Transcript Tuberculosis

Tuberculosis
.
Dr Sajith.VS
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.
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,
Cycloserine
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.
Pharmacokinetics
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. .
Prophylaxis is with one drug usually isoniazid.
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 retreatment is necessary or when the microorganism 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
Other Resources
Tuberculosis Resources (Columbia Medical
School) http://www.cpmc.columbia.edu/tbcpp
Tuberculosis, NIAID Fact Sheet
http://www.niaid.nih.gov/factsheets/tb.htm
Positive Skin Tests for Tuberculosis (American Family Physician)
http://www.aafp.org/afp/961101ap/pat_1991.html
National Tuberculosis Center
http://www.umdnj.edu/~ntbcweb/ntbchome.htm
CDC; Division of Tuberculosis Elimination
http://www.cdc.gov/nchstp/tb/structure.htm
Treatment of Tuberculosis and Tuberculosis Infection in Adults and
Children American Thoracic Society Medical Section of the American Lung
Association American Journal of Respiratory and Critical Care Medicine Vol
149 1994 http://aepo-xdvwww.epo.cdc.gov/wonder/PrevGuid/p0000413/p0000413.htm
Brief History of Tuberculosis http://www.umdnj.edu/~ntbcweb/history.htm