- Mycobacterium infections like tuberculosis are difficult to treat due to their lipid-rich cell walls and ability to reside intracellularly. Combination drug therapy is required to prevent resistance. - Common first-line drugs include isoniazid, rifampin, pyrazinamide, and ethambutol. Second-line alternatives include ethionamide, capreomycin, cycloserine, aminoglycosides, and fluoroquinolones. - Each drug has a unique mechanism of action and potential adverse effects that require monitoring like hepatitis, neuropathy, and optic neuritis. Combination therapy and treatment duration aims to kill both actively growing and dormant bacilli.

1. Presented To: Dr Asif
Presented By: Jameel Ahmed Abro
Topic: Anti-mycobacterial

2. Anti-mycobacterial drugs

3. Mycobacterial infections
 Are slender, rod-shaped bacteria with lipid-rich cell walls.
 Grow slowly compared with other bacteria, antibiotics that are most
active against growing cells are relatively ineffective.
 These are intracellular pathogens, and organisms residing within
macrophages are inaccessible to drugs that penetrate these cells
poorly.
 These microbes are notorious for their ability to develop resistance.
Combinations of two or more drugs are required to overcome these
obstacles and to prevent emergence of resistance during course of
therapy.

4. Mycobacterial infections
 The most widely encountered mycobacterial infections are
tuberculosis, leprosy as well as several tuberculosis-like
human infections.

5. Chemotherapy for Tuberculosis

6. Isoniazi (INH)

7. Isoniazid (INH)
 Is the synthetic analogue of pyridoxine.
 One of the most potent anti-tuberculosis drugs but never given
as a single agent.
 Targeted enzymes are enoyl acyl carrier protein reductase (InhA)
and a ketoacyl-ACP synthase (KasA). The activated drug
covalently binds to and inhibits these enzymes leading to
inhibition of mycolic acid synthesis.

8. Antibacterial spectrum
 Isoniazid penetrates into macrophages and is active against
both extracellular and intracellular organisms.
 Specific for the treatment of M. tuberculosis. Mycobacterium
kansasii susceptible at higher concentrations.
 For bacilli in the stationary phase, isoniazid is bacteriostatic,
but for rapidly dividing organisms, it is bactericidal.

9. Pharmacokinetics
 Readily absorbed after oral administration (food, particularly
carbohydrates, or aluminium-containing antacids impair
absorption).
 Diffuses into body fluids including CSF, cells and necrotic tissue
resembling cheese that is produced in tubercles.
 Infected tissue tends to retain the drug longer.
 INH undergoes N-acetylation and hydrolysis in liver, resulting in
inactive products.

10. Pharmacokinetics
 Excretion is through glomerular filtration, predominantly as
metabolites.
 Chronic liver disease decreases metabolism therefore doses must
be reduced.
 Half life of INH in fast acetylators is short (1 h approx.) while in
slow acetylators it is increased (3 h approx.).
 Slow acetylators excrete more of the parent compound. Severely
depressed renal function results in accumulation of the drug,
primarily in slow acetylators.

11. Adverse reactions
 Related to dose and duration of INH therapy
1) Peripheral neuropathy (paresthesia of hands and feet).
Caused by the deficiency of pyridoxine. IHN promotes excretion of
pyridoxine, and this toxicity is readily reversed by administration of
pyridoxine in a dosage as low as 10 mg/d.
2) Isoniazid-induced hepatitis and idiosyncratic hepatotoxicity
Is the most common major toxic effect of INH. It has been
suggested that this is caused by a toxic metabolite, of
monoacetylhydrazine, formed during the metabolism of isoniazid.

12. Rifamycins
 Rifampin, rifabutin and rifapentine
 A group of structurally similar macrocyclic antibiotics, which
are first-line drugs for the treatment of tuberculosis.
 Must always be used in conjunction with at least one other anti-
tuberculosis drug to which the isolate (mycobacterium) is
susceptible.

13. Rifampin
 Derived from the soil mold Streptomyces.
 Has a broader antimicrobial activity than isoniazid.
 Due to emergence of resistance during therapy, it is never given
as a single agent in the treatment of active tuberculosis.
 It binds with β-subunit of bacterial DNA-dependent RNA
polymerase. This lead to inhibition of transcription and mRNA
synthesis.
 Readily penetrates into most of tissues and phagocytic cells.

14. Rifampin
 Can kill organisms that are poorly accessible to many other
drugs, such as intracellular organisms and those sequestered
in abscesses and lung cavities.
 Bactericidal for both intracellular and extracellular
mycobacteria, including M. tuberculosis, and atypical
mycobacteria, such as M. kansasii.
 Well absorbed after oral administration.
 Undergoes enterohepatic cycling.

15. Rifampin
 Distribute into all body organs and fluids including CSF even
in the absence of inflammation.
 Elimination of metabolites and the parent drug is via the bile into
the feces or via the urine.
 Urine and feces as well as other secretions have an orange-red
color. Tears may permanently stain soft contact lenses orange-
red. Patients should be informed about that.

16. Adverse effects
 Most common adverse reactions include nausea, vomiting, and
rash.
 A flu-like syndrome is associated with fever, chills, and
myalgias when administered in daily doses of 1.2 grams or
greater.
 Should be used with caution in alcoholic, elderly, or in patients
with chronic liver diseases when administered alone or
concomitantly with isoniazid (Can cause hepatic failure).

17. Rifamycins
2) Rifabutin
 A derivative of rifampin.
 Preferred anti-tuberculosis drug in human immunodeficiency
virus (HIV) patients who are concomitantly treated with
protease inhibitors or nonnucleoside reverse transcriptase
inhibitors, because it is a less potent inducer of cytochrome
P450 enzymes.
 Adverse effects similar to rifampin but can also cause skin
hyperpigmentation, and neutropenia.

18. Rifamycins
3) Rifapentine
 Has a longer half-life than rifampin and rifabutin, which permits
weekly dosing.
 In intensive phase (initial 2 months) twice weekly dosing
followed by once per week for 4 months in the subsequent
phase.
 To avoid resistance issues, it should be included in a three to
four-drug regimen.

19. 3. Pyrazinamide
 A synthetic, orally effective agent which is used in combination
with isoniazid, rifampin, and ethambutol.
 Enzymatically hydrolyzed to is its active form (pyrazinoic
acid) by mycobacterial pyrazinamidase.
 Bactericidal towards actively dividing organisms.
 Its mechanism of its action is unknown.
 Taken up by macrophages and exerts its activity against
mycobacteria residing within acidic environment of lysosomes.

20. 3. Pyrazinamide
 Distributed throughout the body including CSF.
 Undergoes extensive metabolism.
 It is an important front-line drug used in conjunction with
isoniazid and rifampin in short-course (i.e., 6-month) therapy as
a "sterilizing" agent active against residual intracellular
organisms that may cause relapse.
 About 1-5 % of patients taking isoniazid, rifampin, and
pyrazinamide may experience liver dysfunction.
 Uric acid retention (hyperuricemia) can also occur and may
precipitate a gouty attack

21. 4. Ethambutol
 Is a bacteriostatic agent which is active against most strains of
M. tuberculosis and M. kansasii.
 Inhibits mycobacterial arabinosyl transferases which is
involved in the polymerization reaction of arabinoglycan, an
essential component of the mycobacterial cell wall.
 Absorbed after oral administration.
 Well distributed throughout the body.
 Penetration into the central nervous system (CNS) is
therapeutically adequate in tuberculous meningitis.

22. 4. Ethambutol
 Parent drug and metabolites are excreted by glomerular filtration
and tubular secretion.
 Most important adverse effect is optic neuritis resulting in
diminished visual acuity (clarity of vision) and loss of ability to
discriminate between red and green color. Discontinuation of
the drug results in reversal of the optic symptoms.
 In addition, urate excretion is decreased by the drug; thus, gout
may be exacerbated.

23. Alternative Second-Line Drugs for Tuberculosis

24. Second line agents
 These agents are used,
(1) In case of resistance to first-line agents.
(2) In case of failure of clinical response to conventional therapy.
(3) Because they are particularly active against atypical strains of
mycobacteria.

25. Ethionamide
 Chemically related to isoniazid
 Blocks the synthesis of mycolic acids.
 It is poorly water soluble and available only in oral form.
 Widely distributed throughout the body, including CSF.
 Metabolized by the liver.
 Adverse effects limiting its use include gastric irritation,
hepatotoxicity, peripheral neuropathies, and optic neuritis.
 Supplementation with vitamin B6 (pyridoxine) may lessen the
severity of the neurologic side effects.

26. Capreomycin
 Is a peptide antibiotic which acts as a protein synthesis
inhibitor obtained from Streptomyces capreolus.
 Administered parenterally (Intramuscular).
 Primarily reserved for the treatment of multidrug-resistant
tuberculosis.
 Capreomycin is nephrotoxic and ototoxic. Tinnitus, deafness,
and vestibular disturbances can occur. The injection causes
significant local pain, and sterile abscesses may occur.

27. Cycloserine
 Is an inhibitor of cell wall synthesis.
 Distributed throughout body fluids, including CSF.
 Undergo metabolism, and both parent drug and metabolite are
excreted in urine.
 Accumulation occurs in renal insufficiency.
 Adverse events include CNS disturbances, and epileptic
seizures may be exacerbated.
 Peripheral neuropathies are also a problem, but they respond
to pyridoxine.

28. Aminoglycoside antibiotics
 Streptomycin, kanamycin and amikacin
 Streptomycin action is directed against extracellular organisms.
 Kanamycin has been used for treatment of tuberculosis caused by
streptomycin-resistant strains, but the availability of less toxic
alternatives (e.g., capreomycin and amikacin) has rendered it
obsolete.
 Amikacin is also active against atypical mycobacteria.
 indicated for treatment of tuberculosis suspected or known to be
caused by streptomycin-resistant or multidrug-resistant strains.

29. Aminoglycoside antibiotics
 Amikacin must be used in combination with at least one and
preferably two or three other drugs to which the isolate is
susceptible for treatment of drug-resistant cases.

30. Fluoroquinolones
 Fluoroquinolones, such as ciprofloxacin, levofloxacin,
gatifloxacin, and moxifloxacin inhibit M tuberculosis strains.
 Some agents are also active against atypical strains of
mycobacteria.
 These agents paly an important role in the treatment of
multidrug-resistant tuberculosis strains.

31. Macrolides
 Azithromycin and clarithromycin.
 These agents are part of the regimen that includes ethambutol
and rifabutin used for the treatment of infections caused by M.
avium-intracellulare complex.
 Azithromycin is preferred for HIV-infected patients because it
is least likely to interfere with the metabolism of antiretroviral
drugs.

32. Linezolid
 Active against M tuberculosis strains.
 Good intracellular penetration, and it is active in murine
models of tuberculosis.
 Used in combination with other drugs to treat multidrug-resistant
strains.
 Treatment-limiting adverse effects, including bone marrow
suppression and irreversible peripheral and optic
neuropathy.
 Should be considered a drug of last resort for infection caused
by multidrug-resistant strains

33. Chemotherapy for Leprosy

34.  Mycobacterium leprae
 World Health Organization recommends the triple-drug regimen of
dapsone, clofazimine, and rifampin for 6 to 24 months.
1) Dapsone
 Structurally related to the sulfonamides.
 Inhibits folate synthesis via dihydropteroate synthetase inhibiton.
 Bacteriostatic for Mycobacterium leprae.
 Well absorbed from GIT.
 Distributed throughout the body.
 Tends to be retained in skin, muscle, liver, and kidney.

35. 1) Dapsone
 Skin heavily infected with M leprae may contain several times
more drug than normal skin.
 Parent drug enters the enterohepatic circulation and undergoes
hepatic acetylation.
 Both parent drug and metabolites are eliminated through the urine.
 Adverse reactions include hemolysis, (patients with glucose 6-
phosphate dehydrogenase deficiency), methemoglobinemia,
peripheral neuropathy, and the possibility of developing
erythema nodosum leprosum (a serious and severe skin
complication of leprosy).

36. 2) Clofazimine
 Is a phenazine dye that can be used as an alternative to dapsone.
 Binds to DNA and prevents it from serving as a template for
future DNA replication.
 Its redox properties may lead to the generation of cytotoxic
oxygen radicals that are also toxic to the bacteria.
 Bactericidal to M. leprae and has some activity against M.
avium-intracellulare complex.
 Has variable absorption after oral administration.

37. 2) Clofazimine
 Stored widely in tissues.
 Slowly released from these deposits resulting in serum half-life
of 2 months approx.
 Major portion of the drug is excreted in feces.
 Given for sulfone (dapsone)-resistant leprosy or when patients
are intolerant to sulfones.
 Prominent untoward effect is skin discoloration ranging from
red-brown to nearly black.

38. 3) Rifampin
 In a dosage of 600 mg daily is highly effective in lepromatous
leprosy.
 Given in combination with dapsone or another antileprosy drug.