This ppt gives you idea about pathophysiology of tuberculosis and the pharmacology of drugs used to treat this infection. And it also give deep introduction of molecular interaction of mycobacteria with body i.e.. immune response by human to this mycobacteria. it also gives you idea about treatment regimens and strategy for TB. discussed the different types of TB and mechanism of development of resistance by mycobacteria for anti-TB drugs.

1. ANTI-TB DRUGS
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2. Tuberculosis (TB)
 Tuberculosis (TB) is an infectious disease usually caused by Mycobacterium tuberculoi (MTB)
bacteria, Tuberculosis generally affects the lungs, but can also affect other parts of the body.
 Most infections show no symptoms, in this case it is known as latent tuberculosis.
 About 10% of latent infections progress to active disease which, if left untreated, kills about half
of those affected. The classic symptoms of active TB are a chronic cough with blood-containing
mucus, fever, night sweats, and weight loss. It was historically called consumption due to the
weight loss.
 The tubercle bacillus was discovered by Robert Koch in 1882, so it is also called as Koch’s bacillus.
 Tuberculosis is a chronic granulomatous infectious disease. Infection occurs via aerosol, and
inhalation of a few droplets containing M. tuberculosis bacilli.
Causative agent: Mycobacterium tuberculosis
Site of infection: pulmonary alveoli of lungs (mycobacterium is a strict aerobe bacteria i.e. It needs
oxygen for survival) so its infection site is alveoli (where oxygen exchange takes place)
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3. History and statics of TB
 In the year 1993, World Health Organization (WHO) declared TB a global public health emergency.
About one-third of the world’s population (> 2 billion), are infected with TB bacilli. 10% of the
people infected with TB bacilli will become sick with active TB in their lifetime.
 According to WHO report, global population with disease caused by TB from 1990-2011 was 6948
million. Highest numbers of incidences were reported in Asia (59%) and Africa (26%).
 As per WHO statistics for 2010, there were 9.4 million active TB cases globally, to which India was
the highest contributor with 2.3 million cases. India has the dubious distinction of being the highest
TB burden country for the past many years; and where about 1000 people die from TB every day.
 In 2012, the Government of India has declared TB to be a notifiable disease, so that any doctor who
treats a TB patient, has to notify it to the Govt.
 In India, control and treatment of TB is covered under a National programme which provides free
treatment to all TB cases. The Revised National Tuberculosis Control Programme (RNTCP) was
launched in 1997, and its treatment guidelines have been further revised in 2010.
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4. Etiology and characteristics of bacteria
The organism is a strict aerobe and grow best in tissues with high oxygen tension such as in the apex of
the lung.
Mycobacterium tuberculosis complex, currently most common is M. tuberculosis hominis (human strain).
while M. tuberculosis bovis (bovine strain) used to be common pathogen to human beings during the era of
consumption of unpasteurised milk but presently constitutes a small number of human cases.
Characteristics of MTB
a) Rod shape, 0.2-0.5µm in D, 2-4µm in L.
b) Mycolic acid present in its cell wall, makes it acid fast,
c) So it resists decolourization with acid & alcohol.
d) Aerobic and non-motile.
e) Multiplies slowly.
f) Can remain dormant for decades.
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5. Types of tuberculosis infection
• After the mycobacterium enters into the lungs it resides in the alveoli of lungs, if immune
system fails to eliminate it start its primary infection.
• There are three possible scenarios in the alveoli after the entry of the mycobacterium into the
lungs they are,
1. Elimination—immune system completely eliminates the infection.
2. Retention--- immune system supress the infection but bacterial cells remain viable this is
called latent tuberculosis (asymptomatic tuberculosis).
3. Active infection--- mycobacteria evades the immune response this case is called active
tuberculosis
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6. 6
Elimination Retention Active infection
Immune system
completely
eliminates the
infection
Mycobacteria evades the
immune response
Immune system supress
the infection but bacterial
cell remain viable
Latent tuberculosis Active tuberculosis
Mycobacterium

7. How TB Transmitted
a) Person-to-person through the air.
b) Less frequently transmitted by:
• 1. Ingestion of Mycobacterium bovis found in unpasteurized milk products or auto ingestion.
• 2. Inoculation (in skin tuberculosis), this type of transmission requires abrasion in the skin.
• 3. Transplacental route (rare route).
All patients infected with M. tuberculosis may not develop the clinical disease and many cases remain reactive
to tuberculin without developing symptomatic disease.
Signs and symptoms
• Tuberculosis may infect any part of the body, but most commonly occurs in the lungs (known as pulmonary
tuberculosis). Extrapulmonary TB occurs when tuberculosis develops outside of the lungs, although
extrapulmonary TB may coexist with pulmonary TB.
• Latent TB doesn’t have symptoms.
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8. Signs and symptoms
Signs of active TB (pulmonary TB) disease include:
• A cough that lasts more than 3 weeks, Chest pain, Coughing up blood, Feeling tired all the time, Night
sweats, Chills, Fever, Loss of appetite, Weight loss.
Extrapulmonary TB
• In 15–20% of active cases, the infection spreads outside the lungs, causing other kinds of TB. These are
collectively denoted as "extrapulmonary tuberculosis".
• When TB occurs outside our lungs, signs and symptoms vary according to the organs involved. For example,
tuberculosis of the spine might cause back pain, and tuberculosis in kidneys might cause blood in urine.
• Extrapulmonary TB occurs more commonly in people with a weakened immune system and young children.
In those with HIV, this occurs in more than 50% of cases.
• A potentially more serious, widespread form of TB is called "disseminated tuberculosis", it is also known as
miliary tuberculosis. Miliary TB currently makes up about 10% of extrapulmonary cases.
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9. Risk factors
There are a number risk factors for tuberculosis infection
Silicosis
• People with silicosis have an approximately 30-fold greater risk for developing TB. Silica particles irritate
the respiratory system. It is probably this interference and blockage of macrophage function that increases
the risk of tuberculosis.
HIV
• HIV is a major risk factor for tuberculosis. The risk of developing TB is estimated to be between 20-37
times greater in people living with HIV than among those without HIV infection. TB is a leading cause of
morbidity and mortality among people living with HIV.
Nutrition
• Low body weight is associated with risk of tuberculosis. A body mass index (BMI) below 18.5 increases the
risk by 2 to 3 times. An increase in body weight lowers the risk. People with diabetes mellitus are at
increased risk of contracting tuberculosis.
• This increased risk could be caused by micronutrient deficiencies: possibly iron, vitamin B12 or vitamin D.
Other
• Other conditions that increase risk include the sharing of needles among IV drug users, prolonged
corticosteroid therapy and other immunosuppressive therapy, smoking more than 20 cigarettes a day
increases the risk of TB by two to four times, and crowding among peoples who are infected with TB for
long period of time, etc...
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10. Diagnosis
There are two types of tests for TB infection: the TB skin test and the TB blood test.
 The TB skin test is also called the Mantoux tuberculin skin test (TST).
 The TB skin test is performed by injecting a small amount of fluid (called tuberculin) into the skin on the lower
part of the arm.
 The result depends on the size of the raised, hard area or swelling.
 TB blood tests or sputum tests are also called interferon-gamma release assays or IGRAs.
 A health care provider will draw a patient’s blood or collect the sputum sample and send it to a laboratory for
analysis of antibodies and results.
 Imaging test a chest X-ray or a CT scan is done, this might show white spots in lungs where immune
system has walled off TB bacteria, or it might reveal changes in the lungs caused by active
tuberculosis.
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11. Any of this risk factors may helps in the conversion of the latent TB into active
TB .
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12. Pathophysiology
Dissolved and
eliminated
 First step is entry of mycobacterium into
pulmonary alveoli,
 Immune system has lodged macrophages in
alveoli, which is called as alveolar macrophage.
 When the macrophages detect the entry of
pathogen it phagocytes the mycobacterium into
cell by process phagocytosis.
 The vesicle like structure in which mycobacterium
inside the macrophage is called phagosome.
 To eradicate the phagosome, macrophages has
lysosome with hydrolytic enzymes.
 In normal immune response lysosome fuses with
phagosome to form phago-lysosome in which
pathogen dissolves and get eliminated.
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13. `
Primary
infection
In TB
 In TB the fusion is inhibited, the pathogen remains
in the macrophage without being detected by
immune system.
 The bacteria replicates inside the macrophages
and cause primary infection.
 3 weeks after primary infection the cell mediated
immunity starts and forms granuloma.
 Formation of granuloma leads to necrosis of tissue
at the sight of infection and it is termed as GHON
focus.
 When GHON focus involves nearby lymph nodes to
the infection it is called as a GHON complex.
 GHON complex undergo fibrosis and calcification it
is termed as a RANKE complex.
At this stage there is complete elimination of TB
or it goes to quiescent stage or dormancy which
is called as latent TB.
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14. Molecular mechanism of TB
• How TB interacts with human immune system i.e. TB(mycobacterium) vs immune system(alveolar
macrophage)
• immune suppression by mycobacterium by 3 major mechanism, they are,
 Inhibition of phagosome maturation (inhibition of acidification)
 Inhibition of phago-lysosome formation
 Inhibition of interferon production.
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15. Acidification inhibition
 In normal condition V-ATPase pump H+ ion into phagosome to increase the acidity of the phagosome
and to digest it.
 In mycobacterium infected phagosome it release the protein called PTPA(Protein Tyrosine
Phosphatase) protein, which binds to the subunit of V-ATPase and inhibits the action of V-ATPase and
ultimately inhibits the acidification.
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16.  Phagolysosome inhibition
 In normal cases phagosome and lysosome inside the macrophage undergo fusion.
 But in TB there is a inhibition of phagosome and lysosome fusion.
 In normal condition, for fusion to occur phagosome releases the protein RAB5 (Ras superfamily of monomeric G-
protein) and it exchanges RAB5 for RAB7 and initiates phagolysosome formation.
 In TB, bacteria contains RAB22a which prevents the exchange of RAB5 with RAB7 and prevents the fusion.
 And this bacteria also contains the another protein called TACO(tryptophan aspartate containing coat protein)
present on the phagosome.
 Detachment of TACO protein leads to the movement of phagosome towards lysosome.
 In case of TB TACO protein retained on phagosome and delays fusion.
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17.  Inhibition of interferon production
 cGAS (cyclic GMP-AMP synthase) molecule inside the macrophage, which detects the foreign DNA and activates
STING pathway (stimulator of interferon genes), which initiates the production of interferon by macrophage.
 But when there is NO degradation of phagosome, their will in no dsDNA of bacterium is detected. i.e. NO STING
pathway activation and interferon production.
• This is how mycobacterium tuberculosis survive inside the macrophage leads to macrophage parasitism.
• The immune system tries to search the mycobacterium tuberculosis outside its own cells, because mycobacterium
uses immune cells to replicate.
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18. Classification of anti-tubercular drug
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19. Isoniazid (isonicotinic acid hydrazide, H)
• Isoniazid is an excellent antitubercular drug, and an essential component of all antitubercular
regimens. It is primarily tuberculocidal. Fast multiplying organisms are rapidly killed, but quiescent
ones are only inhibited.
• It acts on extracellular as well as on intracellular TB, and is equally active in acidic or alkaline
medium.
 The primary mechanism of action of INH is inhibition of
synthesis of mycolic acids which are unique fatty acid
components of mycobacterial cell wall (This explain’s the
high selectivity of INH for mycobacteria).
 Two gene products labelled ‘InhA’ and ‘KasA’, which
function in mycolic acid synthesis are the targets of INH
action.
 INH enters sensitive mycobacteria which convert it by a
catalase-peroxidase enzyme into a reactive metabolite.
This then inhibits InhA and KasA and also inhibits
mycobacterial DHFRase (dihydrofolate reductase)
resulting in interruption of DNA synthesis.
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20. 20
Resistance
 About 1 in 106 tubercle bacilli is inherently resistant to
clinically attained INH concentrations.
 The most common mechanism which confers high level INH
resistance is by mutation of the catalase-peroxidase (KatG)
gene so there is no conversion of INH to its active form.
 INH resistance may also involve mutation in the inhA or
kasA genes.

21. Pharmacokinetics
 INH is completely absorbed orally and penetrates all body tissues, tubercular cavities, placenta and meninges.
 It is extensively metabolized in liver; most important pathway being N-acetylation by NAT2. The acetylated metabolite is excreted in
urine.
 The rate of INH acetylation shows genetic variation. There are either:
• Fast acetylators (30–40% of Indians) t½ of INH 1 hr.
• Slow acetylators (60–70% of Indians) t½ of INH 3 hr.
 However, acetylator status does not matter if INH is taken daily, but biweekly regimens are less effective in fast acetylators.
• Interactions
 Aluminium hydroxide inhibits INH absorption.
 INH retards phenytoin, carbamazepine, diazepam, theophylline and warfarin metabolism by inhibiting CYP2C19 and CYP3A4, and may
raise their blood levels.
 Since rifampin is an enzyme inducer, its concurrent use counteracts the inhibitory effect of INH.
• Adverse effects
 INH is well tolerated by most patients.
 Peripheral neuritis and a variety of neurological manifestations (paraesthesia’s, numbness, mental disturbances, rarely convulsions)
are the most important dose-dependent toxic effects.
 Hepatotoxicity is also one of the most common adverse action seen with INH.
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22. Rifampin (rifampicin, R)
 It is a semisynthetic derivative of rifamycin B obtained from Streptomyces mediterranei. Rifampin is tuberculocidal.
 Against TB bacilli, it is as efficacious as INH and better than all other drugs.
 Acts best on slowly or intermittently dividing ones.
 Both extra- and intracellular organisms are affected. It has good resistance preventing actions.
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Mechanism of action
 Rifampin interrupts RNA synthesis by binding to β subunit of mycobacterial DNA-dependent
RNA polymerase (encoded by rpoB gene) and blocking its polymerizing function.
 The basis of selective toxicity is that mammalian RNA polymerase does not bind to rifampin.
Pharmacokinetics
 It is well absorbed orally, (bioavailability is 70%), but food decreases absorption; rifampin is
to be taken in empty stomach.
 It is widely distributed in the body: penetrates intracellularly, enters tubercular cavities,
caseous masses and placenta.
 It is metabolized in liver to an active deacetylated metabolite which is excreted mainly in
bile, some in urine also. The t½ of rifampin is variable (2–5 hours).
Resistance
 Rifampin resistance is nearly always due to mutation in the rpoB gene reducing its affinity
for the drug.

23. • Pyrazinamide (Z)
 Chemically similar to INH, pyrazinamide (Z). It is weakly tuberculocidal and more active in acidic medium.
 It is more lethal to intracellularly located bacilli and to those at sites showing an inflammatory response (pH is acidic at
both these locations).
 It is highly effective during the first 2 months of therapy when inflammatory changes are present.
 Its inclusion has enabled duration of treatment to be shortened.
• Mechanism of action
 The mechanism of action of Z is not well established, but like INH it is also converted inside the mycobacterial cell into an
active metabolite pyrazinoic acid by an enzyme (pyrazinamidase) encoded by the pncA gene.
 This metabolite gets accumulated in acidic medium and inhibits mycolic acid synthesis.
 Pyrazinoic acid also appears to disrupt mycobacterial cell membrane and its transport function.
 Resistance to Z develops rapidly if it is used alone, and is mostly due to mutation in the pncA gene.
• Pharmacokinetics and adverse effects
 Pyrazinamide is absorbed orally, widely distributed, has good penetration in CSF, because of which it is highly useful in
meningeal TB, extensively metabolized in liver and excreted in urine; plasma t½ is 6–10 hours.
 Hepatotoxicity is the most important dose related adverse effect,
 Daily dose is now limited to 25–30 mg/kg which produces only a low incidence of hepatotoxicity.
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24. • Ethambutol
 Ethambutol is selectively tuberculostatic and is active against MAC as well as some other mycobacteria. Fast
multiplying bacilli are more susceptible. And it prevent development of resistance, it is the primary purpose of using
it.
• Mechanism of action and resistance
 The mechanism of action of E is not fully understood, but it has been found to inhibit arabinosyl transferases
(encoded by embAB genes) involved in arabinogalactan synthesis thereby interfering with mycolic acid incorporation
in mycobacterial cell wall.
 Resistance to E develops slowly and is most commonly associated with mutation in embB gene, reducing the affinity
of the target enzyme for E.
• Pharmacokinetics and adverse effects
 About 3/4 of an oral dose of E is absorbed. It is distributed widely, but penetrates meninges incompletely and is
temporarily stored in RBCs.
 Less than ½ of E is metabolized. It is excreted in urine by glomerular filtration and tubular secretion; plasma t½ is ~4
hrs.
 Patient acceptability of E is very good and side effects are few. Loss of visual acuity/colour vision, field defects due to
optic neuritis is the most important dose and duration of therapy dependent toxicity.
 It is safe during pregnancy. Ethambutol is used in MAC infection as well.
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25. Streptomycin (S)
 It was the first clinically useful antitubercular drug. It is tuberculocidal, but less effective than INH or rifampin;
acts only on extracellular bacilli (because of poor penetration into cells).
 It penetrates tubercular cavities, but does not cross to the CSF, and has poor action in acidic medium.
Resistance developed rapidly when streptomycin was used alone in tuberculosis.
 In case of S-resistant infection, it must be stopped at the earliest because of risk of S-dependence, in which
case the infection flourishes when the drug is continued. Most nontubercular mycobacteria are unaffected by
S.
 Because of need for i.m. injections and lower margin of safety (ototoxicity and nephrotoxicity, especially in
the elderly and in those with impaired renal function) S is used only as an alternative to or in addition to other
1st line antiTB drugs.
 Use is restricted to a maximum of 2 months. It is thus also labelled as a ‘supplemental’ 1st line drug.
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26. SECOND LINE ANTI-TB DRUGS
These are less effective and or less well tolerated anti-TB drugs that are used only in case the bacilli are resistant to
one or more 1st line drugs or when these are not tolerated or contraindicated.
• Kanamycin (Km), Amikacin (Am)
 These are tuberculocidal aminoglycoside antibiotics, very similar in antitubercular activity, pharmacokinetic
properties and types of adverse effects to S. Many S resistant and MDR strains of M.tuberculosis remain sensitive to
them.
 One of these is mostly included in the regimen for MDR-TB during the intensive phase. The RNTCP standardized
regimen for MDR-TB includes Km (probably because it is less expensive than Am), but in many countries Am is
preferred, because it is considered less toxic.
 Cross resistance between Km and Am is very common. Both Km and Am produce less vestibular toxicity than
hearing loss, but are equally nephrotoxic.
• Capreomycin (Cm)
 It is a cyclic peptide antibiotic, chemically very different from aminoglycosides, but with similar mycobactericidal
activity, ototoxicity and nephrotoxicity.
 Cm often causes eosinophilia, rashes, fever and injection site pain. It has to be injected i.m. and is used only as
alternative to aminoglycoside antibiotics.
 Many M.tuberculosis isolates resistant to S and Am, as well as MDR-TB remain susceptible to Cm
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27. • Fluroquinolones (FQs)
 Fluoroquinolones (FQs) like ofloxacin (Ofx), levofloxacin (Lfx), ciprofloxacin (Cfx) and moxifloxacin (Mfx) are relatively
new potent oral bactericidal drugs for TB, that have gained prominence as well tolerated alternatives to 1st line anti-
TB drugs.
 They are active against MAC, and some other atypical mycobacteria as well. Mfx is the most active FQ against
M.tuberculosis, while Lfx is more active than Ofx and Cfx.
 The FQs penetrate cells and kill mycobacteria lodged inside macrophages as well. Though Cfx was initially used in TB,
it is not favoured now because of its extensive use in other bacterial infections and chances of resistance.
 The primary indication of FQs is for treatment of drug resistant TB.
• Ethionamide (Eto)
 It is an antitubercular drug of moderate efficacy, which acts on both extra- and intracellular bacilli. Few atypical
mycobacteria including MAC are also susceptible.
 Chemically it resembles INH, but contains sulphur.
 The mechanism of action is also similar to INH: it is converted by mycobacteria into an active intermediate which
interferes with mycolic acid synthesis.
 Resistance to Eto mostly results from mutation of the gene that encodes for the Eto activating enzyme.
 Eto is nearly completely absorbed orally, distributed all over and crosses into CSF. It is completely metabolized in liver
and has a short t½ of 2–3 hours.
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28. • Cycloserine (Cs)
 This antibiotic obtained from S.orchidaceus is an analogue of D-alanine.
 Accordingly, it inhibits bacterial cell well synthesis by inactivating the enzymes which racemize L-alanine
and link two D-alanine residues.
 Cs is tuberculostatic; in addition inhibits MAC as well as some other. Resistance to Cs develops slowly.
 Oral absorption of Cs is good; it diffuses all over the body; CSF concentration is equal to that in plasma.
About 1/3 of a dose is metabolized; the rest is excreted unchanged in urine; plasma t½ is 9 hours.
• Para-amino salicylic acid (PAS)
 Introduced in 1946, PAS is related to sulphonamides and acts probably by the same mechanism, i.e.
inhibition of folate synthase.
 It is not active against other bacteria, and this selectivity may be due to difference in the affinity for folate
synthase of M.tuberculosis compared to that of other bacteria. However, other mechanisms of action are
also possible.
 PAS is absorbed completely by the oral route and distributed all over except in CSF. About 50% PAS is
acetylated; competes with acetylation of INH and prolongs its t½. It is excreted rapidly by glomerular
filtration and tubular secretion; t½ is short, 1 hour.
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29. • Terizidone
It contains 2 molecules of cycloserine and has antibacterial properties as well as mechanism of action similar
to it; but is believed to be less neurotoxic; reported incidence of adverse effects is lower. It is used as a
substitute of Cs.
• Rifabutin
It is related to rifampin in structure and mechanism of action, but is less active against M.tuberculosis, and
more active against MAC. Majority of M.tuberculosis isolates resistant to R are cross resistant to rifabutin.
Thus, it is not an option for treatment of MDR-TB.
The only place of rifabutin in the treatment of TB is as a substitute for R to minimize drug interactions due to
strong enzyme inducing property of R. Rifabutin is a much weaker inducer of CYP enzymes than R.
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30. Treatment of TB
• The therapy of tuberculosis has undergone remarkable changes. The ‘conventional’ 12–18 month treatment
has been replaced by more effective and less toxic 6 month (short course) treatment with higher success
rates.
• This has been possible due to better understanding of biology of infection.
• Biology of tubercular infection
• In body bacilli may exist in different state, like
 Rapidly growing with high bacillary load as in the wall of a cavitary lesion where oxygen is high and pH is
neutral. These bacilli are highly susceptible to H and to a lesser extent to R, E and S.
 Slow growing located intracellularly (inside macrophages) and at inflamed sites where pH is low. They are
particularly vulnerable to Z, while H, R and E are less active, and S is inactive.
 Spurters found mostly within caseous material where oxygen is low but pH is neutral: the bacilli grow
intermittently with occasional spurts of active metabolism.
 Dormant some bacilli remain totally inactive for prolonged periods. No antitubercular drug is significantly
active against them.
• However, there is continuous shifting of bacilli between these subpopulations.
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31. • The goals of antitubercular chemotherapy are:
1. Kill dividing bacilli
2. Kill persisting bacilli
3. Prevent emergence of resistance
• Drug combinations are selected to maximise the above actions together with considerations of cost, convenience and
feasibility.
• The general principles of antitubercular chemotherapy are:
 Use of any single drug in tuberculosis results in the emergence of resistant organisms and relapse in almost 70%
patients.
 The ‘directly observed treatment short course’ (DOTS) was recommended by the WHO in 1995, Prefers a daily single
dose of all first line drugs.
 Response is fast in the first few weeks as the fast dividing bacilli are eliminated rapidly. Symptomatic relief is evident
within 2–4 weeks.
• The adequacy of any regimen is decided by observing sputum conversion rates and 2–5 year relapse rates after
completion of treatment.
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32. SHORT COURSE CHEMOTHERAPY
• After several years of trial, the WHO introduced 6–8 month multidrug ‘short course’ regimens in 1995 under
the DOTS programme.
• The dose of all first line drugs was standardized on body weight basis, applicable to both adults and children.
These guidelines were implemented by India and other WHO member countries, to control TB.
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33. 33

34. Multidrug-resistant (MDR) TB
Multidrug-resistant (MDR) TB MDR-TB is
defined as resistance to both H and R, and
may be any number of other (1st line)
drug(s). its treatment requires complex
multiple 2nd line drug regimens which are
longer, more expensive and more toxic.
 The RNTCP has devised a
‘standardized’ treatment regimen of, 6
drugs intensive phase lasting 6–9
months and 4 drugs continuation
phase of 18 months.
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Extensively drug-resistant
 TB These are MDR-TB cases that are also resistant to FQs as well as one of the injectable 2nd line
drugs and may be any number of other drugs.
 The XDR-TB is very difficult to treat, has a rapid course and high mortality. However, to prevent
further amplification of resistance, the standardized MDR regimen must be immediately stopped
when XDR-TB is detected or suspected.
 Some new drugs like PA-824 and TMC-207 are also being evaluated, for the treatment of XDR-TB.

35. • Tuberculosis in pregnant women
 The WHO and British Thoracic Society consider H, R, E and Z to be safe to the foetus and recommend the
standard 6 month (2HRZE + 4HR) regimen for pregnant women with TB. S is contraindicated because it is
ototoxic to the foetus.
 Treatment of TB should not be withheld or delayed because of pregnancy. All pregnant women being treated
with INH should receive pyridoxine 10–25 mg/day.
• Treatment of breastfeeding women
 All anti-TB drugs are compatible with breastfeeding; full course should be given to the mother, but the baby
should be watched.
 The infant should receive BCG vaccination and 6 month isoniazid preventive treatment after ruling out active
TB.
• Management of patients with adverse drug reactions to antitubercular drugs
 Minor side effects are to be managed symptomatically without altering medication; e.g. nausea, anorexia—give
the drugs with small meals; drowsiness—give drugs before bed time; flu syndrome due to intermittent dosing
of R—change to daily dosing of R; Z induced arthralgia can be treated by analgesic-NSAIDs; peripheral neuritis
due to H can be mitigated by pyridoxine.
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36.  If more severe reactions like skin rashes, itching develop, all drugs should be stopped promptly.
 After the adverse reaction is resolved the drugs are reintroduced one at a time with small doses and increasing
every 3 days. When the side effect causing drug is identified it should be stopped and the regimen is
reconstituted.
 Hepatotoxicity is the most common problem with antitubercular drugs. Any one or more of H, R and Z could be
causative and the reaction occurs more frequently when, as per standard protocol, combination of these drugs is
used.
 In case hepatitis develops, all drugs should be stopped and the reaction allowed to subside. If TB is severe,
nonhepatotoxic drugs S + E + One FQ should be started while the reaction clears.
• Chemoprophylaxis
 The purpose is to prevent progression of latent tubercular infection to active disease. This is indicated only in:
• (a) Contacts of open cases who show recent Mantoux conversion.
• (b) Children with positive Mantoux and a TB patient in the family.
• (c) Neonate of tubercular mother.
• (d) Patients of leukaemia, diabetes, silicosis, or those who are HIV positive.
 The standard drug for chemoprophylaxis of TB is H 300 mg (10 mg/kg in children) daily for 6 months.
 Several regimens, including one with E + Z ± one FQ, have been suggested for subjects exposed to MDR-TB.
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37. • Tuberculosis in AIDS patients
 HIV positive cases have a higher incidence of extrapulmonary, more severe, more lethal and more infectious
TB.
 HIV infection is the strongest risk factor for unmasking latent TB. Moreover, adverse reactions to anti-TB
drugs are more common in HIV patients.
 5% of TB patients in India are HIV positive.
 On the other hand, institution of ‘highly active antiretroviral therapy’ (HAART) and improvement in CD4 cell
count of the subject markedly reduces the incidence of TB among HIV-AIDS patients. When CD4 count is
<150 cells/µL, extrapulmonary and dual TB is more commonly encountered.
 Drugs used are the same as in non-HIV cases, and at least 4 drugs are used.
 Initial intensive phase therapy with daily HRZE for 2 months is started immediately on the diagnosis of TB,
and is followed by a continuation phase of HR for 4–7 months (total 6–9 months).
 Thrice weekly regimen should not be used, because it may increase the rate of relapse and failure among HIV
positive patients.
 Consideration also has to be given to possible drug interactions between anti-TB and antiretroviral (ARV)
drugs. Rifampin, a potent inducer of CYP isoenzymes, should be substituted with rifabutin.
 MDR-TB in HIV-AIDS patients should be treated in the same way as that in non-HIV infected patient for a
total of 18–24 months.
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38. Mycobacterium avium complex (MAC) infection
 MAC is an opportunistic pathogen which causes disseminated and multifocal disease in immunocompromised
(HIV-AIDS) patients. The disease develops when cell mediated immunity is markedly depressed, i.e. when CD4
count drops to <50 cells/μL, HIV-RNA load is high and other opportunistic infections (P. jirovecii, etc.) are also
present.
 The duration of intensive phase is dependent on the response, viz. till CD4 count rises > 100 cells/μL and
symptomatic relief is obtained, which may take 2–6 months. The maintenance therapy is continued till a
minimum of 12 months.
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39. BCG Vaccine
• BCG, or bacille Calmette-Guerin, is a vaccine for tuberculosis (TB) disease. BCG is used in many countries
with a high prevalence of TB to prevent childhood tuberculous meningitis and miliary disease.
• In India many of us vaccinated by BCG, in other countries it is only recommended for children's and health
care workers.
• BCG vaccination can cause a false positive Mantoux test. The most controversial aspect of BCG is the variable
efficacy found in different clinical trials, which appears to depend on geography.
• BCG vaccine has been the "standard of care for patients with bladder cancer (NMIBC)"non–muscle-invasive
bladder cancer.
• The BCG vaccine contains a weakened strain of TB bacteria, which builds up immunity and encourages the
body to fight TB if infected with it, without causing the disease itself.
• BCG vaccinated person may test false-positive reaction to the TST(tuberculosis skin test).
• BCG is given as a single intradermal injection at the deltoid muscle region.
• Use of the BCG vaccine may provide protection against COVID-19.
• The WHO does not recommend its use for prevention as of 12 January 2021.
• As of January 2021, twenty BCG trials are in various clinical stages.
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40. Reference
1. Essentials of Medical Pharmacology, 7th Edition, KD TRIPATHI.
2. Goodman & Gilman’s The Pharmacological Basis of THERAPEUTICS.
3. RANG AND DALE’S Pharmacology, 7th edition.
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41. Questions
1. Explain the treatment regimen for TB and MDR-TB
2. Write a note on pharmacology of first line drugs used for treatment
of TB.
3. Write the pharmacology of isoniazid and rifampin.
4. Write a note on treatment of TB in HIV infected patients.
5. Write a note on second line drugs used in the treatment of TB.
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42. Thank you
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