Tuberculosis

Robert L. Copeland, Jr., Ph.D.

October 1, 2009
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.
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
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-xdv-www.epo.cdc.gov/wonder/PrevGuid/p0000413/p0000413.htm

Brief History of Tuberculosis http://www.umdnj.edu/~ntbcweb/history.htm