Tuberculosis

Tuberculosis (TB) remains the leading cause of

death worldwide from a single infectious
disease agent. Indeed up to 1/2 of the
world's population is infected with TB.  The
registered number of new cases of TB
worldwide roughly correlates with economic
conditions: the highest incidences are seen in
those countries of Africa, Asia, and Latin
America with the lowest gross national
products. WHO estimates that eight million
people get TB every year, of whom 95% live in
developing countries. An estimated 2 million
people die from TB every year. 
It is estimated that between 2000 and 2020,
nearly one billion people will be newly
infected, 200 million people will get sick, and
35 million will die from TB - if control is not
further strengthened. The mechanisms,
pathogenesis, and prophylaxis knowledge is
minimal. After a century of decline TB is
increasing and there are strains emerging
which are resistant to antibiotics. This excess
of cases is attributable to the changes in the
social structure in cities, the human
immunodeficiency virus epidemic, and failure
of most cities to improve public health
programs, and the economic cost of treating.
TB is an ancient infectious disease
caused by Mycobacterium tuberculosis.
It has been known since 1000 B.C., so it
not a new disease. Since TB is a disease
of respiratory transmission, optimal
conditions for transmission include:
 overcrowding

 poor personal hygiene

 poor public hygiene

With the increased incidence of AIDS,
TB has become more a problem in the
U.S., and the world.
It is currently estimated that 1/2 of the
world's population (3.1 billion) is
infected with Mycobacterium
tuberculosis. Mycobacterium avium
complex is associated with AIDS related
TB.
Transmission
Pulmonary tuberculosis is a
disease of respiratory
transmission, Patients with the
active disease (bacilli) expel them
into the air by:
 coughing,
 sneezing,
 shouting,
 or any other way that will expel bacilli
into the air
Once inhaled by a tuberculin free
person, the bacilli multiply 4 -6 weeks
and spreads throughout the body. The
bacilli implant in areas of high partial
pressure of oxygen:
lung
renal cortex
reticuloendothelial system
This is known as the primary infection. The
patient will heal and a scar will appear in the
infected loci. There will also be a few viable
bacilli/spores may remain in these areas
(particularly in the lung). The bacteria at this
time goes into a dormant state, as long as the
person's immune system remains active and
functions normally this person isn't bothered by
the dormant bacillus.
When a person's immune system is depressed., a
secondary reactivation occurs. 85-90% of the
cases seen which are of secondary reactivation
type occurs in the lungs.
Symptoms and signs
common cough with a progressive
increase in production of mucus
and
coughing up blood.
Other symptoms include the
following:
fever,
loss of appetite,
weight loss, and
night sweats.
Symptoms and signs
About 15% of people may develop
tuberculosis in an organ other than their
lungs. The most common sites include
the following:
lymph nodes,
genitourinary tract,
bone and joint sites,
meninges, and
the lining covering the outside of the
gastrointestinal tract.
 Imaging studies
Chest X-ray: The most common
diagnostic test that leads to the
suspicion of infection is a chest X-ray.
In primary TB, an X-ray will show an
abnormality in the mid and lower lung
fields, and lymph nodes may be
enlarged.
Reactivated TB bacteria usually
infiltrate the upper lobes of the lungs.
Miliary tuberculosis exhibits diffuse
nodules.
X- Ray Findings
 Medical treatment
Standard therapy for active TB consists of a
six-month regimen:
two months with Rifater (isoniazid, rifampin,
and pyrazinamide)
four months of isoniazid and rifampin (
Rifamate, Rimactane)
ethambutol (Myambutol) or streptomycin
added until your drug sensitivity is known
(from the results of bacterial cultures)
Treatment takes that long because the disease
organisms grow very slowly and,
unfortunately, also die very slowly.
Doctors use multiple drugs to reduce the
likelihood of resistant organisms emerging.
 Surgical treatment
Failure of chemotherapy
Performance of diagnostic
procedures
Destroyed lung
Postsurgical complications
Persistent bronchopleural fistula
Intractable hemorrhage
Tuberculous cavities in the
right upper lobe are shown
here.
Kinyoun stain shows
presence of mycobacteria in
sputum sample
Tubercle bacilli in the lung
tissue
A 48-year-old woman developed cough, sputum production, and blood-tinged
sputum. Sputum staining showed tubercle bacilli. chest X-ray showed a cavity-
like lesion in right upper lobe of her lung.
Doctors treated the same woman with three medications
for TB. One month later, she showed significant
improvement, as seen by this repeat chest X-ray.
Classification of Drugs
3 Groups depending upon the degree
of effectiveness and potential side
effects
 First Line: (Primary agents)

 are the most effective and have lowest

toxicity. Isoniazid Rifampin
 Second Line:
 Less effective and more toxic effects
 include (in no particular order): p-amino salicylic
acid, Streptomycin, Ethambutol
 Third Line
 are least effective and most toxic. Amikacin,
Kanamycin, Capreomycin, Viomycin, Kanamycin,
Isoniazid

Considered the drug of choice for the

chemotherapy of TB. discovered in
1945 a hydrazide of isonicotonic acid
 is bacteriostatic for resting bacilli,
 bactericidal for growing bacilli.
Mechanism of action
Unknown, but the hypothesis
include effects on lipids, nucleic
acid and biosynthesis.
Primary action seems to inhibit the
biosynthesis of mycolic acids which
are part of cell wall structure.
Resistance
Organism eventually develops
resistance.
The mechanism of resistance is
related to the failure of the drug to
penetrate or be taken up by the
micro-organism (by active
transport system),
Remember treatment is up to 2 years.
Pharmacokineti
cs
Absorption: INH rapidly absorbed
either oral or parenteral route.
Peak [plasma] of 3-5
micrograms/milliliter after oral
administration.
Distribution:
 Diffuses readily into all bodily fluids
does not bind to plasma proteins
 In the CSF the [conc] is about 20% of
[plasma],
 t1/2 =1-3 hrs.
Excretion
75-95% of a dose excreted in the urine in
24 hr.
- Mostly as a metabolite.
- The main excretory product-
acetylisoniazid. This is a result of
enzymatic acetylation, Very important in
terms of metabolism, Isoniazid is under
genetic control, There are 2 groups of
people. Fast and slow acetylators
Excretion cont.
Those that have slow acetyl transferase
activity are slow acetylators, may produce
more of the toxic intermediate.
This is an inherited trait ==> Autosomal
Dominant
The average [plasma] will be (1/3) to (1/2)
of the slow acetylators Average t1/2, is less
than 90 minutes, in the slow acetylators,
t1/2 will be about 3 hours.
Ethnicity- Eskimos,Native American Indians,
and Asians are fast aceytlators,
Adverse Effects
Induced Hepatitis (2% of Population) due
to the buildup of toxic metabolic products
of acetylisoniazid --> acetylhydrazine. This
is more frequent in slow acetylators.
Hepatic reactions to Isoniazid are also age
dependent
 There is a 250X increase in the incidence of
hepatitis over age. More frequent in the fast
acetylators when measured intragroup,
(Compare elderly fast acetylators patients with
elderly slow patients,) Ranges from mild
hepatitis to serious tissue necrosis.
Age dependency
% incidence age
 0.13 25
.59 35
1.09 45
1.75 55
2.5 >60
Patients with renal failure, the normal
dose can be given, because it is secreted
in the inactive form.
Patients with hepatic insufficiency - give
a reduced dose of the drug.
ETOH causes induction of drug
metabolizing enzymes, Isoniazid is
broken down faster. Leads to lsoniazid
hepatotoxicity.
Glucose 6- Phosphate deficiency. People
with a deficiency of Glucose-6-phosphate
cannot adequately process the drug.
Drug Interaction
Competition between Isoniazid and
Phenytoin (anticonvulsant). They
both compete for drug metabolism
enzymes. Phenytoin interferes with
metabolism of isoniazid by
reduction in excretion or
enhancement of effect of isoniazid
Rifampin
Mechanism of Action
Rifampin inhibits DNA dependent
RNA polymerase of the bacilli.
Resistance:
Due to alteration of the target
(DNA dependent RNA
polymerase) of the drug,
prevents further initiation but
not elongation. The micro-
organism can change the structure
of the enzyme so that the drug no
longer has an effect.
Pharmacokinetics
Absorption
peak levels reached 2-4 hrs. after oral
dose
rapidly eliminated in the bile and
reabsorbed (enterohepatic circulation) It
can be delayed with use of
aminosalicylic acid.
during this time there is a progressive
deacylation of the drug;
the metabolites maintain full effect
Half life is 6 hours.
Distribution:
Throughout the total body water
Present in effective concentrations in
many organs and body fluids including
CSF,
With Rifampin you must warn patients:
The drug has an orange red color in
body excretions, This color will be
imparted to all body fluids.
Adverse Effects:
Does not cause many side effects in
any great frequency.
G.I. reactions: Anorexia, Nausea
,Vomiting Mild abdominal pain, Hepatic
Reactions in children, pregnant women
and alcoholics, can result in minor
elevations in serum transaminase as some
jaundice
Allergic Reactions
Fever
Skin Eruptions
Rash
Pruritis
Rifampin does induce microsomal drug
metabolizing enzymes. This will decrease
the half-life of some other drugs. (ie.
phenytoin, digitoxin)
WARNING!
Rifampin and Isoniazid are the most effective
drugs for the treatment of TB, The drug
enjoys high patient compliance and
acceptability. But these 2 drugs should never
be given alone! They are always used in
combination because resistance occurs to one
drug alone very rapidly. They are used in
combination with each other initially as well
as other drugs. Bacilli must become resistant
to two drugs in order to remain viable.
Statistically, the chances are verv small of the
bacilli becoming resistant to both. .
2nd Line Drugs: Not as effective
and have more toxicity

Streptomycin
The first drug used clinically for
treatment of TB 1947-1952; was the
only drug available at that time.
is an aminoglycoside antibiotic
acts by protein synthesis inhibitor and
decreases the fidelity mRNA and
garbles the message, leads to nonsense
proteins.
Streptomycin only binds to the 30s
subunit.
Adverse Effects:
affects C. Nerve 8: auditory and
vestibular functions. - this drug is
now 2nd 'line because of its
toxicity. 
para- Aminosalicylic Acid

a structural analog of PABA (p-aminobenzoic

acid) is bacteriostatic inhibits de novo folate
synthesis
half life = 1 hour after 4 g. dose
you can give this drug up to 12 grams per
day. 80% of the drug is excreted in the urine
and 50% of that is as an acetylated
metabolite which is insoluble. You must
make sure the patient's urine is normal or
alkaline.
Adverse effects
GI irritation due to the amount of drug
given (high doses) nausea, vomiting,
bleeding, occurs in 30-40% of the patients.
be careful with those who have peptic ulcers
Hypersensitivity reactions Rash, Fever some
hepatotoxicity
All will disappear when the drug is stopped
This drug has poor patient acceptability
and compliance: 
Third Line Drugs - least
effective and most toxic

Third line drugs are used when

resistance is developed to 1st and
2nd line drugs; these drugs are
also used in combination.
Aminoglycosides
Capreomycin - Viomycin -
Kanamycin
Adverse effects
These drugs are: Nephrotoxic - will
cause Proteinuria, Hematuria,
Nitrogen metabolism, and Electrolyte
disturbances
However effect is reversible when drug
is stopped.
Ototoxic will result in deafness and
some loss of vestibular function, leads
to cranial nerve 8 damage. The nerve
damage is permanent.
Capreomycin has replaced viomycin
because of less toxic effects, but all
three drugs have the same effects.
Cycloserine
can cause CNS disturbances
Therapeutic States
Cycloserine should be used when re-
treatment is necessary or when the
micro-organism is resistant to the other
drugs.
It must be given in combination with
other anti-tuberculosis drugs.

Mechanism of Action:
An analog of D-alanine synthetase, will
block bacterial cell wall synthesis.
Pharmacokinetics: Rapidly absorbed
Peak [plasma] occurs in 3-4 hours
Distributed throughout all body fluids,
including CSF About 50% is excreted in
unchanged form in the urine during the
first 12 hours. Only about 35% of the
drug metabolized This drug can
accumulate to toxic conc in patients
with renal insufficiency
Toxicity:
Most common in the CNS:
Headache, Tremor, Vertigo, Confusion,
Nervousness, Psychotic states with
suicidal tendencies , Paranoid
reactions, Catatonic and depressed
reactions
Chemoprophylaxis of TB
Used only in high risk groups

Household members and other

close contacts of a patient with
active TB.
A positive skin test in persons less
than 35 years.
A positive skin test reactive in the
immunosuppressed, persons with
leukemia, and Hodgkin's Disease,
HIV + patients with a positive TB
test,
The drug of choice for
chemoprophylaxis is isoniazid.
Prophylaxis uses only one drug. In
patients who are HIV+ and TB+ and
have the disease; they are treated for a
minimum of 9 months, The first 2
months using isoniazid and rifampin and
for the next 7 months or longer, use
only 2 or 3 of the 2nd/3rd line drugs and
Isoniazid/Rifampin.
Chemotherapy of TB
Most patients are treated in an
ambulatory setting - admitted to the
hospital - diagnosis is established -
initiate and stabilize therapy - send
patient home , usually after 2 or 3 weeks
First and second line agents are usually
given orally. Third line drugs are given
parenterally.
Treatment
Isoniazid, Ethambutol, & Rifampin are given
for 2 months.
Isoniazid & Rifampin are given for 4 months.
If you suspect resistance to isoniazid use
Isoniazid, Ethambutol, Rifampin &
Parazinamide. Incidence of drug
resistance is 2-5% in the U.S.
Prolonged bed rest is not necessary or
helpful in obtaining a speedy recovery. The
patient must be seen at regular and
frequent intervals to follow the course of the
disease and treatment. Look for toxic effects