This document discusses anti-mycobacterial drugs used to treat tuberculosis. It begins by describing tuberculosis and how it is caused by the bacterium Mycobacterium tuberculosis. First-line drugs to treat tuberculosis are listed as isoniazid, rifampin, pyrazinamide, ethambutol, and streptomycin. Each drug's mechanism of action and potential resistance issues are then explained individually. Second-line drugs discussed include ethionamide, capreomycin, cycloserine, aminosalicylic acid, and fluoroquinolones. Common adverse drug reactions are also outlined.

1. Anti mycobacterial drugs
Ravish Yadav

2. 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

3. Tuberculosis
• Tuberculosis occurs disproportionately among disadvantaged
populations such as the malnourished, homeless, and those living in
overcrowded and sub – standard housing.
• There is an increased occurrence of tuberculosis among HIV +ve
individuals.

4. Tuberculosis
• Infection with M tuberculosis begins when a susceptible person
inhales airborne droplet nuclei containing viable organisms. Tubercle
bacilli that reach the alveoli are ingested by alveolar macrophages.
Infection follows if the inoculum escapes alveolar macrophage.

5. Tuberculosis
• Once infection is established, lymphatic and hematogenous
dissemination of tuberculosis typically occurs before the
development of an effective immune response. This stage of
infection is called primary tuberculosis and usually clinically and
radiologically silent.

6. Tuberculosis
• In most persons with intact cell – mediated immunity, T
cells and macrophages surround the organisms in
granulomas that limit their multiplication and spread. The
infection is contained but not eradicated, since viable
organisms may lie dormant within granulomas for years to
decades. This is called latent tuberculosis.
• Individuals with this latent tuberculosis infection do not
have active disease and can not transmit the organism to
others. However, reactivation of disease may occur if the
host’s immune defenses are impaired.

7. Tuberculosis
Symptoms and Signs:
1. Malaise
2. Anorexia
3. Weight loss
4. Fever
5. Night sweats
6. Chronic cough, blood with sputum
7. Rarely, dyspnea

8. Tuberculosis
• Investigations:
• Chest radiograph shows pulmonary infiltrates most often apical
• Positive tuberculin skin test reaction (most cases)
• Acid fast bacilli on smear of sputum or sputum culture positive for
Mycobacterium tuberculosis

9. Anti Mycobacterial Drugs
• Mycobacteria are intrinsically resistant to most antibiotics.
• They grow slowly compared with other bacteria,
• Antibiotics that are most active against growing cells are relatively
ineffective. so, that’s why we use combination of drugs.
• Mycobacterial cells can also be dormant and thus completely
resistant to many drugs or killed only very slowly.

10. Anti Mycobacterial Drugs
• The lipid rich mycobacterial cell wall is impermeable to many
agents(e.g. drugs).
• Mycobacterial species are intracellular pathogens, and organisms
residing within macrophages are inaccessible to drugs that penetrate
these cells poorly.
• Finally, mycobacteria are notorious for their ability to develop
resistance.

11. • Combinations of two or more drugs are required to overcome these
obstacle and to prevent emergence of resistance during the course of
therapy.
• The response of mycobacterial infections to chemotherapy is slow,
and treatment must be administered for months to years, depending
on which drugs are used.

13. FIRST-LINE DRUGS FOR
TUBERCULOSIS
 Drugs Used in Tuberculosis
First-line drugs :
1. Rifampin,
2. Isoniazid (INH),
3. Pyrazinamide,
4. Ethambutol, and
5. Streptomycin
These drugs are the first-line agents for the treatment of
tuberculosis.
 Isoniazid and Rifampin are the two most active drugs.
Mnemonics 
RIPES

14. • It is a Isonicotinic acid hydrazide, or isonicotinyl
hydrazide, or INH.
• Isoniazid is the most active drug for the treatment of
tuberculosis caused by susceptible strains.
• It has the structural similarity to pyridoxine (Vit.B6)

15. ISONIAZID (INH)
• It is less effective against atypical mycobacterial species.
• Isoniazid penetrates into macrophages and is active against both
extra- and intracellular organisms.

16. Mechanism of Action

17. • The principal effect of isoniazid is to inhibit the synthesis of
mycolic acids, high–molecular-weight, branched ß-hydroxy
fatty acids that constitute important components of the cell
walls of mycobacteria.
• A mycobacterial catalase–peroxidase enzyme complex is
required for the bioactivation of isoniazid. A reactive
species, generated through the action of these enzymes on
the drug, is believed to attack a critical enzyme(enoyl-ACP
reductase ) required for mycolic acid synthesis in
mycobacteria.
• InhA gene encodes an enoyl-ACP reductase of fatty acid
synthase II which converts ∆2 -unsaturated to saturated
fatty acids on the pathway to mycolic acid biosynthesis.
• Activated INH inhibits this enzyme.

18. Mechanism of Resistance:
• Resistance can emerge rapidly if the drug is used alone.
• Resistance can occur due to either
1. Deletion in the katG gene that codes for a catalase peroxidase involved
in the bioactivation of INH.
2. Deletions in the inhA gene that encodes “target enzyme” an acyl carrier
protein reductase.

19. PHARMACOKINETICS:
• Isoniazid is readily absorbed from the gastrointestinal tract
• Isoniazid diffuses readily into all body fluids and tissues.
• Metabolism of isoniazid, especially acetylation by liver N-acetyl transferase,
is genetically determined.
• Isoniazid metabolites and a small amount of unchanged drug are excreted
mainly in the urine.

20. Pharmacokinetics of Isoniazid
 The average plasma concentration of isoniazid in rapid acetylators
is about one third to one half of that in slow acetylators, and
average half lives are less than 1hour and 3 hours, respectively.
 More rapid clearance of isoniazid by rapid acetylators is usually of
no therapeutic consequence when appropriate doses are
administered daily, but subtherapeutic concentration may occur if
drug is administered as a once-weekly dose or if there is
malabsorption

21. •Rifampin is a semisynthetic
derivative of rifamycin, an
antibiotic produced by
Streptomyces mediterranei.
•It belong to a class of
antibiotics called the
ansamycins that contain a
macrocyclic ring bridged
across two nonadjacent
positions of an aromatic
nucleus.

22. ANTIMICROBIAL ACTIVITY AND
RESISTANCE
• Rifampin binds to the β subunit of
bacterial DNA–dependent RNA
polymerase and thereby inhibits RNA synthesis and their
action is bactericidal..
• Resistance results from any one of
several possible point mutations in rpoB,
the gene for the β subunit of RNA
polymerase.

23. Rifampin
• These mutations result in reduced binding of rifampin to RNA
polymerase.
• Human RNA polymerase does not bind rifampin and is not inhibited
by it.
• Rifampin is bactericidal for mycobacteria. It readily penetrates most
tissues and phagocytic cells.

24. Rifampin
•It can kill organisms that are poorly accessible to
many other drugs, such as intracellular organisms
and those sequestered in abscesses and lung
cavities.
Pharmacokinetics:
• Rifampin is well absorbed after oral administration.
• It is unstable to moisture, and a desiccant (silica gel)
should be included with rifampin capsule containers.
• It is well distributed and the bulk excreted as a de-
acylated metabolite in feces and a small amount in the
urine.

25. Ethambutol is a synthetic water soluble, heat stable compound,
the dextro-isomer is dispensed as the dihydrochloride salt.
(+)-2,2-(ethylenediimino)-di-1-butanol
The dextro isomer is 16 times as active as the meso isomer.

26. Ethambutol inhibits mycobacterial arabinosyl
transferases. Arabinosyl transferases are involved in
the polymerization reaction of arabinoglycan, an
essential component of the mycobacterial cell wall.

27. • Resistance to ethambutol is due to mutations resulting in
overexpression of emb gene products or within the emb B structural
gene.
• Resistance to ethambutol emerges rapidly when used alone, therefore
it is always given with other antitubercular agents.

28.  Pyrazinamide (PZA) is a related to nicotinamide, stable and
slightly soluble in water.
• Pyrazinecarboxamide (PZA) is a heterocyclic isosteric analogs of
nicotinic acid.
• pyrazinamide is bioactivated to pyrazinoic acid by mycobacterial
amidase , which is encoded by pncA..
• Because bacterial resistance to pyrazinamide develops rapidly, it
should always be used in combination with other drugs.

29. • The drug is taken up by macrophages and exerts its activity against
mycobacteria residing within the acidic environment of lysosomes.
• The drug target and mechanism of action are unknown.
• Resistance may be due to impaired uptake of pyrazinamide or
mutations in pncA that impair conversion of pyrazinamide to its
active form.

30. Streptomycin was isolated from a strain of Streptomyces griseus.

31. Mechanism of Action of Strept.
Mechanism of action:
•Like all aminoglycosides, streptomycin irreversibly
inhibits bacterial protein synthesis. Protein synthesis
is inhibited in at least three ways:
1. interference with the initiation complex of peptide
formation.
2. Misreading of mRNA, leading to incorporation of
incorrect amino acids into the peptide, resulting
in a nonfunctional or toxic protein.
3. Breakup of polysomes into nonfunctional
monosomes.

32. Mechanism of resistance
1. Production of a transferase enzyme or enzymes inactivates the
aminoglycosides by acetylation, adenylylation or phosphorylation
(major action).
2. Impaired entry of drug into the cell.
3. The receptor protein on the 30s ribosomal subunit may be deleted
or altered as a result of mutation.

33. SECOND-LINE DRUGS FOR
TUBERCULOSIS
• The alternative drugs are usually consider only;
• 1. In case of resistance to first line agents.
• 2. In case of failure of clinical response to
• convential therapy
• 3. In case of serious treatment limiting
• adverse drug reactions
• 4. when expert guidance is available to
• deal with the toxic effects.

34. 1.ETHIONAMIDE
• Ethionamide is chemically related to isoniazid.
• It is 2- Ethylthioisonicotinamide.
• In contrast to the isoniazid series, 2-substitution enhances
activity in the thioisonicotinamide series.
Mechanism of action: Ethionamide blocks synthesis of mycolic
acids in susceptible organisms.

35. Pharmacokinetics
• Ethionamide is considered a secondary drug for the treatment of
tuberculosis. It is used in the treatment of isoniazid resistant
tuberculosis.
• Dosage : usual dose, 500 - 750mg/day.
• It is metabolized by the liver

36. 2.CAPREOMYCIN
•Capreomycin is a strongly basic cyclic Peptide (an
antibiotic) from streptomyces capreolus.

37. Mechanism of action :
It is a peptide protein synthesis inhibitor.
• Capreomycin is an important agent for the treatment of
drug resistant tuberculosis.
• Strains of M tuberculosis that are resistant to
streptomycin or amikacin usually susceptible to
capreomycin
• it may be used in place of streptomycin when either the
patient is sensitive to, or the strain of M. tuberculosis is
resistant to, streptomycin.
Adverse drug reactions :
• Nephrotoxicity
• Ototoxicity – tinnitus, deafness, vestibular disturbance
may occur.
• Local pain & sterile abscesses due to injection.

38. 3.CYCLOSERINE :
Cycloserine is an antibiotic produced by streptomyces
orchidaceus.
• Cycloserine is a structural analog of D- alanine.
• It is stable in alkaline, but unstable in acidic, solutions. The
compound slowly dimerizes to 2,5 bis(aminoxymethyl)-3,6-
diketopiperazine in solution or standing.

39. Mechanism of action :
• It inhibits the incorporation of D- alanine into peptidoglycan
pentapeptide by inhibiting alanine racemase, which converts L-alanine
to D- alanine, and D- alanyl-D –alanine ligase (finally inhibits
mycobacterial cell wall synthesis).
• Cycloserine used exclusively to treat
tuberculosis caused by mycobacterium tuberculosis resistant to first line
agents

40. Adverse effects
• CNS dysfunction, including depression and psychotic reactions.
• Peripheral neuropathy.
• Seizures
• Tremors
• Pyridoxine 150mg/day should be given with cycloserine because this
ameliorates neurologic toxicity.

41. 4.Aminosalicylic acid (PAS):
Aminosalicylic acid is a folate synthesis antagonist that is active
almost exclusively against mycobacterium tuberculosis.
• it is structurally similar to p-aminobenzoic acid (PABA).

42. SAR
• The amino and carboxyl groups must be para to each other and
free; thus, esters and amides(produrgs) must readily undergo
hydrolysis in vivo to be effective.
• The hydroxyl group may be ortho or meta to the carboxyl group,
but optimal activity is seen in the former(ortho).

43. Pharmacokinetics :
• It is readily absorbed from GIT.
• The drug is widely distributed in tissues and body fluids except
CSF.
• The N-acetyl derivative is the principal metabolite, with
significant amounts of the glycine conjugate also being formed.
• When administered with isoniazid (which also undergoes N-
acetylation), PAS increases the level of free isoniazid(i.e it inhibits
metabolism of INH).

44. 5.Fluoroquinolones :
Ciprofloxacin, Levofloxacin, gatifloxacin, can inhibit strains M
tuberculosis.
• They are also active against atypical mycobacteria.
• Fluoroquinolones are an important addition to the drugs available for
tuberculosis, especially for strains that are resistant to first line
agents.

45. Mechanism of action:
They inhibit bacterial DNA synthesis by inhibiting
bacterial topoisomerase II (DNA Gyrase) and
topoisomerase IV.
•Inhibition of DNA Gyrase prevents the relaxation of
positively supercoiled DNA that is required for
normal transcription and replication.
•Inhibition of topoisomerase IV interferes with
separation of replicated chromosomal DNA into the
respective daughter cells during cell division.

46. 6.RIFAPENTINE :
Rifapentine is an analog of rifampin.
•It is active against both M tuberculosis and M avium
Mechanism of action:
•It is a bacterial RNA polymerase inhibitor.
•Pharmacokinetics:
•Rifapentine and its active metabolite, 25 desacetyl
rifapentine have an elimination half life of 13 hours.

47. Common Adverse Reactions to
Drug Treatment (1)
Caused by Adverse Reaction Signs and Symptoms
Any drug Allergy Skin rash
Ethambutol Eye damage Blurred or changed vision
Changed color vision
Isoniazid,
Pyrazinamide,
or
Rifampin
Hepatitis Abdominal pain
Abnormal liver function test
results
Fatigue
Lack of appetite
Nausea
Vomiting
Yellowish skin or eyes
Dark urine

48. Common Adverse Reactions to
Drug Treatment (2)
Caused by Adverse Reaction Signs and Symptoms
Isoniazid Peripheral
neuropathy
Tingling sensation in hands and
feet
Pyrazinamide Gastrointestinal
intolerance
Arthralgia
Arthritis
Upset stomach, vomiting, lack
of appetite
Joint aches
Gout (rare)
Streptomycin Ear damage
Kidney damage
Balance problems
Hearing loss
Ringing in the ears
Abnormal kidney function test
results
Capreomycin Damage to the eighth
cranial nerve and renal
damage

49. Common Adverse Reactions to
Drug Treatment (3)
Caused by Adverse Reaction Signs and Symptoms
Rifamycins
• Rifabutin
• Rifapentine
• Rifampin
Thrombocytopenia
Gastrointestinal
intolerance
Drug interactions
Easy bruising
Slow blood clotting
Upset stomach
Interferes with certain
medications, such as birth
control pills, birth control
implants, and methadone
treatment

50. Drug combination to treat TB
• An isoniazid - rifampin combination administered for 9 months will
cure 95-98% of cases of tuberculosis caused by susceptible strains.
• The addition of pyrazinamide to an isoniazid rifampin combination
for the first two months allow the total duration of therapy to be
reduced to 6 months without loss of efficacy.

51. Drug combination to treat TB
• In practice therapy is initiated with a four drug regimen of isoniazid,
rifampin, pyrazinamide, and either ethambutol or streptomycin to
determine susceptibility to the clinical isolate.

52. Drug combination to treat TB
Initial phase: standard four drug
regimens (INH + RIF + PZA + EMB), for
2 months, (except one regimen that
excludes PZA)
Continuation phase: additional 4 months
of INH + RIF (7 months for some
patients)

53. LEPROSY
• Leprosy is a chronic infectious disease caused by the acid – fast rod
Mycobacterium leprae.
• The mode of transmission probably is respiratory and involves
prolonged exposure in childhood.

54. LEPROSY
• Symptoms and Signs:
1. onset is insidious
2. Lesions involve the cooler body tissues:
skin, superficial nerves, nose, pharynx,
larynx, eyes, and testicles.
3. skin lesions may occur as pale,
anesthetic macular lesions 1 – 10 cm in
diameter

55. LEPROSY
Discrete erythematous, infiltrated nodules 1- 5 cm in diameter; or a
diffuse skin infiltration.
Neurologic disturbances are manifested by nerve infiltration and
thickening, with resultant anesthesia, neuritis and paraesthesia.
Bilateral ulnar neuropathy is highly suggestive.

56. LEPROSY
• In untreated cases, disfigurement due to the skin infiltration and
nerve involvement may be extreme, leading to trophic ulcers, bone
resorption, and loss of digits.

57. DRUGS USED IN LEPROSY :
1.SULFONES: Several sulfones have proved useful in the
treatment of leprosy, but among them only dapsone is
clinically used today.
• The parent sulfone, dapsone is the prototype for various
analogs that have been widely studied.
Dapsone
4,4-sulfonylbisbenzeneamine; or
4,4-sulfonyldianiline or
p,p-diaminodiphenylsulfone or
DDS

58. DAPSONE
•used effectively in the long-term treatment of
leprosy.
Mechanism of action :
•Dapsone like the sulfonamides, inhibits folate
synthesis (PABA antagonist).
•bacteriostatic
Resistance can emerge in large populations of M
leprae, eg, in lepromatous leprosy, if very low doses
are given.
•combination of dapsone, rifampin and clofazimine
is recommended for initial therapy.

59. DAPSONE & OTHER SULFONES:
Clinical uses :
 Leprosy:
1. Tuberculoid leprosy: with rifampin
2. Lempromatous leprosy: with rifampin and
clofazimine
Prevention and treatment of pneumocystis jiroveci
pneumonia in AIDS patients.
 Pharmacokinetics:
Sulfones are well absorbed from the gut and widely
distributed throughout body fluids and tissues.
T1/2 = 1-2 days

60. DAPSONE &OTHER DRUGS
Drug tends to be retained in the skin, muscle, liver and kidney.
Skin heavily infected with M leprae may contain several times more
drug than normal skin.

61. DAPSONE & OHER SULFONES
Dosage : 100mg daily in leprosy.
(for children the dose is depending on weight)
 Adverse effects :
Haemolysis ( in patients having G6PD deficiency).
Methemoglobenemmia
GI intolerance
Fever
Pruritus and various rashes

62. DAPSONE & OTHER SULFONES
• Erythema nodosum leprosum reaction Develops during dapsone
therapy of lepromatous leprosy.
• Suppressed by corticosteroids or thalidomide

63. 2.RIFAMPIN
Rifampin is highly effective in lepromatous leprosy.
Because of resistant, the drug is given in combination with dapsone
or another anti leprosy drug.

64. 3.CLOFAZIMINE
• Clofazimine is a rihimino phenazine dye that can be used as an
alternative to dapsone that exerts a slow bactericidal effect on M.
leprae.

65. Pharmacokinetics :
Mechanism of action :
Unknown, but may involve DNA binding.
Clofazimine binds to DNA & inhibits template function. Its redox
properties may lead to generation of cytotoxic oxygen radicals that
are also toxic to the bacteria. Thus bactericidal
Clofazimine is stored widely in reticulo endothelial tissues and skin,
and its crystal can be seen inside phagocytic reticulo endothelial cells.

66. Pharmacokinetics :
•It is slowly released from these deposits, so that the
serum half life may be 2 months.
•Clofazimine is given for sulfone – resistant leprosy or
when patients are intolerent to sulfones.
•In addition to its antibacterial action, the drug
appears to possess anti-inflammatory and immune-
modulating effects that are of value in controlling
neuritic complications and in suppressing erythema
nodosum leprosum reactions associated with
lepromatous leprosy

67. Adverse effects
• Skin discoloration ranging from red brown to nearly black (major
adverse effect)
• Gastrointestinal intolerance occurs occasionally.(eosinophilic
enteritis)

68. Drug combination to treat Leprosy
• Initial phase:
Dapsone + Clofazimine + Rifampin
Continuation phase: Dapsone alone