Tuberculosis

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Tuberculosis

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• A series battles between the host and the
  tubercle bacillus

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The weapons of the host are

• Activated macrophage
• Stop the intracellualr graowth of bacilli in
  nonactivated macrophages by killing the
  macrophages (transform into solid caseous tissue)

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The weapons of the bacillus are

• Multiply logarithmically within non-activated
  macrophage
• Multiply extracelluarly in liquefied caseous
  material.

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The vulnerabilities of the host are

• Non-activated macrophage ?intracellular growth of
  the bacilli
• Liquefied caseous material ? extracellular growth
  of the bacilli

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The vulnerabilities of the bacilli are

• Inability to survive within a fully activated
  macrophage
• Inability to multiply in solid caseous tissue

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IMMUNOLOGY

• Cell-Mediated Immunity (CMI)
• Delayed-Type Hypersensitivity (DTH)
• The TB bacillus apparently is not injurious to
  the host until the time when both of these immune
  responses begin to develop

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Cell-Mediated Immunity

• Beneficial host response
• TH1-lymphocyte ? cytokines (IFN-?,TNF-a, IL-2) ?
  attract and activate monocytes and macrophages
• Activated macrophages produce reactive oxygen and
  nitrogen, lysosomal enzymes

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Delayed-Type Hypersensitivity

• The immunologic reaction that causes caseous
  necrosis
• Destroying bacilli-laden, non-activated
  macrophages and nearby tissue
• Eliminating the intracellular environment

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Diagnosis

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Diagnosis

• Acid-Fast Stain
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• /- ? 1-2/300 fields (105/ml)
• ? 1-9/100 fields (106/ml)
• 2 ? 1-9/10 fields (107/ml)
• 3 ?1-9/ 1 field (108/ml)
• 4 ? gt9/ 1 field (109/ml)

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Diagnosis

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Diagnosis

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• ??????(apical segment)???(posterior segment)
• ??????(superior segment)
• ???? exudative and fibrotic
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Differential Diagnosis
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Treatment
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Subgroups of TB bacilli
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Theoretical Basis

• Bactericidal phase
• Group 1 killed
• Sterilizing phase
• Group 2 and 3 killed
• Naturally occurring drug-resistant mutants
  develop at a rate of 10-6 to 10-7
• The number of bacilli in a patient with active TB
  rarely exceed 109

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Drug Resistance

• Resistant to one drug is independent of
  resistance to any other drug
• Probability of resistance to two drugs is
  negligent
• Therefore, antituberculosis therapy should always
  consist of at least two effective drugs

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Isoniazid (INH)

• Bactericidal
• Food and antacids interfere with absorption
• Should be included in all regimens except when a
  high proportion of INH-resistant organisms are
  present
• Metabolized in the liver by cytochrome P-450
  system
• Excreted in urine
• Daily dose 300 mg po
• Tiw dose 600 mg, biw dose 900 mg

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Isoniazid (INH)

• Peripheral neuritis
• Sensory dysfunctions of stocking-glove
  distribution, esp. the lower extremities
• Dose related
• Inhibits pyridoxine-requiring reactions
• Can be prevented with pyridoxine 10 mg/d
• Symptomatic treatment with 100-200 mg/d

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Isoniazid (INH)

• Toxic hepatitis
• Potentiated by other hepatotoxic drugs, esp. RIF
  (not so much PZA)
• Rarely causes clinically significant disease if
  given alone even in view of transaminases
  elevation
• Monthly monitoring of transaminases
• Age dependent
• Weakness, fatigue, and malaise may occur before
  jaundice

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Isoniazid (INH)

• If used in a patient with advanced liver disease,
  dose reduced to 150-200 mg/d
• Dose adjustment only in patients with severe
  renal insufficiency (creatinine clearances less
  than 10 normal or creatinine levels 12mg/dl)
• For dialysis patients give usual dose just
  following dialysis

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Rifampin (RIF)

• Inhibits RNA synthesis
• sterilizing agent
• Food and antacids interfere with absorption
• Metabolized in the liver
• Dose reduction not necessary in renal failure
• Passes BBB only if inflamed
• Colors secretions red-orange

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Rifampin (RIF)

• Daily dose 600 mg po
• Tiw dose 600 mg po, biw dose 600 mg po
• GI upset, skin eruptions, fever
• High dose may cause influenza-like reaction,
  hemolytic anemia, acute renal failure, and
  thrombocytoopenia

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Rifampin (RIF)

• Hepatic toxicity
• Concurrent INH and RIF may cause jaundice in
  first 2 weeks of therapy instead of usual 2
  months with INH alone
• Potent inducer of hepatic microsomal enzymes

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Rifampin (RIF)

• Increased rate of metabolism of methadone,
  coumadin, glucocorticoids, estrogens, oral
  hypoglycemic agents, and antiarrhythmic agents
• Rebound toxicity of other drugs when RIF
  discontinued

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Rifampin (RIF)

• Lupus erythematosis syndrome in patients taking
  RIF with clarithromycin or ciprofloxacin
• Other rifamycins include rifabutine and
  rifapentine
• Resistance to one usually means resistance to
  another

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Pyrazinamide (PZA)

• 3rd most important drug after INH and RIF in its
  ability to reduce duration of treatment
• Lack of additional utility when given beyond the
  first 2 months in patients with drug-susceptible
  TB
• Works in acid pH
• Sterilizing agent

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Pyrazinamide (PZA)

• Daily dose 15-30 mg/kg up to 2g/d po
• Tiw dose 30-40mg/kg, biw 30-40 mg/kg
• Arthralgia with elevated uric acid level
• Less uric acid retention if given intermittent
  PZA therapy

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Pyrazinamide (PZA)

• Cutaneous reactions rarely requires
  discontinuation of the drug
• GI distress generally abate
• Hepatitis infrequent with standard doses
• PZA-induced hepatitis may persist for 4-6 weeks
  after discontinuation (14 days for INH or RIF)

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Ethambutol (EMB)

• A class of its own
• Largely cleared by the kidneys
• At 15-25 mg/kg optic neuritis nearly eliminated
• Tiw dose 30 mg/kg, biw 50 mg/kg
• Antituberculosis activity comparable to PZA at
  this dose

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Ethambutol (EMB)

• High concentrations have considerable
  bactericidal activity against TB
• A role in short-course, 2 or 3x weekly treatment
• For patients with drug-susceptible TB, EMB
  contributes only modestly in regimens with INH,
  RIF, and PZA

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Ethambutol (EMB)

• Major utility for cases with initial drug
  resistance to INH or SM
• No substantial sterilizing activity
• Prevent treatment failure and further acquisition
  of drug resistance
• EMB should be added during the initial phase of
  treatment until drug susceptibility is established

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Streptomycin (SM)

• Aminoglycoside antibiotic
• Inhibits protein synthesis by binding to 30S
  ribosomes
• Does not penetrate the CNS well
• 15 mg/kg/d up to 1g/d for age lt55 with renal
  function
• 750 mg if gt55 y

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Streptomycin (SM)

• Tiw and biw dose 1000 mg im
• Renal insufficiency load 5-7.5 mg/kg followed by
  daily dose x creatinine clearance/100
• When used in highly potent regimens (3 or 4 drugs
  including INH or RIF), higher dosage may not be
  needed

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Streptomycin (SM)

• Toxicity more related to trough levels and dosage
  intervals than to peak levels
• More vestibular and less ototoxicity compared to
  amikacin or kanamycin
• Vestibular toxicity functionally less well
  tolerated
• Nephrotoxicity slightly less common than other
  aminoglycosides

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Pregnancy and lactation

• INH and EMB safe for pregnancy
• RIF probably safe
• SM may cause auditory dysfunction in the infant
• PZA not recommended
• Breastfeeding while on anti-TB medications
  considered safe

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