Drug treatment of Pulmonary Tuberculosis

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Drug treatment of Pulmonary Tuberculosis

• 4th medical year Pharmacology

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Tuberculosis

• Kills 3 million/yr worldwide
• In UK 10 drug resistance

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Tuberculosis

• Primary TB Initial infxn usually pulmonary
  (droplet spread). Peripheral lesion forms (Ghon
  focus) its draining nodes infected (Ghon
  complex). Often asymptomatic or fever, lassitude,
  sweats, anorexia, cough, sputum, erythema
  nodosum. AFB may be in sputum. Commonest
  non-pulmonary primary infxn is GI (affecting
  ileocaecal junction its LNs)
• Post-primary TB Any form of immunocompromise may
  reactivate TB e.g. malignancy, DM, steroids,
  debilitation (HIV, elderly). Lung lesions
  (usually upper lobe) progress fibrose.
  Tuberculomas contain few AFB unless erode into
  bronchus, where can rapidly multiply make pt
  highly contagious (open TB). In elderly,
  immunocompromised, 3rd world dissemination of
  multiple foci throughout body results in miliary
  TB.

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Tuberculosis

• Pulmonary TB
• silent or cough, sputum, malaise, weight
  loss, night sweats, pleurisy, haemoptysis,
  pleural effusion, superimposed pulmonary
  infection
• Miliary TB
• following haematogenous dissemination.
  Clinical features non-specific. CXR
  reticulonodular shadowing. Bx of lung, liver, LN
  or marrow may give AFB/granulomata
• Meningeal TB
• Subacute onset meningitic symptoms fever,
  headache, nv, neck stiffness, photophobia
• GU TB
• frequency, dysuria, loin/back pain,
  haematuria, sterile pyuria. 3 EMU for AFB. Renal
  US. Renal TB may spread to bladder, seminal
  vesicles, epididymis or fallopian tubes

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Tuberculosis

• Bone TB vertebral collapse adjacent to
  paravertebral abscess (Potts vertebra). X-rays
  biopsies (for AFB culture)
• Skin TB (lupus vulgaris) jelly-like nodules,
  e.g. face/neck
• Acute TB pericarditis primary exudative allergic
  lesion
• Chronic pericardial effusion constrictive
  pericarditis reflect chronic granulomata.
  Fibrosis calcification may be prominent with
  spread to myocardium (Steroids for 11 wks with
  anti-TB meds ? need for pericardiectomy)

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TB

• Diagnosis
• If suspected obtain relevant clinical samples
  (sputum, pleural fluid, pleura, urine, pus,
  ascites, peritoneum or CSF) for culture
• Microbiology multiple sputum for AFB, pleural
  aspiration biopsy (if effusion). If sputum neg
  bronchoscopy for biopsy BAL. Biopsy if
  suspicious lesion in liver, LN, bone marrow.
• AFB bacilli that resist acid-alcohol
  decolourization under auramine/ZN staining.
  Cultures have prolonged incubation (12 wks).
• TB PCR rapid id of rifampicin resistance. Useful
  for diagnosis in sterile specimens

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TB

• Histology caseating granulomata
• Radiology CXR consolidation, cavitation,
  fibrosis calcification in pulmonary TB
• Immunological
• Tuberculin skin test/Mantoux tuberculin purified
  protein derivative (PPD) injected intradermally
  cell-mediated response at 48-72h . ve if gt/
  10mm induration
• ve test indicated immunity (may be previous
  exposure, BCG) Strong ve test active infxn.
  False neg tests in immunosuppression (miliary TB,
  sarcoid, AIDS, lymphoma)
• Heaf for screening. Circle of primed needles
  which inject tuberculin (no longer available)

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First Line Antituberculous drugs

• Isoniazid
• Rifampicin
• Pyrazinamide
• Ethambutol
• Streptomycin

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Isoniazid

• MOA - Unknown, but may include the inhibition of
  myocolic acid synthesis resulting in disruption
  of the bacterial cell wall
• The most effective Bactericidal agent
• Half-life Fast acetylators 30-100 minutes Slow
  acetylators 2-5 hours
• Metabolized in liver excreted by kidneys
• Substrate of CYP2E1 (major)
• Inhibits CYP 2C19 2C8/9 2D6
• Major S/E s -
• - Hepatitis (up to x5 ?AST/ALT acceptable,
  stop if bilirubin?)
• - Peripheral neuropathy
• (preventable with pyridoxine (Vit B6) -
  given to high risk patients)

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Rifampicin

• MOA - Inhibits bacterial RNA synthesis by
  binding to the beta subunit of DNA-dependent RNA
  polymerase, blocking RNA transcription
• Substrate of CYP2A6, 2C8/9, 3A4
• Induces CYP1A2 , 2A6, 2B6, 2C8/9, 2C19, 3A4
• Major S/E s -
• - Hepatitis (up to x5 ?AST/ALT acceptable,
  stop if bilirubin?)
• - orange urine tears (contact lens
  staining useful for assessing compliance)
• - inactivation OCP
• - flu-like syndrome
• - thrombocytopenic purpura if intermittent use

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Pyrazinamide

• MOA - Converted to pyrazinoic acid in
  susceptible strains of Mycobacterium which lowers
  the pH of the environment exact mechanism of
  action has not been elucidated
• Crosses Blood brain barrier well
• Active against intracellular dividing forms of M.
  tuberculosis
• Bacteriostatic or bactericidal depending on
  tissue concentration
• Major S/E s -
• - Hepatitis (up to x5 ?AST/ALT acceptable,
  stop if bilirubin?)
• - Arthralgia
• -hyperuricaemia(gout is a CI)
• - nv

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Ethambutol

• MOA - Suppresses mycobacteria multiplication by
  interfering with RNA synthesis
• Major S/E s -
• - Optic neuritis (colour vision is first to
  deteriorate)
• - test acuity prior to treatment with
  Snellen chart Ishihara chart
• - avoid in patients who cannot report visual
  change

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Streptomycin

• MOA - Aminoglycoside - Inhibits bacterial
  protein synthesis by binding directly to the 30S
  ribosomal subunits causing faulty peptide
  sequence to form in the protein chain
• Major S/E s -
• - ototoxic nephrotoxic neurotoxic
• - C/I in pregnancy

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NB Interactions

• Rifampicin hepatic enzyme p450 inducer
  (therefore ? level of)
• affects
• OCP( NB to warn pt of ?
  effectiveness)
• corticosteroids protease inhibitors
• phenytoin anticoagulants
• sulphonylureas methadone
• Isoniazid hepatic enzyme inhibitor (therefore ?
  level of)
• affects
• phenytoin
• carbamazepine
• anticoagulants

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Basic Principles

• TB is a Notifiable illness
• Obtain bacteriological confirmation and drug
  susceptibility testing wherever possible
• Specialist supervised treatment
• Advise HIV testing (with consent counselling)
• Notify public health to arrange contact tracing
  screening
• Prolonged tx necessary adherence NB. DOT may be
  required if non-adherence issue

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Treatment of pulmonary TB

• NB of compliance (helps pt prevents spread of
  resistance)
• Before tx baseline FBC, LFTs, RP
• Isoniazid, rifampicin pyrazinamide all
  hepatotoxic
• Test colour vision (Ishihara chart) acuity
  (Snellen chart) before after tx (ethambutol may
  cause (reversible) ocular toxicity
• Consider pyridoxine 10 mg OD (Vit B6 ) to prevent
  isoniazid neuropathy

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Treatment regimens

• Six month regimen (all forms except CNS)
• - two months of 3 or 4 drugs
• (Isoniazid Rifampicin Pyrazinamide /-
  Ethambutol)
• - four months of 2 drugs (Isoniazid
  Rifampicin)
• - best given as combination preparations
• 12 month regimen (meningeal TB)
• - two months of 4 drugs
• - ten months of 2 drugs

If resistance likely or immunosuppressed
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Additional points

• Criteria for using fourth drug in first 2 months
• - previous TB, immunosuppressed, in contact
  with organism
• likely to be drug resistant
• Corticosteroids
• - severe TB meningitis
• - constrictive pericarditis

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Directly Observed Therapy of Pulmonary TB

• DOT in pts who cant comply reliably with tx
  regimen (eg homeless, C2H5OH abuse, mentally ill,
  hx of non-compliance)
• Given isoniazid, rifampicin, pyrazinamide
  ethambutol (or streptomycin) 3 times/wk under
  supervision for initial 2/12 then isoniazid
  rifampicin 3 times/wk for further 4/12

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TB in HIV positive patients

• 30-50 of pts with AIDS in developing world have
  concurrent TB
• Increased reactivation of latent TB
• Mantoux may be ve
• Smears may be ve for AFB
• NB to culture organism assess drug
  sensitivities/resistance
• Previous BCG doesnt prevent infection
• Atypical presentation findings
• Extrapulmonary disseminated disease more common

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TB in HIV positive patients

• Confirmed M. tuberculosis infxn sensitive to 1st
  line drugs should be tx with standard 6-mth
  regimen regimen may need modification if
  resistant organism? specialist advice
• Compliance issues drug absorption
• CYP 3A P450 induced by rifampicin lower levels
  of protease inhibitors
• More toxicity from HAART tx anti-TB tx due to
  interactions? specialist advice
• HAART tx reconstitutes CD4 count immune fn, may
  lead to paradoxical worsening of TB symptoms
  (Immune reconstitution inflammatory response)

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MDR-TB TB in pts with HIV/AIDs

• Isolation necessary if TB pts near HIVve pts
• MDR-TB high mortality. Need negative pressure
  ventiated room
• Test TB cultures against 1st 2nd line
  chemotherapeutic agents
• May need 5 drugs in MDR-TB. Liaise early with
  Microbiologist/Infectious Disease specialist.
  Duration usually 9-24 mths.
• FU for 1yr if MDR TB, long term if also HIV ve

1st line anti-TB agents 2nd line anti-TB agents
Isoniazid Ofloxacin
Rifampicin Ciprofloxacin
Pyrazinamide Cycloserine
Ethambutol Ethionamide
Streptomycin Aminosalicylic acid
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Preventing TB in HIV ve pts

• Primary prophylaxis against TB indicated in some
  HIV ve pts ( if no BCG mantoux gt5mm, if BCG
  mantoux gt10mm, if recent exposure to active TB)
• Isoniazid given with pyroxidine for 9 months
• If known isoniazid-resistant TB contact give
  rifampicin

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Chemoprophylaxis for asymptomatic TB

• Immigrant/contact screening may id pts with no
  symptoms/CXR findings
• Chemoprophylaxis useful to kill organisms
  prevent disease progression
• Chemoprophylaxis may be required in latent
  disease receiving tx with immunosuppressants
  (eg cytotoxics, long term tx with steroids)

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Chemoprophylaxis

• Positive tuberculin test (cf BCG)
• normal CXR asymptomatic
• 1 drug x six months OR
• 2 drugs for three months

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BCG vaccine

• BCG is live attenuated strain derived from M.
  bovis ? stimulates development of
  hypersensitivity to M. tubercolosis
• Given intradermally
• Within 2-4wks swelling at injection site,
  progresses to papule about 10mm diam heals in
  6-12 wks
• BCG recommended if immunisation not previously
  carried out neg for tuberculoprotein
  hypersensitivity
• Infants in area of TB incidence gt 40/100,000
• Infants with parent/grandparent born in country
  with incidence of TB gt40/100,000
• Contacts of pts with active pulmonary TB
• Health care staff
• Veterinary staff
• Prison staff
• If intending to stay for gt1 mth in country with
  high incidence TB

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BCG vaccine

• Live vaccines CI if
• -acute infxn
• -pregnant women
• -pts with impaired immune fn
• -BCG also CI if generalised septic skin conditions

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BTS Guidelines

• http//www.brit-thoracic.org.uk/c2/uploads/Chemoth
  erapy.pdf
• http//www.brit-thoracic.org.uk/c2/uploads/TB.pdf