Treatment of T.B.

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TREATMENT OF T.B.

• A special problem within the field of
  chemotherapy.

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TREATMENT OF T.B.

• Treatment is often complex and protracted.
• Host immune defenses are often variable and
  inadequate.

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TREATMENT OF T.B.

• Chemotherapy is probably the keystone in the
  management of T.B.
• Ancillary treatments are used only in special
  circumstances.

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TREATMENT OF T.B.

• Divided into chemoprophylaxis and treatment of
  active disease.
• Careful diagnostic studies must always precede
  therapy.

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CHEMOPROPHYLAXIS

• To prevent clinically active disease in people
  already infected.
• Given only to those who will derive the greatest
  benefit and the least risk.

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CHEMOPROPHYLAXIS

• Household contacts and close associates who have
  negative tuberculin tests.
• Recent converters (preceding 2 yrs).
• Positive tuberculin test and underlying disease.

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CHEMOPROPHYLAXIS

• Positive tuberculin test and abnormal chest
  X-ray.
• Positive test and under 30.
• Immunosuppressed patients.

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CHEMOPROPHYLAXIS

• 300 mg Isoniazid once daily for 6-12 months.

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TREATMENT OF ACTIVE T.B.

• First line drugs (used in the initial treatment
  of T.B.) isoniazid, rifampin, streptomycin,
  ethambutol and pyrazinamide.

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TREATMENT OF ACTIVE T.B.

• Secondary agents PAS, ethionamide, amikacin,
  kanamycin, capreomycin, cycloserine,
  ciprofloxacin, levofloxacin and clofazimine.

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TREATMENT OF ACTIVE T.B.

• Therapy requires at least two effective drugs
  concurrently.

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TREATMENT OF ACTIVE T.B.

• If the treatment is appropriate improvement is
  usually seen within 2 weeks.
• Continue treatment for at least 3-6 mths after
  the sputum becomes negative.

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TREATMENT OF ACTIVE T.B.

• Never use 1 drug and never add a single drug to
  a failing regimen.

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TREATMENT OF ACTIVE T.B.

• Minimum length of therapy is 6-9 months.

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TREATMENT OF ACTIVE T.B.

• Initiation phase of 2 months.
• Continuation phase of 4-7 months.

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TREATMENT OF ACTIVE T.B.

• Initial therapy is a 4 drug regimen of INH,
  rifampin, pyrazinamide and ethambutol.
• For patients with drug-susceptible disease the
  pyrazinamide can be discontinued after 2 months.
• Ethambutol can also be discontinued.

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TREATMENT OF ACTIVE T.B.

• Combining daily therapy with intermittent therapy.

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INTERMITTENT THERAPY

• Daily therapy for 2 weeks (INH, rifampin,
  pyrazinamide and streptomycin) followed by
  therapy 2 times a week for six weeks. Then INH
  Rifampin 2x weekly for 16 weeks.

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DOT
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DIRECTLY OBSERVED THERAPY (DOT)

• Now recommended for all patients.

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DRUG RESISTANCE

• Major cause is inadequate therapy.
• Treatment is difficult and requires good
  laboratory support and experience with the less
  frequently used drugs.

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MULTIPLE DRUG RESISTANT T.B.

• Combined resistance to at least INH and rifampin.
• Caused by improper treatment, inadequate drug
  supplies, or poor patient supervision.

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MULTIPLE DRUG RESISTANT T.B.

• Patients face chronic disability and death and
  represent an infectious hazard for the community.
  

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MULTIPLE DRUG RESISTANT T.B.

• High cure rates have been obtained but require
  prompt recognition, rapid and accurate
  susceptibility results and early administration
  of an individualized retreatment regimen.

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MULTIPLE DRUG RESISTANT T.B.

• Regimens are usually based on a quinolone and an
  injectable agent (e.g.aminoglycoside)
  supplemented with other second line drugs.

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MULTIPLE DRUG RESISTANT T.B.

• DOT is crucial.
• Therapy is often prolonged (24 mths.), expensive
  and has multiple adverse effects.
• Prevention is therefore very important.

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TREATMENT OF HIV-RELATED TB

• Possibility of increased drug toxicity and
  possible drug-drug interactions (rifamycins plus
  PI and/or NNRI).

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NONTUBERCULOUSMYCOBACTERIA

• Atypical mycobacterial infections.
• Resistant to many of the commonly used drugs.
• Examine for sensitivity and treat on this basis.
• Increased in AIDS (e.g. MAC).

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MECHANISM OF ACTION OF ANTITUBERCULOSIS AGENTS

• Drugs which interfere with mycolic acid synthesis
• Drugs which inhibit nucleic acid synthesis
• Drugs inhibiting protein synthesis

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MYCOBACTERIAL CELL WALL
Porin
Lipid of intermediate length
Lipid with C14-C18 acids
Mycolic Acid
Arabinogalactan
Peptidoglycan
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ISONIAZID-MECHANISM OF ACTION

• Interferes with biosynthesis of cell wall mycolic
  acids.
• Mycolate depleted cell walls are structurally
  weak.

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katG
Active Form
Isoniazid (Prodrug)
Catalase/Peroxidase
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INH MECHANISM OF ACTION

• InhA gene encodes an enoyl-ACP reductase of fatty
  acid synthase II which converts ?2 -unsaturated
  to saturated fatty acids on the pathway to
  mycolic acid biosynthesis.
• Activated INH inhibits this enzyme.

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Mycobacterial Cell Wall
Porin
Lipid of intermediate length
Lipid with C14-C18 acids
Mycolic Acid
Arabinogalactan
Peptidoglycan
INH
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RESISTANCE

• Mutations in the katG gene can lead to loss of
  catalase-peroxidase activity.
• Resistance also maps to mutations in four other
  genes including inhA

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RESISTANCE

• Overall incidence of resistance is higher in
  certain ethnic groups such as African Americans,
  Mexican Americans and Indochinese refugees.

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ETHAMBUTOL-MECHANISM OF ACTION

• It is not bactericidal.
• Inhibits synthesis of the mycobacterial cell
  wall.

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MECHANISM OF ACTION

• It is an inhibitor of mycobacterial arabinosyl
  transferases (encoded by the embAB genes).
• Arabinoglycan an essential component of the cell
  wall.

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MYCOBACTERIAL CELL WALL
Porin
Lipid of intermediate length
Lipid with C14-C18 acids
Mycolic Acid
Arabinogalactan
Peptidoglycan
Ethambutol
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RESISTANCE

• Mutations in the emb genes.

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PYRAZINAMIDE-MECHANISM OF ACTION

• PZA

POA (pyrazinoic acid)
pyrazinamidase
Occurs mostly in the liver.
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MECHANISM OF ACTION

• Inhibits fatty acid synthetase I of Mycobacterium
  tuberculosis.

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Pyrazinamide
Short chain fatty acid precursors
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RESISTANCE

• Mutations in the pncA gene which results in
  impairment in the conversion of PZA to its active
  form.

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DRUGS INHIBITING NUCLEIC ACID SYNTHESIS

• Rifampin

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RESISTANCE

• Results from an alteration in the polymerase
  enzyme (mutation in the rpoB gene).

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STREPTOMYCIN-ANTI TB ACTIVITY

• Most strains of M.Tuberculosis are sensitive.
• Bactericidal only against the extracellular
  tuberculosis bacilli.
• Overall only suppressive.

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RESISTANCE

• Major problem with streptomycin use in T.B.
• Combination therapy will delay or prevent
  resistance.

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THERAPEUTIC USES IN T.B.

• It is used in drug resistant disease.
• More serious forms of T.B. (disseminated T.B. or
  meningitis).

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o
o
C
C
OH
NH2
N
N
NICOTINIC ACID
NICOTINAMIDE
o
N
C
NH2
C
NHNH2
ISONIAZID
o
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ANTITUBERCULAR ACTIVITY

• Bactericidal vs actively growing tubercle bacilli
  .
• Also bactericidal vs intracellular bacteria.
• Poor activity against atypical organisms.

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ABSORPTION AND DISTRIBUTION

• Readily absorbed when given orally or
  parenterally (food and Al decrease
  absorption).
• INH diffuses well into all body fluids and cells
  including the CNS.

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DISTRIBUTION

• Penetrates cells with ease and is effective
  against organisms growing within cells.

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METABOLISM

• Primary route is by acetylation.
• Genetic heterogeneity with regard to the rate of
  acetylation. There are slow and rapid
  acetylators.
• Among American and northern European pops. 50-65
  are slow acetylators.

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METABOLISM

• Rapid acetylation is an autosomal dominant trait.

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METABOLISM

• More rapid clearance of INH by rapid acetylators
  is of no therapeutic consequence when given
  daily.
• Subtherapeutic concns may occur if INH is given
  to rapid acetylators as a once-weekly dose.

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METABOLISM

• Slow acetylators may be more susceptible to toxic
  side effects related to higher blood levels of
  INH whereas rapid acetylators have a higher
  frequency of hepatotoxicity.

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Isoniazid
Peripheral Neuropathy Acute Seizures
Acetylated
Microsomal Oxidation
Hydrazine
Acetyl INH
Acetylated
Reactive Metabolite
Hydrolyzed
Acetyl Hydrazine
Microsomal Oxidation
Isonicotinic Acid
Hepatic Necrosis
(nontoxic)
Diacetyl Hydrazine (nontoxic)
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EXCRETION

• 75-95 of a dose is excreted in the urine in 24
  hrs., mostly as metabolites.

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THERAPEUTIC STATUS

• Most important drug for all types of T.B.
• Chemoprophylaxis.

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CONTRAINDICATIONS

• Liver disease

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DRUG INTERACTIONS

• Aluminum salts.
• INH inhibits cytochrome P-450 enzymes.
• INH is a potential inhibitor of MAO and diamine
  oxidase (histaminase).
• Induces Cytochrome P4502E1 (acetaminophen).

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ETHAMBUTOL-ANTIMICROBIAL ACTIVITY

• Nearly all strains of Mycobacterium tuberculosis
  are sensitive.
• A few atypical organisms are also sensitive
  (MAC).

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PHARMACOKINETICS

• Well absorbed from the GI Tract.
• Mostly excreted unchanged in the urine.

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THERAPEUTIC STATUS

• Initial treatment of TB.
• Used to treat MAC infections in certain
  combinations.

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RIFAMPIN (Rifampicin)

• Semi-synthetic derivative of one of the
  rifamycins, a group of complex macrocyclic
  antibiotics.

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RIFAMPIN-ANTI T.B. ACTIVITY

• Mycobacterium tuberculosis as well as several
  atypical organisms.
• Bactericidal against extracellular cavitary
  bacilli and to organisms in closed lesions.
• Some non-Mycobacterial bacteria and some viruses.

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PHARMACOKINETICS

• Well absorbed from the GI tract.
• Widely distributed throughout the body including
  the CNS.

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Deacetylation
Rifampin
Rifampin
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PHARMACOKINETICS

• Induces its own metabolism.
• About 1/3 of the drug is excreted in urine, and
  2/3 in the intestine.
• Adjust dose with decreased liver function.

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THERAPEUTIC STATUS

• Used in combination with INH for the initial
  treatment of T.B., in the retreatment of T.B. and
  in intermittent therapy.

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THERAPEUTIC STATUS

• Possible alternative to INH to prevent T.B (with
  pyrazinamide)?
• Used to treat atypical mycobacterial infections.

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Azoles
Protease inhibitors
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RIFAPENTINE AND RIFABUTIN

• Rifabutin-better activity vs MAC than rifampin
  less an inducer of cytochrome P-450 enzymes
• Rifapentine-long acting analog.

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N
o
o
C
C
NH2
OH
N
N
NICOTINAMIDE
PYRAZINOIC ACID
o
N
C
NH2
PYRAZINAMIDE
N
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ANTIBACTERIAL ACTIVITY

• Eliminates bacilli that are growing at slightly
  acidic pH.

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PHARMACOKINETICS

• Well absorbed from the GI tract.
• Excreted primarily through the kidney.

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THERAPEUTIC USES

• Important component of short-term (6 month)
  multiple-drug therapy of TB .
• Preventative therapy in combination with rifampin
  when INH resistance is suspected.

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FIXED-DOSE COMBINATIONS

• They are strongly encouraged for adults who are
  self-administering their medications.
• Enhance adherence, may reduce inappropriate
  monotherapy and may prevent drug resistance.

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FIXED-DOSE COMBINATIONS

• Fixed-dose combinations are available as Rifamate
  (INH rifampin) and Rifater (INH rifampin
  pyrazinamide).

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ADVERSE EFFECTS OF ANTITUBERCULOSIS DRUGS
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GI DISTRESS AND UPSET

• Most anti TB drugs are irritating to the GI
  tract-INH, rifampin, pyrazinamide

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ISONIAZID-HEPATOTOXICITY
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Liver enzymes
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HEPATOTOXICITY

• Hepatitis is the most severe toxicity.

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Isoniazid
Peripheral Neuropathy Acute Seizures
Acetylated
Microsomal Oxidation
Hydrazine
Acetyl INH
Acetylated
Reactive Metabolite
Hydrolyzed
Acetyl Hydrazine
Microsomal Oxidation
Isonicotinic Acid
Hepatic Necrosis
(nontoxic)
Diacetyl Hydrazine (nontoxic)
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RIFAMPIN

• Jaundice

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PYRAZINAMIDE

• Hepatotoxicity is common and can be serious

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NEUROTOXICITY
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NEUROTOXICITY

• Peripheral neuritis is common (without
  pyridoxine).
• CNS effects of various types can occur
  (convulsions,ataxia).

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OCULAR TOXICITY
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ETHAMBUTOL

• Optic Neuritis and color blindness.
• Base-line and monthly vision tests.

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HYPERURICEMIA

• Pyrazinamide

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HIGH DOSE INTERMITTENT THERAPY

• Additional toxicities especially with rifampin

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ADVERSE EFFECTS

• Orange - pink color is imparted to saliva, tears
  and other body fluids.

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