Date 2075/11/02
 Tuberculosis
is a global pandemic, killing
someone approximately every 18 seconds —
about 1.6 million every year.
 A major health problem in developing
countries
 Chronic granulomatous disease
 Caused by Mycobacterium tuberculosis

Non-tuberculous mycobacteria also called
atypical mycobacteria
 The


two main aims of TB treatment are
(1) to prevent morbidity and death by curing TB
while preventing the emergence of drug
resistance
(2) to interrupt transmission by rendering
patients noninfectious to others.
 First
line
 Second line
Isonicotinic acid hydrazide, also called INH
 It is effective against intra- as well as extracellular mycobacteria


penetrates into macrophages
Tuberculostatic against resting and tuberculocidal
against rapidly multiplying organisms
 Spectrum of activity
 Activity against Mycobacterium bovis and
Mycobacterium kansasii is moderate.
 Poor activity against Mycobacterium avium
complex (MAC)
 No activity against other microorganisms.

Isoniazid inhibits synthesis of mycolic acids,
which are essential components of mycobacterial
cell walls.
 Isoniazid, a prodrug, enters bacilli by passive
diffusion.
 Gets activated by mycobacterial enzyme:
catalase-peroxidase ( KatG)
 Activated drug inhibits two enzymes




enoyl acyl carrier protein reductase (InhA)
and a beta-ketoacyl acyl carrier protein Synthase
(KasA)
 Inhibition of synthesis of mycolic acid, an
essential component of the mycobacterial cell
wall, leading to cell death
 Mutations


low-level isoniazid resistance
cross-resistance to ethionamide
 Mutation

resulting in overexpression of inhA
or deletion of the katG gene
high-level isoniazid resistance
 Mutations
in kasA gene.
 Well

absorbed
Food interferes absorption
 Widely
distributed including CSF, Caseous
tubercular lesions
 Metabolised by acetylation, genetically
determined


Slow acetylators
and fast acetylators


Hepatotoxicity
Peripheral neuritis that can be prevented and treated
by pyridoxine in a dosage as low as 10 mg/day

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




Peripheral neuropathy is more likely to occur in slow
acetylators and patients with predisposing conditions such
as malnutrition, alcoholism, diabetes, AIDS, and uremia
CNS toxicity: memory loss, psychosis, ataxia, and
seizures.
Hematologic abnormalities, provocation of pyridoxine
deficiency anemia.
Hemolysis in G-6PD deficient patients
Rash, fever, arthralgia, lupus like syndrome
Tinnitus, gastrointestinal discomfort
Gynaecomastia
 Inhibits
several cytochrome P450 enzymes,
 increased concentrations of drugs as
phenytoin, carbamazepine, and
benzodiazepines.
 Isoniazid also inhibits MAO-A; thus can result
in cheese reaction.
 It
is an essential component of multi-drug
therapy of tuberculosis.


Adult dose: 300 mg once daily
5 mg/kg/day in children
 Drug
of choice (used solely) for prophylaxis
of tuberculosis and for treatment of latent
tuberculosis infection

The dosage is 300 mg/d (5 mg/kg/d) or 900 mg
twice weekly, and the duration is usually 9
months

Derivative of rifamycin B, also called rifampin.


Other derivatives are rifabutin and rifapentine.
Tuberculocidal against both dividing and nondividing mycobacteria

Acts best on slowly and intermittently dividing
ones(spurters)
Equally effective against intra- and extracellular bacilli.
 Only drug active against dormant bacilli in solid
caseous lesions and those sequestered in
abscesses and lung cavities.
 Also active against non-tuberculous
mycobacteria, some Gram-positive and Gramnegative organisms and chlamydiae.

 Rifampicin
binds to the β subunit of bacterial
DNA-dependent RNA polymerase (encoded by
rpoB gene)  inhibition of RNA synthesis
Rifampicin is well absorbed after oral
administration
 Food interferes with absorption, given on empty
stomach.
 Distributed widely in body fluids and tissues
 It readily penetrates all membranes including
blood brain and placental barrier and phagocytic
cells as well.
 Coloured metabolites orange discolouration of
the urine and secretions
 Excreted mainly through the liver into bile
 safe in renal disease.

 Least
toxic antitubercular drug
 Safest drug in pregnancy.
 Hepatotoxicity: cholestatic jaundice and
occasionally hepatitis

Jaundice requires drug discontinuation
 Orange

discoloration of urine, sweat, and tears
Harmless
 Cutaneous
syndrome: skin rash, flushing, pruritus,
redness and watering of eyes
 Flu like syndrome (fever, chills, myalgias,headache)
 Abdominal syndrome: nausea,vomiting, cramps
 Anemia, thrombocytopenia, hemolysis rarely
 Light-chain proteinuria, Nephritis
 Being
a strong inducer of CYP450 enzymes,
enhances the metabolism of many drugs like
anticonvulsants, oral contraceptives, oral
anticoagulants, antiretroviral drugs etc.

The female on concurrent oral contraceptives should
either increase the dose of the pill or use an
alternative method of contraception.
 Rifabutin has
less chances of drug interactions and
is equally effective, so it is used in the treatment
of tuberculosis in AIDS patients
 PAS delays absorption, therefore concomitant
administration should be avoided.
 Active

TB
Both intensive and continuation phase of short
course regimen @ 600 mg/day (10 mg/kg/day)
PO
 Rifampin,
600 mg daily for 4 months as a
single drug, is an alternative to isoniazid for
patients with latent tuberculosis

who are unable to take isoniazid or who have had
exposure to a case of active tuberculosis caused
by an isoniazid-resistant, rifampin-susceptible
strain.

Leprosy


Prophylactic drug for meningococcal and
staphylococcal carrier states


600 mg twice daily for 2 days can eliminate
meningococcalcarriage.
Prophylaxis of Haemophilus influenzae type b
disease in children


most effective and fastest acting drug in leprosy.
Rifampin, 20 mg/kg (maximum 600 mg) once daily for
4 days
Rifampin combination therapy also used for
treatment of serious staphylococcal infections
such as osteomyelitis, prosthetic joint infections,
and prosthetic valve endocarditis.
 Weakly
tuberculocidal drug
 It is effective only against intracellular
mycobacteria.
 More active against slowly replicating
bacteria (than rapidly multiplying) and in the
acidic media (intracellular sites and at the
sites of inflammation).
 Highly effective during first 2 months of
therapy (when inflammatory changes are
present)
 Passively
diffuses into mycobacterial cells 
converted to pyrazinoic acid (active form) by
mycobacterial pyrazinamidase (encoded by
pncA gene).
 Pyrazinoic acid(PA) disrupts mycobacterial
cell membrane metabolism and transport
functions  cell death

PA also Inhibits mycolic acid synthesis
 well
absorbed from the gastrointestinal tract
 Widely distributed in body tissues including
inflamed meninges
 The half-life is 8–11 hours.
 Hepatotoxicity
(in 1–5% of patients)
 GI upset: nausea, vomiting
 Drug fever, photosensitivity
 Hyperuricemia (asymptomatic)
 Non-gouty arthralgia (in 40%)
 Loss of glycemic control
 Contraindicated in:


Liver disease
Pregnancy (relative)

Category C (Safety uncertain/unsafe)
 Used
only for TB
 One of the first line drugs for short-course
regimens

as a “sterilizing” agent against residual
intracellular organisms that may cause relapse.
 Dose:
25-30 mg/kg/d.
 Ethambutol
is selectively tuberculostatic.
 Active against MAC as well as some other
mycobacteria, but not other types of
bacteria
 Ethambutol
inhibits mycobacterial arabinosyl
transferases (encoded by the embAB genes)
thereby disrupting arabinogalactan
biosynthesis, an essential component of the
mycobacterial cell wall.
 Well
absorbed
 It is distributed throughout the body except
in the CSF

Ethambutol crosses the bloodbrain barrier only
when the meninges are inflamed





The most common serious ADR is retrobulbar neuritis,
resulting in loss of visual acuity and red-green color
blindness.
 Dose dependent and reversible
 Baseline and monthly visual acuity and color
discrimination testing recommended
 Because children are unable to report early visual
impairment, this drug is relatively contra-indicated in
children.
Hyperuricemia and peripheral neuritis.
Requires dose adjustment in renal failure.
Rarely hypersensitivity
Safe in pregnancy
TB:
 Dose: 15–25 mg/kg


Often given as a single daily dose in combination with
isoniazid, rifampin and pyrazinamide during the initial
intensive phase of active tuberculosis treatment
 In
combination with other agents for the
treatment of nontuberculous mycobacterial
infections, such as Mycobacterium avium
complex (MAC) or M. kansasii

dose for these infections is 15 mg/kg once daily.
 Tuberculocidal aminoglycoside.
 It
is not absorbed orally and must be administered
by i.m injection.
 It is active only against extra-cellular bacteria.
 Ototoxicity and nephrotoxicity are major ADR.
 Contraindicated in PREGNANCY (X)
 Dose:
 15mg/kg/day
 Other
aminoglycosides used for the treatment of
tuberculosis are amikacin, kanamycin and
capreomycin.
 Fluoroquinolones
used for this indication
include ofloxacin, moxifloxacin and
levofloxacin.

These are also effective against mycobacterium
avium complex in AIDS patients.
 Newer
macrolides like azithromycin and
clarithromycin are effective against
nontubercular atypical mycobacteria.





Rifabutin is more effective than rifampicin against MAC. It
has a longer t1/2 (45 hrs) as compared ro rifampicin (3-5
hours).
Clarithromycin and fluconazole inhibit its hepatic
metabolism and increase t1/2. It has less potential than
rifampicin to induce microsomal
enzymes and thus preferred in patients on anti-HIV drugs
(protease inhibitors or NNRTIs mainly nevirapine). It
commonly causes gastrointestinal adverse effects.
Rarely, it can cause anterior uveitis, hepatitis, clostridium
difficile-associated diarrhea, diffuse polymyalgia
syndrome, yellow skin discoloration (Pseudo-jaundice) and
pancytopenia. Unlike rifampicin, it does not require dose
adjustment in liver disease.
Rifapentine is similar to rifampicin but is more lipophilic
and longer acting. It is not approved for administration to
patients with HIV disease because of higher rates of
relapse. Its absorption increases with meals
 Thioacetazone
is a tuberculostatic drug.
 Major adverse effects include hepatitis, bone
marrow suppression and Steven Johnson
syndrome (not used in HIV positive patients
 due to risk of severe hypersensitivity
reactions including exfoliative dermatitis).
 It is not used in intermittent regimens
 Para
amino salicylic acid (PAS) is related to
sulfonamides, acts by similar mechanism
 and is bacteriostatic. It can cause kidney,
liver and thyroid dysfunction.
 • Ethionamide is another tuberculostatic
drug that can cause hepatitis, optic neuritis
and
 hypothyroidism. It can also be used in
leprosy. It has mechanism similiar to INH and
 bacteria resistant to INH are cross resistant
to ethionamide also.
 Cycloserine
is a cell wall synthesis inhibiting
drug and can cause neuropsychiatric
 adverse effects.
 • Kanamycin and amikacin are injectable
aminoglycosides, which can be used in the
 treatment of MDR tuberculosis.
 • Capreomycin is an injectable polypeptide.
It can cause ototoxicity, nephrotoxicity,
 hypokalemia and hypomagnesemia
 Bedaquiline
is an inhibitor of mycobacterial
ATP synthase.
 It is indicated as a part of MDT in adults with
pulmonary MDR-TB.
 It can cause QT prolongation
 DOTS
 Directly
observed treatment, short-course
 Initial
intensive phase
 Continuation phase
 Intensive
 3-4
phase (2-3 months)
drugs
 Rapidly kill the bacteria
 Minimise the chance of developing resistance
 Bring about sputum conversion
 Symptomatic relief
 Continuation
phase (4-6 months)
 Elimination of the remaining bacilli
 To minimize the chance of relapse
 Directly
Observed Treatment Short course
(DOTS) is the most effective strategy
available today for tuberculosis control
 4,344 DOTS treatment centres in Nepal
TB+HIV: A Dual Epidemic
 TB and HIV/AIDS are a deadly duo. HIV weakens
people’s immune systems, allowing TB to
flourish. TB is the leading killer of people with
HIV/AIDS, claiming over one in four lives of
people with HIV. And, in countries where TB is
prevalent, people with HIV/AIDS are 20 times
more likely to contract TB than others without
HIV. Despite enormous gains made in battling the
HIV epidemic, TB’s deadly synergy with HIV/AIDS
threatens to destabilize gains in TB control.
While people are living with HIV, they are now
dying of TB.

 MARCH
24
 WORLD TB DAY
 TB
is an airborne disease that can be spread
by coughing or sneezing and is the leading
cause of infectious disease worldwide. It is
responsible for economic devastation and the
cycle of poverty and illness that entraps
families, communities and even entire
countries. Among the most vulnerable are
women, children, and those with HIV/AIDS.
There is growing resistance to available
drugs, which means the disease is becoming
more deadly and difficult to treat. There
were 558,000 cases of drug resistant TB last
year
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A 60-year-old man presents to the emergency department
with a 2-month history of fatigue, weight loss (10 kg), fevers,
night sweats, and a productive cough. He is currently living
with friends and has been intermittently homeless, spending
time in shelters. He reports drinking about 6 beers per day.
In the emergency department, a chest x-ray shows a right
apical infiltrate. Given the high suspicion for pulmonary
tuberculosis, the patient is placed in respiratory isolation.
His first sputum smear shows many acid-fast bacilli, and an
HIV test returns with a positive result. What drugs should
be started for treatment of presumptive pulmonary tuberculosis?
Does the patient have a heightened risk of developing
medication toxicity? If so, which medication(s) would be
likely to cause toxicity?