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1. ANTI MYCOBACTERIAL
DRUGS

2. MYCOBACTERIA
• They are acid-fast bacilli belonging to the
Mycobacteriaceae
• Responsible for tuberculosis and leprosy and other
less common diseases
• They are slow-growing and difficult to stain
• They possess abnormally high lipid content in the
cell wall
• Complex cell envelope is responsible for
pathogenicity or virulence and multiple drug
resistance
• Several successful agents inhibits cell envelope
synthesis as their MOA

3. TUBERCULOSIS
• Tuberculosis is one of the world’s most
widespread and deadly illnesses.
• Mycobacterium tuberculosis, the
organism that causes tuberculosis
infection and disease, infects an
estimated 20 – 43% of the world’s
population.
• 3 million people worldwide die each year
from the disease

4. TUBERCULOSIS
• Tuberculosis occurs among disadvantaged
populations such as the malnourished, homeless,
and those living in overcrowded and sub -standard
housing.
• There is an increased occurance of tuberculosis
among HIV +ve individuals.

5. TUBERCULOSIS
• M tuberculosis is transmitted primarily via respiratory
route
• Infection begins when a susceptible person inhales
airborne droplet containing viable organisms.
• Droplets consisting organisms are expelled during
coughing, sneezing, or talking
• Tubercle bacilli that reach the alveoli are ingested by
alveolar macrophages (Alveolar macrophages are
the primary phagocytes of the innate immune
system)
• Infection follows if the inoculum escapes alveolar
macrophage mirobicidal activity.
• TB mainly affects the lungs (80-85%)
• But it can spread through blood & lymphatic system
to brain, bones, eyes, & skin

6. TUBERCULOSIS
• Pathogenic mycobacterium can be divided into
a. organisms that are actively metabolizing &
rapidly growing
b. dormant…….problematic & responsible for
treatment failures
• Most TB drugs are effective against rapidly
growing bacilli
• Therefore successful treatment involves
combination therapy for extended period of
timing

7. TUBERCULOSIS
Symptoms and Signs:
 chronic cough with bloodcontaining s
putum
 fever
 night sweats
 weight loss
 nail clubbing

9. ANTI-TB DRUGS
• First line drugs: These drugs have high antitubercular
efficacy as well as low toxicity; are used routinely.
• Second line drugs: These drugs have either low
antitubercular efficacy or higher toxicity or both;
and are used as reserve drugs.

10. ANTI MYCOBACTERIAL DRUGS
 Drugs Used in Tuberculosis
First-line drugs :
1. Rifampicin,
2. Isoniazid (INH),
3. Pyrazinamide,
4. Ethambutol, and
5. Streptomycin
 Isoniazid and Rifampin are the two most active
drugs.
Mnemonics
 RIPES
PAS*, ethonamide,
isonamide,
pyrazinamide,
ethambutol*,

11. FIRST LINE DRUGS
Rifampicin
Isoniazid
(INH)

12. Pyrazinamide
(PZA)
Ethambutol

13. Streptomycin

14. SECOND LINE DRUGS
• Ethionamide
• Para-aminosalicylic acid
• Cycloserine
• Prothionamide
• Terizidone
Fluoroquinolones
• Ofloxacin
• Levofloxacin
• Moxifloxacin
• Ciprofloxacin

15. Ethionamide Para-aminosalicylic acid Cycloserine
Prothionamide Terizidone

16. FLUOROQUINOLONES
Ofloxacin
O
NN
N
O
OH
O
F
O
NN
N
O
OH
O
F
H
Levofloxacin
Racemic mixture Pure (-) S isomer

17. Moxifloxacin Ciprofloxacin

18. ISONIAZIDE (ISONICOTINIC ACID HYDRAZIDE,
OR INH)
• INH is remarkably effective first line primary agent
• Resistance to INH during therapy was major shortcoming of
the drug
• This problem largely overcome with the use of
combinations
• Active against growing tubercle bacilli & not on resting
form
• INH is bactericidal, it cause to lose lipid content of cell wall
pyridine-4-carbohydrazide

19. MOA-NOT FULLY UNDERSTOOD
• 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 explains the high selectivity of INH for
mycobacteria (it is not active against any
other microorganism).
• Two gene products (Enzymes) ‘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 forms adduct with NAD that inhibits
InhA and KasA.

20. RIFAMPICIN
MECHANISM OF ACTION
• It is a semisynthetic derivative of rifamycin B
obtained from Streptomyces mediterranei.
• Rifampin is bactericidal to M. tuberculosis and many
other gram-positive and gram-negative bacteria.
• 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 avidly bind rifampin.

21. PYRAZINAMIDE (PYRAZINECARBOXAMIDE,
PZA)
• Pyrazinamide is used as first-line agent for short-term
tuberculosis treatment regimens because of its
• PZA has tuberculocidal activity and comparatively
low short-term toxicity.
• Since pyrazinamide is not active against
metabolically inactive tubercle bacilli, it is not
considered suitable for long-term therapy
• Bacterial resistance to pyrazinamide develops rapidly
• So it should always be used in combination
• The mechanism of action of pyrazinamide is not well
established, but like INH it is also converted inside the
mycobacterial cell into an active metabolite
pyrazinoic acid
pyrazine-2-carboxamide

22. ETHAMBUTOL (EMB)
• Ethambutol is active only against dividing
mycobacteria.
• The dextro isomer is 16 times as active as the meso
isomer.
• length of the alkylene chain, the nature of the
branching of the alkyl substituents on the nitrogens,
and the extent of N-alkylation all have a
pronounced effect on the activity.
• Ethambutol is use in combinations with other
antitubercular drugs in the chemotherapy of
pulmonary tuberculosis.
• MOA : related to the inhibition of the incorporation of
mycolic acids into the cell walls of mycobacteria.
(+)-2,2-(ethylenediimino)-di-1-butanol

23. ETHIONAMIDE
• Ethionamide is considered a secondary drug for
the treatment of tuberculosis.
• It is used in the treatment of isoniazid resistant
tuberculosis
• or when the patient is intolerant to isoniazid and
other drugs.
• Because of its low potency, the highest tolerated
dose of ethionamide is usually recommended
2-Ethylthioisonicotinamide

24. P-AMINOSALICYLIC ACID (PAS)
• For many years PAS was considered as first-line
drug for the chemotherapy of tuberculosis.
• and was generally included in combination
regimens with isoniazid and streptomycin.
• Due to introduction of the more effective and
better tolerated agents, ethambutol and
rifampin, it is considered as alternative drug.
• MOA: The mechanism of antibacterial action of
PAS is similar to that of the sulfonamides.
• Thus, it prevent the incorporation of p-
aminobenzoic acid (PABA) into the dihydrofolic
acid molecule catalyzed by the enzyme
dihydrofolate synthetase.

25. ANTITUBERCULAR ANTIBIOTICS
CYCLOSERINE (SEROMYCIN)
• Isolated from the fermentation brewing of three
different Streptomyces species: S. orchidaceus, S.
garyphalus, and S. lavendulus.
• It is recommended for patients who fail to
respond to other tuberculostatic drugs or who
are infected with organisms resistant to other
agents.
• It is usually administered orally in combination
with other drugs, commonly isoniazid
• MOA: Prevent the synthesis of cross-linking peptide in the
bacterial cell walls by irreversible inactivation of the
enzyme alanine racemase.
• thereby deprives the cell of the D-alanine required for the
synthesis of the cross-linking peptide
D-(+)-4-Amino-3-isoxazolidinone

26. RIFAMPIN :RIFAMPIN IS THE MOST ACTIVE AGENT IN
CLINICAL USE FOR THE TREATMENT OF TUBERCULOSIS
• Belongs to rifamycins group of antibiotics obtained by
fermentation from cultures of Streptomyces mediterranei.
• They are called ansamycins that contain a macrocyclic
ring bridged across two nonadjacent positions of an
aromatic nucleus
macrocyclic ring
Alcoholic hydroxyl
Aromatic nucleus
Phenolic hydroxyl
N-piperazine methanimine
 MOA : Potent inhibitor of DNA directed
RNA polymerase in bacteria
interrupts RNA synthesis

27. Viomycin is a member of the tuberactinomycin family, a group of
nonribosomal peptide antibiotics having anti
tuberculosis properties

28. TREATMENT OF TUBERCULOSIS
• 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 which also yields higher completion rates.
• This has been possible due to better understanding of the
biology of tubercular infection and the differential properties
of the antitubercular drugs.

29. SHORT COURSE CHEMOTHERAPY
• After several years of trial, the WHO introduced 6–8 month multidrug ‘short
course’ regimens in 1995 under the DOTS programme. An expert group
framed clearcut treatment guidelines in 1997 for different categories of TB
patients, who were grouped according to site and severity of disease, sputum
smear positivity/negativity and history of previous treatment (new case/
previously treated case) into 4 categories:
• Category I: New case of sputum smear positive or severe pulmonary TB, or
severe forms of extrapulmonary TB (meningitis, etc.).
• Category II: Defaulted, irregularly treated and relapse cases.
• Category III: New sputum smear negative pulmonary TB and less severe forms
of extrapulmonary TB (glandular/skin TB, etc.).
• Category IV: Chronic cases who remained or again became sputum smear
positive after receiving fully supervised category II treatment.

30. PROBLEMS IN CHEMOTHERAPY OF TB
1. Chemotherapy of tuberculosis faced some special problems because of slow
growth rate of mycobacteria and their intracellular location.
2. Since the disease is chronic by its nature, the therapy needs to be continued for at
least about 1–2 years in most of the cases.
3. In such a chronic treatment, if only single drug is used, the risk of development of
drug resistant strains of mycobacteria is always high. This is coupled with the risk
of drug toxicity due to high doses of a single drug needed.

31. 4. The solution to this problem is to use combination therapy. When two or
more effective drugs are used in combination, resistance will not develop.
However drugs with similar toxological profiles should not be used
together.
5. The drugs used in the combination therapy are usually selected from
ethambutol, isoniazid and rifampin. The choice is dependent upon the type
of disease and some patient-related factors

32. COMBINATION THERAPY
Chemotherapy of tuberculosis faced some problems because of slow
growth rate of the mycobacteria and their intracellular location. Since the
disease is chronic by its nature, the therapy needs to be continued for at
least 1 to 2 years in most of the cases.
In such a chronic treatment, if only single drug is used, the risk of the
development of drug resistance strain of mycobacteria is always high. This
is coupled with the drug toxicity due to high doses of the single drug.
The obvious solution to this problem is to use combination therapy. When
two or more effective drugs are used in combination, resistance will not
develop. However, in combination therapy, drugs with similar toxicological
profile should not be used.

33. Method
As single drug may cause resistance as well drug toxicity, to avoid such problem, different
combination are used.
In 1952, the combination drug used were: Isoniazid + Streptomycin + PAS
These drugs are given in three phases
 Intensive phase
 stabilization phase
 consolidation phase
1. Intensive phase
All three drugs are administered simultaneously for 6 to 7 days in a week in order to
achieve as rapid as the quickest possible elimination of the resistant organism. This
phase lasted for 3 to 6 month.
2. Stabilization Phase
During this phase only two drugs has been given, these are isoniazid + PAS were given for
6 to 9 months, the main purpose behind this is that reduction in bacterial count and total
elimination of the resistant mutants.

34. 3. Consolidation phase
This phase is lasted up to the two years. Isoniazide was given as mono
therapy in order to destroy persisting organism and so to provide greater
protection against micro-organism.
This combination therapy change according to the invention of the new
drug.
In 1962 Isoniazid + Streptomycin + Ethambutol.
Later
• Isoniazid + Rifampicin + Ethambutol

35. LEPROSY
Leprosy or Hansen’s disease is a chronic human disease caused due to an
acid-fast bacillus which produces nodules in the skin and loss of sensation
in the affected region.
This dermatological infection is caused by Mycobacterium leprae and the
disease develops very slowly over a period of years.

36. Based upon the area under infection and intensity of lepra reactions, leprosy
can be categorised into:
1. Tuberculoid leprosy: It is characterized by the presence of infection in restricted
area and less pronounced lepra reaction. The latter indicates that very few numbers
of microorganisms are present in the infected area of the skin. Hence dapsone alone
may be effective.
2. Lepromatous leprosy: It is characterized by a widely disseminated disease with a
high number of infecting micro-organisms. Hence this form needs more drastic (i.e.
multidrug) and prolonged treatment.
3. Indeterminate leprosy: In very early stages of the disease, microorganisms are not
multiplied to the extent to induce lepra reactions. This early form of the disease is
known as indeterminate leprosy.
4. Borderline leprosy: Tuberculoid leprosy and lepromatous leprosy are the two
extremities of the active form of the disease. All other forms that lie in between
these two extremities are known as borderline forms of leprosy.

38. Rifampicin

39. P-aminosalicylic acid

41. 4,4-dinitrodiphenyl sulfide bis (4-nitro phenyl) sulfone Dapsone

42. THANK
YOU