxford University Press: Oxford,1996: 652-654

Dr Anshu P Gokarn

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.

Dr Anshu P Gokarn

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.


Dr Anshu P Gokarn

General rules of MDRTB treatment contd…
• 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.

Dr Anshu P Gokarn

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.

Dr Anshu P Gokarn

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

Dr Anshu P Gokarn

How Tuberculosis Develops
Inhalation of
M.tuberculosis Pulmonary
Tuberculosis

Dormant inside
Infected macrophages are
macrophages for
carried by
years or get activated lyphatics,,spreads
to cause infection Extrapulmonary
throughoout the body bvia
Tuberculosis bloodstream

Pathogen reaches lungs
where multiplication Destroys alveolar
begins macrophages,monocytes

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.

Dr Anshu P Gokarn

Granulomatous Lesions: Typical
of Tuberculosis

Dr Anshu P Gokarn

Complications of Tuberculosis
Toxicity 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)
Hill;2001.

Dr Anshu P Gokarn

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.


Dr Anshu P Gokarn

TB and HIV infection
TB 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

Dr Anshu P Gokarn

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
Hill;2001.

Dr Anshu P Gokarn

Microscopy
Films of sputum ,pus can be stained by

• Ziehl Neelson

• Fluorescent (Auramine – Rhodamine)
method.

Dr Anshu P Gokarn

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.

Dr Anshu P Gokarn

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.

Dr Anshu P Gokarn

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.
Hill;2001.

Dr Anshu P Gokarn

Fluorescent staining
• Smears are flooded
with Auramine
Rhodamine stain.
• Decolorize by 0.5% of
Acid Alcohol.
• Acceptable result:
Orange to yellow
flourescence
Hill;2001.

Dr Anshu P Gokarn

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

1.
microscopy.
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

Dr Anshu P Gokarn

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 Acceptable result: Red
• Counterstained with bacilli against blue
methylene blue background
Hill;2001.

Dr Anshu P Gokarn

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.

Hill;2001.

Dr Anshu P Gokarn

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.
Hill;2001.

Dr Anshu P Gokarn

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

Dr Anshu P Gokarn

History
Until 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

Dr Anshu P Gokarn

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
Simple Bed Rest
infection.
Dr Anshu P Gokarn

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

Dr Anshu P Gokarn

• 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

Dr Anshu P Gokarn

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

Dr Anshu P Gokarn

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

Dr Anshu P Gokarn

Classification of agents.
Drugs used in the treatment of

tuberculosis can be divided into two

major categories.

First line agents

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

Dr Anshu P Gokarn

First line drugs
These 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.

Dr Anshu P Gokarn

Second line drugs
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.

Dr Anshu P Gokarn

Second line drugs
The drugs in this class include:
Ofloxacin
Ciprofloxacin
Ethionamide
Aminosalicylic acid
Cycloserine
Amikacin
Kanamycin
Capreomycin

Dr Anshu P Gokarn

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

Dr Anshu P Gokarn

Mechanism of action (MOA)
• Inhibitory action on the
biosynthesis of mycolic Porin

acid, an important INH
Mycolic
constituent of the acid

mycobacterial cell wall.

• High degree of Lipid
bilayer
mycobacterial selectivity.


Dr Anshu P Gokarn

Bacterial resistance
Due 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.


Dr Anshu P Gokarn

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.
Dr Anshu P Gokarn

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.

Dr Anshu P Gokarn

Dosage of Isoniazid
Daily dose Twice daily dose Thrice weekly
dose
Children Adults Children Adults Children Adults

10-20 5 20-40 15 20-40 15
< 300mg < 300mg < 900mg < 900mg < 900mg <900mg

Dr Anshu P Gokarn

Rifampin
Group- Antimycobacterial agent
Synonyms - Rifampin Rifaldazine Rifamycin
Origin-. semisynthetic derivative of rifamycin
antibiotics
Molecular formula- C43H58N4O12
Molecular weight – 822.96

Daily dose Twice daily dose Thrice weekly dose


10-20 10 10-20 10 10-20 10
< 600mg < 600mg < 600mg < 600mg < 600mg <600mg
Dr Anshu P Gokarn

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.


Dr Anshu P Gokarn

Pharmacokinetics
Readily 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.

Dr Anshu P Gokarn

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.

Dr Anshu P Gokarn

Ethambutol
Group- 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 15-25 mg 50mg 50mg 25-30 25-30 mg
mg mg
Dr Anshu P Gokarn

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.


Dr Anshu P Gokarn

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.

Dr Anshu P Gokarn

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

Dr Anshu P Gokarn

Pyrazinamide
• Synthetic pyrazine analog of nicotinamide.
• Bactericidal
• Well absorbed orally
• Widely distributed.
• Metabolized by hydroxylation
• Primary excretion by glomerular filtration.

15-30 15-30 50-70 50-70 50-70 50-70
<2g <2g <4g <4g <3g <3g

Dr Anshu P Gokarn

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.
20-40 15 25-30 25-30 25-30 25-30
< 1.0g < 1.0g < 1.5g < 1.5 g < 1.5g < 1.5g

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

Dr Anshu P Gokarn

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.

Dr Anshu P Gokarn

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.

Dr Anshu P Gokarn

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

Dr Anshu P Gokarn

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.
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.

Dr Anshu P Gokarn

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.

Dr Anshu P Gokarn

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

Dr Anshu P Gokarn

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

Dr Anshu P Gokarn

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
Dr Anshu P Gokarn

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.
Dr Anshu P Gokarn

Treatment of choice for pulmonary
tuberculosis.

Recommended by the International Union
Against Tuberculosis and Lung Disease
(IUAT- LD).

Dr Anshu P Gokarn

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)
Dr Anshu P Gokarn

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.
Dr Anshu P Gokarn

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.
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.
Dr Anshu P Gokarn

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.

Hill;2001.

Dr Anshu P Gokarn

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)

Dr Anshu P Gokarn

Recommended Daily Dosage Regimen for
Adults (wt. 33-50 kg)
Zucox Range
Treatment Description Daily Regimen
Category
Initial phase Continuati
on phase

I New smear positive pulmonary TB
New cases of smear negative
Zucox -4
(For 2 months)
Zucox-2
(For 4
severe Pulmonary/ months)
Extrapulmonary TB

II Smear Positive
Relapse
Zucox -4
(For 3 months)
Zucox-3
(For 5
Treatment failure Streptomycin inj months)
Treatment after interruption (for 2 months)

III New smear negative Pulmonary
TB other than Category I and less
Zucox Kit
(For 2 months)
Zucox-2
(For 4
severe forms of Extrapulmonary months)
TB
Dr Anshu P Gokarn

Training on Tuberculosis & Its Treatment

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