2. The main cause of TB is Mycobacterium tuberculosis, small, aerobic,
nonmotile bacillus.
Slow dividing bacteria.
stains very weakly "Gram-positive" or does not retain dye as a result
of the high lipid and mycolic acid content of its cell wall.
MTB can withstand weak disinfectants and survive in a dry state for
weeks.
M. tuberculosis can be cultured in the laboratory.
Using histological stains on expectorated samples from sputum,
scientists can identify MTB under a microscope.
Since MTB retains certain stains even after being treated with acidic
solution, it is classified as an acid-fast bacillus. The most common
acid-fast staining techniques are the Ziehl–Neelsen stain and
the Kinyoun stain, which dye acid-fast bacilli a bright red that stands
out against a blue background. Auramine-rhodamine staining
and fluorescence microscopy are also used.
3. The M. tuberculosis complex (MTBC) includes four other TB-
causing mycobacteria:
◦ M. bovis,
◦ M. africanum
◦ M. canetti, and
◦ M. microti.
M. africanum is not widespread, but it is a significant cause of
tuberculosis in parts of Africa.
M. bovis was once a common cause of tuberculosis, but the
introduction of pasteurized milk has almost completely eliminated
this as a public health problem in developed countries.
M. canetti is rare and seems to be limited to the Horn of Africa,
although a few cases have been seen in African emigrants.
M. microti is also rare and is seen almost only in immuno deficient
people, although its prevalence may be significantly underestimated.
Non tuberculous mycobacteria -Pathogenic mycobacteria include M.
leprae, M. avium and M. kansasii. The latter two species are classified
as "nontuberculous mycobacteria" (NTM). NTM cause neither TB
nor leprosy, but they do cause pulmonary diseases that resemble TB.[
4. Tuberculosis (TB) is an infectious disease.
Tuberculosis generally affects the lungs, but can also
affect other parts of the body.
Latent tuberculosis-Most infections do not have symptoms, known
as latent tuberculosis.
Active TB- About 10% of latent infections progress to active disease
which, if left untreated, kills about half of those infected The classic
symptoms of active TB are a chronic cough with blood containing
sputum, fever, night sweats, and weight loss. The historical term
"consumption" came about due to the weight loss. Infection of other
organs can cause a wide range of symptoms.
Type of Tuberculosis on the bases of symptoms
5. Tuberculosis is spread through the air when people
who have active TB in their lungs cough, spit,
speak, or sneeze.
People with latent TB do not spread the disease.
Active infection occurs more often in people
with HIV/AIDS and in those who smoke.
Diagnosis of active TB- is based on chest X-rays,
as well as microscopic examination and culture of
body fluids.
Diagnosis of latent TB- relies on the tuberculin
skin test (TST) or blood tests.
6. Prevention of TB involves screening those at high risk,
early detection and treatment of cases,
and vaccination with the bacillus Calmette-
Guérin vaccine. Those at high risk include household,
workplace, and social contacts of people with active TB.
Type of T.B.
Pulmonary Tuberculosis
Extrapulmonary Tuberculosis
7.
8. Include
fever, chills, night sweats, loss of appetite, weight loss, and fatigue.
Significant nail clubbing may also occur
If a tuberculosis infection does become active, it most
commonly involves the lungs (in about 90% of cases).
Symptoms may include chest pain and a prolonged cough
producing sputum, cough up blood in small amounts, and in
very rare cases, the infection may erode into the pulmonary
artery or a Rasmussen's aneurysm, resulting in massive
bleeding.
Tuberculosis may become a chronic illness and cause
extensive scarring in the upper lobes of the lungs. The upper
lung lobes are more frequently affected by tuberculosis than
the lower ones. It may be due either to better air flow, or to
poor lymph drainage within the upper lungs.
Pulmonary Tuberculosis
General signs and symptoms
9. In 15–20% of active cases, the infection spreads outside the lungs,
causing other kinds of TB.
These are collectively denoted as "extrapulmonary tuberculosis".
Extrapulmonary TB occurs more commonly in immunosuppressed
persons (HIV) and young children.
Notable extrapulmonary infection sites include
o the pleura (in tuberculous pleurisy),
o the central nervous system (in tuberculous meningitis),
o the lymphatic system (in scrofula of the neck),
o the genitourinary system (inurogenital tuberculosis), and
o the bones and joints (in Pott disease of the spine), among others.
When it spreads to the bones, it is also known as "osseous
tuberculosis", a form of osteomyelitis.
o Sometimes, bursting of a tubercular abscess through skin results
in tuberculous ulcer. An ulcer originating from nearby infected
lymph nodes is painless, slowly enlarging and has an appearance
of "wash leather".
o A potentially more serious, widespread form of TB is called
"disseminated tuberculosis", also known as miliary
tuberculosis. Miliary TB makes up about 10% of extrapulmonary
cases.
10. The standard "short" course treatment for TB is isoniazid (along
with pyridoxal phosphate to obviate peripheral neuropathy caused by
isoniazid), rifampicin (also known as rifampin in the United
States), pyrazinamide, and ethambutol for two months, then isoniazid and
rifampicin alone for a further four months.
The patient is considered to be free of living bacteria after six months
(although there is still a relapse rate of up to 7%).
For latent tuberculosis, the standard treatment is six to nine months of daily
isoniazid alone or three months of weekly (12 doses total) of
isoniazid/rifapentine combination.
If the organism is known to be fully sensitive, then treatment is with
isoniazid, rifampicin, and pyrazinamide for two months, followed by
isoniazid and rifampicin for four months. Ethambutol need not be used.
Tuberculosis treatment refers to the medical treatment of the infectious Disease
tuberculosis (TB).
TREATMENT OF TB WITH FIRST LINE DRUGS
11. The second line drugs (WHO groups 2, 3 and 4) are only used to treat
disease that is resistant to first line therapy (i.e., for extensively
drug-resistant tuberculosis (XDR-TB) or multidrug-resistant
tuberculosis (MDR-TB)).
A drug may be classed as second-line instead of first-line for one of
three possible reasons:
◦ it may be less effective than the first-line drugs (e.g.,p-
aminosalicylic acid); or,
◦ it may have toxic side-effects (e.g., cycloserine); or
◦ it may be effective, but unavailable in many developing countries
(e.g., fluoroquinolones):
Note- Objective of combined TB therapy
Kill the multiplying bacilli
Kill the persisting bacilli
Prevent the development of resistance
13. Ethambutol is EMB or E
Streptomycin is SM or S
Isoniazid is INH or H
Pyrazinamide is PZA or Z
Rifampicin is RMP or R
14. Aminoglycosides (WHO group 2):
e.g., amikacin (AMK), kanamycin (KM)
polypeptides (WHO group 2):
e.g., capreomycin, viomycin, enviomycin
fluoroquinolones (WHO group 3):
e.g., ciprofloxacin (CIP), levofloxacin, moxifloxacin (MXF)
thioamides (WHO group 4):
e.g. ethionamide, prothionamide
cycloserine (WHO group 4)
terizidone (WHO group 5)
15. Isoniazid, also known as
isonicotinylhydrazide (INH), is
an antibiotic used as a first-line
agent for the prevention and
treatment of both latent and
active tuberculosis.
It is effective against mycobacteria,
particularly Mycobacterium
tuberculosis. Isonicotinylhydrazide
It is also active against some atypical types of
mycobacteria, such as M. kansasii and M.
xenopi. Isoniazid is an organic compound that is
available in tablet, syrup, and injectable forms.
16. Isoniazid is a prodrug and must be activated by a bacterial
catalase-peroxidase enzyme in Mycobacterium
tuberculosis called KatG.
KatG couples the isonicotinic acyl with NADH to form
isonicotinic acyl-NADH complex.
This complex binds tightly to the enoyl-acyl carrier protein
reductase known as InhA, thereby blocking the natural enoyl-
AcpM substrate and the action of fatty acid synthase.
This process inhibits the synthesis of mycolic acids, which are
required components of the mycobacterial cell wall. A range of
radicals are produced by KatG activation of isoniazid,
including nitric oxide, which has also been shown to be
important in the action of another ant imycobacterial prodrug
pretomanid.
Isoniazid is bactericidal to rapidly dividing mycobacteria, but
is bacteriostatic if the mycobacteria are slow-growing. It
inhibits the cytochrome P450 system and hence acts as a
source of free radicals.
17. Isoniazid reaches therapeutic concentrations in serum, cerebrospinal
fluid, and within caseous granulomas.
It is metabolized in the liver via acetylation. Two forms of the
enzyme are responsible for acetylation, so some patients metabolize
the drug more quickly than others.
Hence, the half-life is bimodal, with "slow acetylators" and "fast
acetylators". A graph of number of people versus time shows peaks
at one and three hours. The height of the peaks depends on the
ethnicities of the people being tested.
The metabolites are excreted in the urine.
NOTE- Doses do not usually have to be adjusted in case of renal
failure.
Note-
INH should be given with vitamin B6
In slow acetylator-Chances of peripheral neuropathy more
18. loss of vitamin B6 occur due to structure similarity with INH- cause
peripheral neuropathy
Gastrointestinal reactions include nausea and vomiting.
Aplastic anemia, thrombocytopenia, and agranulocytosis due to lack
of production of red blood cells, platelets, and white blood cells by
the bone marrow, respectively can also occur.
Hypersensitivity reactions are also common and can present with a
maculopapular rash and fever.
severe and sometimes fatal hepatitis. Black and Hispanic women are
at higher risk for isoniazid-induced hepatotoxicity.
liver function should be monitored carefully in all people receiving it.
Isoniazid is associated with pyridoxine deficiency due to the
increased excretion of pyridoxine. Pyridoxal phosphate (a derivative
of pyridoxine) is required for d-aminolevulinic acid synthase, the
enzyme responsible for the rate-limiting step in heme synthesis.
Therefore, isoniazid-induced pyridoxine deficiency causes
insufficient heme formation in early red blood cells, leading
to sideroblastic anemia.
19. Rifampicin, also known as rifampin, is
an antibiotic used to treat a several types
of bacterial infections. This includes
tuberculosis, leprosy etc
Before treating someone for a long period
of time, measurement of liver enzymes
and blood counts are recommended.
It can be given either by mouth or
intravenously.
Semi synthetic dvt of
Rifamicin B
MOA
Rifampicin inhibits bacterial DNA-dependent RNA synthesis by inhibiting
bacterial DNA-dependent RNA polymerase. (It works by stopping the making
of RNA by bacteria.)
Crystal structure data and biochemical data suggest that rifampicin binds to
RNA polymerase at a site adjacent to the RNA polymerase active center and
prevents RNA synthesis by physically blocking the formation of the
phosphodiester bond in the RNA backbone, preventing extension of RNA more
than 2 to 3 nucleotides ("steric-occlusion" mechanism)
20. Metabolites Form by deacetylation at C25 named as-
Des-acetyl-rifampin
3-formyl-rifamycin
Common side effects include
nausea, vomiting, diarrhea, and loss of appetite.
It often turns urine, sweat, and tears a red or orange color.
Liver problems/Hepatitis or allergic reactions may occur.
Flu like symptoms
Side effects
Metabolites
NOTE-
It is part of the recommended treatment of active tuberculosis
during pregnancy, even though its safety in pregnancy is not
known..
Rifampicin is of the rifamycin group of antibiotics.
21. Pyrazinamide is
a drug used to treat
tuberculosis.
The drug is largely
bacteriostatic, but can
be bacteriocidal on actively
replicating tuberculosis
bacteria.
IUPAC Name-
pyrazine-2-carboxamide
Pyrazinamide is only used in combination with other drugs
such as isoniazid and rifampicin in
the treatment of Mycobacterium tuberculosis. It is never
used on its own.
22. Pyrazinamide is a prodrug that stops the growth of Mycobacterium
tuberculosis.
Pyrazinamide diffuses into the granuloma of M. tuberculosis, where
the enzyme pyrazinamidase converts pyrazinamide to the active
form pyrazinoic acid. Under acidic conditions, the pyrazinoic acid
that slowly leaks out converts to the protonated conjugate acid,
which is thought to diffuse easily back into the bacilli and
accumulate. The net effect is that more pyrazinoic acid accumulates
inside the bacillus at acid pH than at neutral pH.
Pyrazinoic acid was thought to inhibit the enzyme fatty acid
synthase (FAS) I, which is required by the bacterium to
synthesise fatty acids (inhibition of fatty acid synthesis takes
place) although this has been discounted. So stop the growth of
M.tuberculosis.
It was also suggested that the accumulation of pyrazinoic acid
disrupts membrane potential and interferes with energy production,
necessary for survival of M. tuberculosis at an acidic site of infection.
23. • Pyrazinamide is well absorbed orally. It crosses inflamed meninges
and is an essential part of the treatment of tuberculous meningitis.
USES
• Pyrazinamide is used in the first two months of treatment to reduce
the duration of treatment required. Regimens not containing
pyrazinamide must be taken for nine months or more.
• Pyrazinamide is routinely used in pregnancy in the UK and the rest of
the world; the WHO recommend its use in pregnancy; and there is
extensive clinical experience to show that it is safe.
Latent tuberculosis
• Pyrazinamide in conjunction with rifampin is a preferred treatment
for latent tuberculosis.
Note-
•It is metabolised by the liver.
•The metabolic products are excreted by the kidneys.
Adverse effects
•Hepatitis
•Precipitate gout
24. Ethambutol (commonly abbreviated EMB or simply E) is a medication
primarily used to treat tuberculosis. It is usually given in combination
with other tuberculosis drugs, such
as isoniazid, rifampicin and pyrazinamide.
It may also be used to treatMycobacterium avium complex,
and Mycobacterium kansasii.
•Ethambutol is bacteriostatic against actively growing TB bacilli.
•It works by obstructing the formation of cell wall.
•Mycolic acids attach to the 5'-hydroxyl groups of D-arabinose residues
of arabinogalactan and form mycolyl-arabinogalactan-peptidoglycan complex
in the cell wall.
•It disrupts arabinogalactan synthesis by inhibiting the enzyme arabinosyl
transferase. Disruption of the arabinogalactan synthesis inhibits the formation
of this complex and leads to increased permeability of the cell wall.
Mechanism of action