2. Tuberculosis
ā¢ Is prototype example of granulomatous
inflammation.
ā¢ It is a chronic specific inflammatory infectious
disease caused by Mycobacterium
tuberculosis in humans.
ā¢ Tuberculosis usually attacks the lungs but it
can also affect any parts of the body
9. MODE OF TRANSMISSION. :
ā¢ 1. Inhalation of organisms present in fresh cough droplets or in
dried sputum from an open case of pulmonary tuberculosis.
ā¢ 2. Ingestion of the organisms leads to development of tonsillar or
intestinal tuberculosis. This mode of infection of human tubercle
bacilli is from self-swallowing of infected sputum of an open case of
pulmonary tuberculosis, or ingestion of bovine tubercle bacilli from
milk of diseased cows.
ā¢ 3. Inoculation of the organisms into the skin may rarely occur
ā¢ from infected postmortem tissue.
ā¢ 4. Transplacental route results in development of congenital
tuberculosis in foetus from infected mother and is a rare mode of
transmission.
10. Five patterns of the TB disease are recognised:
i) Pulmonary disease produced by M. kansasii or M. avium
intracellulare.
ii) Lymphadenitis caused by M. avium-intracellulare or M.
scrofulaceum.
iii) Ulcerated skin lesions produced by M. ulcerans or M.
marinum.
iv) Abscesses caused by M.fortuitum or M. chelonae.
v) Bacteraemias by M. avium-intracellulare as seen in
immunosuppressed patients of AIDS.
11.
12. ā¢ Known as āAcid-fast bacilli" because of their
lipid-rich cell walls, which are relatively
impermeable to various basic dyes unless the
dyes are combined with phenol.
13.
14. Mycobacterium avium complex (MAC)
ā¢ consists of two species: M avium and M
intracellulare; because these species are
difficult to differentiate, they are also
collectively referred to as Mycobacterium
avium-intracellulare (MAI)
15. ā¢ The diagnosis is made by the following tests:
ā¢ i) Positive Mantoux skin test.
ā¢ ii) Positive sputum for AFB (on smear or culture).
ā¢ iii) Complete haemogram (lymphocytosis and raised
ERR).
ā¢ iv) Chest X-ray (characteristic hilar nodules and other
ā¢ parenchymal changes).
ā¢ v) Fine needle aspiration cytology of an enlarged
peripheral
ā¢ lymph node is quite helpful for confirmation of
diagnosis
16. ā¢ First line: These drugs have high
antitubercular efficacy as well as low toxicity;
are used routinely.
ā¢ Second line: These drugs have either low
antitubercular efficacy or higher toxicity or
both; and are used as reserve drugs.
17.
18. Rifampin (Rifampicin, R)
ā¢ It is a semisynthetic derivative of rifamycin B
obtained from Streptomyces mediterranei.
ā¢ Rifampin is bactericidal to M. tuberculosis
ā¢ It is well absorbed orally, (bioavailability is ~
70%), but food decreases absorption; rifampin
is to be taken in empty stomach.
19. MOA
ā¢ The rifamycins (rifampin, rifabutin, rifapentine) are bactericidal
and inhibit deoxyribonucleic acid (DNA)-dependent ribonucleic
acid (RNA) polymerase of mycobacteria (but not mammals). This
enzyme is composed of four subunits; rifamycins bind to the Ī²-
subunit, which results in blocking the growing RNA chain .
ā¢ Mechanism of resistance
ā¢ Resistance is conferred by single mutations that tend to occur
(>95%) in an 81-base pair region of the rpoB gene that codes for the
Ī²-subunit.
20.
21. ADR
ā¢ Hepatitis
ā¢ Cutaneous syndrome: flushing, pruritus + rash (especially
on face and scalp), redness and watering of eyes.
ā¢ Flu syndrome: with chills, fever, headache, malaise and bone
pain.
ā¢ Abdominal syndrome: nausea, vomiting, abdominal cramps
with or without diarrhoea.
Urine and secretions may become orange-redā but this is
harmless.
ā¢ Respiratory syndrome: breathlessness which may be
associated with shock and collapse.
ā¢ Purpura, haemolysis, shock and renal failure
22. isoniazid
ā¢ INH enters by passive diffusion
and is activated by katG to a
range of reactive species or
radicals and isonicotinic acid.
ā¢ These attack multiple targets,
including mycolic acid
synthesis, lipid peroxidation,
DNA, and NAD metabolism.
ā¢ Deficient efflux and
insufficient antagonism of INH-
derived radicals, such as
defective antioxidative
defense, may underlie the
unique susceptibility of M.
tuberculosis to INH.
23. ā¢ inhibition of synthesis of mycolic acids which are unique fatty acid
components of mycobacterial cell wall.
ā¢ The lipid content of mycobacteria exposed to INH is reduced.
ā¢ Two gene products labelled āInhAā and āKasAā, which function in
mycolic acid synthesis are the targets of INH action.
ā¢ INH enters sensitive mycobacteria which convert it by a catalase-
peroxidase enzyme into a reactive metabolite.
ā¢ This then forms adduct with NAD that inhibits InhA and KasA.
ā¢ The reactive INH metabolite forms adduct with NADP as well which
inhibits mycobacterial DHFRase resulting in interruption of DNA
synthesis.
24. pharmacokinetics
ā¢ It is extensively metabolized in liver; most important pathway being
N-acetylation by NAT2.
ā¢ The rate of INH acetylation shows genetic variation. There are
ā¢ either:
ā¢ Fast acetylators (30ā40% of Indians) tĀ½ of INH 1 hr.
ā¢ Slow acetylators (60ā70% of Indians) tĀ½ of INH 3 hr.
ā¢ The proportion of fast and slow acetylators differs in different parts
of the world.
ā¢ However, acetylator status does not matter if INH is taken daily, but
biweekly regimens are less effective in fast acetylators. Isoniazid
induced peripheral neuritis is more common in slow acetylators.
25. ADR
ā¢ Dosedependant toxic effect like Peripheral neuritis and a variety
of neurological manifestations (paresthesias, numbness, mental
disturbances, rarely convulsions)
ā¢ These are due to interference with production of the active
coenzyme pyridoxal phosphate from pyridoxine, and its increased
excretion in urine
ā¢ Pyridoxine given prophylactically (10 mg/day) prevents the
neurotoxicity even with higher doses.
ā¢ INH induced hepatotoxicity
26. pyrazinamide
ā¢ Pyrazinamide is inactive at neutral pH but
tuberculostatic at acid pH.
ā¢ It is effective against the intracellular
organisms in macrophages because, after
phagocytosis, the organisms are contained in
phagolysosomes where the pH is low.
ā¢ Resistance develops rather readily, but cross-
resistance with isoniazid does not occur.
27. ā¢ PZA is converted to
pyrazinoic acid (POA) by the
enzyme encoded by pncA.
Its ability to kill M.
tuberculosis and not
other Mycobacteria species
may be due to a selective
defect in POA efflux in M.
tuberculosis.
ā¢ Proposed targets include
the mycobacterial fatty acid
synthase 1 and disruption of
mycobacterial membranes
by acidic action.
28. ADR
ā¢ Hepatotoxicity. Daily dose is limited to 25ā30
mg/kg
ā¢ Hyperuricaemia is common and is due to
inhibition of uric acid secretion in kidney: gout
can occur.
ā¢ Hyperuricaemia is common and is due to
inhibition of uric acid secretion in kidney: gout
can occur.
29. Ethambutol
ā¢ Ethambutol is selectively tuberculostatic and
is active against MAC as well as some other
mycobacteria, but not other types of bacteria.
ā¢ Resistance emerges rapidly if the drug is used
alone.
ā¢ Ethambutol is given orally and is well
absorbed.
ā¢ It can reach therapeutic concentrations in the
CSF in tuberculous meningitis.
30. ā¢ MOA
ā¢ 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.
ā¢ Mechanism of resistance
ā¢ Resistance to E develops slowly and is most commonly associated
with mutation in embB gene, reducing the affinity of the target
enzyme for E.
ā¢ No cross resistance with any other antitubercular drug has been
noted
31. ADR
ā¢ Safe during pregnancy
ā¢ Dose and duration dependant toxicities-Loss
of visual acuity/colour vision, field defects due
to optic neuritis
ā¢ nausea, rashes, fever, rarely peripheral
neuritis,Hyperuricemia
32. Streptomycin (S)
ā¢ an aminoglycoside antibiotic, acts by inhibiting bacterial protein
synthesis.
ā¢ It is given intramuscularly.
ā¢ Unwanted effects are ototoxicity (mainly vestibular) and
nephrotoxicity.
ā¢ acts only on extracellular bacilli (because of poor penetration into
cells)
ā¢ Donot cross CSF
ā¢ Develop resistance when used alone
ā¢ Due to low margin of safety -Use is restricted to a maximum
of 2 months. It is thus also labelled as a āsupplementalā 1st line
drug.
33. Second line drugs
ā¢ 1. Kanamycin (Km), Amikacin (Am)- similar to streptomycin
ā¢ 2. Capreomycin (Cm)
ā¢ 3. Fluoroquinolones (FQs)
ā¢ 4. Ethionamide (Eto) āsimilar to INH
ā¢ 5. Prothionamide (Pto)-similar to Eto
ā¢ 6. Cycloserine (Cs)
ā¢ 7. Terizidone-contain 2 molecules of cycloserine
ā¢ 8. Para-amino salicylic acid (PAS)-similar to sulphonamides
ā¢ 9. Thiacetazone (Thz)-not understood
ā¢ 10. Rifabutin
34. Capreomycin(Cm)
ā¢ It is a cyclic peptide antibiotic, chemically very
different from aminoglycosides, but with similar
mycobactericidal activity, ototoxicity and
nephrotoxicity.
ā¢ Unwanted effects include kidney damage and
injury to the auditory
ā¢ nerve, with consequent deafness and ataxia.
ā¢ The drug should not be given at the same time as
streptomycin or other drugs that may cause
deafness.
35. Cycloserine (Cs)
ā¢ This polypeptide antibiotic obtained from S.orchidaceus is an
analogue of D-alanine.
ā¢ Accordingly, it inhibits bacterial cell well synthesis by inactivating
the enzymes which racemize L-alanine and link two D-alanine
residues.
ā¢ Cs is tuberculostatic; given as intramuscular injection
ā¢ inhibits MAC as well as some other gram-positive bacteria,
ā¢ Given orally, it penetrates the CSF.
ā¢ ADR-headache and irritability to depression, convulsions and
psychotic states.
ā¢ Its use is limited to tuberculosis that is resistant to other
drugs.
36. Biology of tubercular infection
ā¢ (a) Rapidly growing with high bacillary load as in the wall of a
cavitary lesion where oxygen tension is high and pH is neutral.
These bacilli are highly susceptible to H and to a lesser extent to R,
E and S.
ā¢ (b) 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.
ā¢ (c) Spurters found mostly within caseous material where oxygen
tension is low but pH is neutral: the bacilli grow intermittently with
occasional spurts of active metabolism. R is most active on this
subpopulation.
ā¢ (d) Dormant some bacilli remain totally inactive for prolonged
periods. No antitubercular drug is significantly active against them.
37. Goals of therapy
ā¢ (a) Kill dividing bacilli
ā¢ b) Kill persisting bacilli
ā¢ (c) Prevent emergence of resistance
38. DOTS or Directly Observed Treatment
Short course
ā¢ 1. Sustained political and financial committment.
ā¢ 2.Diagnosis by quality ensured sputum-smear microscopy.
ā¢ 3.Standardized short-course anti-TB treatment (SCC) given under
direct and supportive observation (DOT).
ā¢ 4.A regular, uninterrupted supply of high quality anti-TB
drugs.
ā¢ 5. Standardized recording and reporting.
39.
40. Multidrug-resistant (MDR) TB
ā¢ MDR-TB is defined as resistance to both H and
R, and may be any number of other (1st line)
ā¢ drug(s).
ā¢ MDR-TB has a more rapid course with
ā¢ worse outcomes.
ā¢ Its treatment requires complex multiple 2nd
line drug regimens which are longer, more
expensive and more toxic.
41.
42. Extensively drug-resistant TB
ā¢ 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.
ā¢ The bacilli thus are resistant to at least 4 most
effective cidal drugs, viz. H,R,FQ and one of
Km/Am/Cm.
43. Mycobacterium avium complex (MAC)
infection
ā¢ MAC is an opportunistic pathogen which causes disseminated and
multifocal disease in immunocompromized (HIV-AIDS) patients.
ā¢ The disease develops when cell mediated immunity is markedly
depressed, i.e. when CD4 count drops to <50 cells/Ī¼L, HIV-RNA load
is high and other opportunistic infections
46. ā¢ Leprosy is a chronic, progressive bacterial
infection caused by the
bacterium Mycobacterium leprae.
ā¢ It primarily affects the nerves of the
extremities, the lining of the nose, and the
upper respiratory tract.
ā¢ Leprosy produces skin sores, nerve damage,
and muscle weakness.
47. Leprosy is caused by a slow-growing type of bacteria
called Mycobacterium leprae (M. leprae)
Also known as Hansen's disease, after the scientist ho
discovered M. leprae in 1873
It primarily affects the skin and the peripheral nerves
Long Incubation period (3 ā 5 years)
49. The simplest, oldest, cheapest
MOA: Leprostatic even at low concentration
Chemically related to Sulfonamides ā same mechanism ā
inhibition of incorporation of PABA into folic acid (folic acid
synthase)
Specificity to M leprae ā affinity for folate synthase
Activity: Used alone ā resistance ā MDT needed
Resistance ā Primary and Secondary (mutation of folate synthase
ā lower affinity)
However, 100 mg/day ā high MIC -500 times and continued to be
effective to low and moderately resistant Bacilli (low % of resistant
patient) Persisters. Also has antiprotozoal action (Falciparum
and T. gondii)
50. Pharmacokinetics: Complete oral absorption and high
distribution (less CNS penetration) Half life 24-36 Hrs, but
cumulative
70% bound to plasma protein ā concentrated in Skin, liver, muscle
and kidney
Acetylated and glucoronidated and sulfate conjugated ā
enterohepatic circulation
ADRs: Generally Well tolerated drug
Haemolytic anaemia (oxidizing property) - G-6-PD are
more susceptible
Gastric - intolerance, nausea, gastritis
Methaemoglobinaemia, paresthesia, allergic rashes, FDE,
phototoxicity, exfoliative dermatitis and hepatotoxicity etc.
51. Active against protozoa
Combined with pyrimethamine alternative to
sulfadoxine-pyrimethamine for P.falciparum and
toxoplasma gondii infection
Active against Pneumocystis jirovecii
Also has anti-inflammatory property
52. Symptoms: Fever, malaise, lymph node enlargement,
desquamation of skin, jaundice and anemia
Starts after 4- 6 weeks of therapy, more common with
MDT
Management: stopping of Dapsone, corticosteroid
therapy
Dapsone contraindications: Severe anaemia and G-6-
PD deficiency
53. Phenazine dye ā antileprotic, anti-inflammatory and
Bacteriostatic
MOA:
ļ± Interference with template function of DNA
ļ±Alteration of membrane structure and transport
ļ±Disruption of mitochondrial electron transport
Monotherapy causes resistance in 1 ā 3 years
Dapsone resistants respond to Clofazimine
Kinetics: absorbed orally (70%) and gets deposited in
subcutaneous tissues ā as crystals
Half life ā 70 days
54. ADRs: well tolerated
Skin: Reddish-black discolouration of skin,
discolouration of hair and body secretions
Dryness of skin and troublesome itching,
phototoxicity, conjunctival pigmentation
GIT: Nausea, anorexia, abdominal pain and loose
stool (early and late) ā dreaded enteritis
Contraindication: Early pregnancy, liver and kidney
diseases
55. Rifampicin: Cidal. 99.99% killed in 3-7 days, skin
symptoms regress within 2 months
Included in MDT to shorten the duration of
treatment and also to prevent resistance
No toxic dose as single dose only Should
not be used in ENL and Reversal
phenomenon
Ofloxacin: all fluoroquinolones except ciprofloxacin are
active. Used as alternative to Rifampicin
Minocycline: Lipophillic - enters M leprae. Less marked
effect than Rifampicin
56. Anti leprotic and anti tubercular
It is a fast acting drug than dapsone
But it is more expensive and more toxic
It is orally effective and it is administered daily
Poorly tolerated āhepatotoxicity
250mg/day
57. Only macrolide with activity against M. leprae
Less bactericidal than rifampin
Monotherapy- 500mg daily/ 8wks- 99.9% killing
Synergistic action with minocycline
Used in alternative MDT regimen
MINOCYCLINE
High lipophilicity āpenetrates into M.leprae
100mg/day
Antileprotic activity rif>mino >Clari
8 wks treatment
58. ļ¼The acute exacerbation which occurs during the course of leprosy
is called as lepra reaction
ļ¼It occursin LL type- after starting with chemotherapy and
intercurrent infections
ļ¼Jerish Hexheimer (Arthus) type reaction due to release of
antigens from killed bacilli
ļ¼May be mild severe or life threatening
ļ¼ENL- erythema Nodosum Leprosum
ļ¼Treatment-clofazimine -200mg
Dapsone temporary withdrawal
ļ¼Severe reaction- prednisone-40-60 mg.. Tapered in 2-3 months
ļ¼Thalidomide āalternative to prednisolone in ENL
59. ļ¼TT and BL cases
ļ¼Manisfestation of delayed hypersensitivity to M.leprae
antigens
ļ¼Cutaneous ulceration, multiple nerve involvement
with tender nerves
ļ¼Treatment-Clofazimine/ corticosteroids