Tuberculosis

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Tuberculosis

• Robert L. Copeland, Jr., Ph.D.12 March 2021

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• 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. 

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• 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.

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• 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

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• 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.

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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

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• 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

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• 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.

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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

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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.

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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.

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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.

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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.

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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

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Excretion cont.

• Those that have slow acetyl transferase activity
  are slow acetylators, may produce more of the
  toxic intermediate.
• This is an inherited trait gt 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,

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Adverse Effects

• Induced Hepatitis (2 of Population) due to the
  buildup of toxic metabolic products of
  acetylisoniazid --gt 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.

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Age dependency
incidence age
 0.13 25
.59 35
1.09 45
1.75 55
2.5 gt60
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• 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.

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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

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Rifampin

• Mechanism of Action
• Rifampin inhibits DNA dependent RNA polymerase of
  the bacilli.

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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.

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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.

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• 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.

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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

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• 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)

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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.
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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.

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• Adverse Effects
• affects C. Nerve 8 auditory and vestibular
  functions. - this drug is now 2nd 'line because
  of its toxicity. 

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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.

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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 

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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

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Adverse effects

• These drugs are Nephrotoxic - will cause
  Proteinuria, Hematuria, Nitrogen metabolism, and
  Electrolyte disturbances However effect is
  reversible when drug is stopped.

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• 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.

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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.

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• 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

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• Toxicity
• Most common in the CNS Headache, Tremor,
  Vertigo, Confusion, Nervousness, Psychotic states
  with suicidal tendencies , Paranoid reactions,
  Catatonic and depressed reactions

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Chemoprophylaxis of TBUsed 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,

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• 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.

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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.

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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

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Other Resources

• Tuberculosis Resources (Columbia Medical School) 
  http//www.cpmc.columbia.edu/tbcpp
• Tuberculosis, NIAID Fact Sheet http//www.niaid.ni
  h.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/p0
  000413/p0000413.htm
• Brief History of Tuberculosis http//www.umdnj.edu
  /ntbcweb/history.htm