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Drug tx of Pulmonary TB

Drug tx of Pulmonary TB. 09/10/07 3rd medical year Pharmacology. TB. 2004 14.6 million people worldwide had active TB, 1.7 million deaths mostly developing countries. When TB meds misused/mismanaged emergence of resistance

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Drug tx of Pulmonary TB

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  1. Drug tx of Pulmonary TB 09/10/07 3rd medical year Pharmacology

  2. TB • 2004 14.6 million people worldwide had active TB, 1.7 million deaths mostly developing countries. • When TB meds misused/mismanagedemergence of resistance • ~10% of all new TB cases are resistant to at least one drug, if more than one = MDR TB • XDR TB-resistant to fluoroquinolone & at least one of injectable agents

  3. AFB = bacilli that resist acid-alcohol decolourization under auramine/ZN staining.

  4. TB • Primary TB: Initial infxn usually pulmonary (droplet spread). Peripheral lesion forms (Ghon focus) & its draining nodes infected (Ghon complex). Often asymptomatic or fever, lassitude, night sweats, anorexia, cough, sputum, erythema nodosum. AFB may be in sputum. Commonest non-pulmonary primary infxn is GI (affecting ileocaecal junction & its LNs)

  5. TB • 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.

  6. TB • Pulmonary TB: silent or cough, sputum, malaise, weight loss, night sweats, haemoptysis, pleural effusion

  7. TB • 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, n&v, 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.

  8. TB • Bone TB: vertebral collapse adjacent to paravertebral abscess (Pott’s 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)

  9. TB • Advise HIV & hepatitis 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 Diagnosis • Relevant clinical samples (sputum, pleural fluid, pleura, urine, ascites, peritoneum or CSF) for culture • Microbiology: 3 EMS for AFB (smear & culture), pleural aspiration & biopsy (if effusion). If sputum neg/unable to expectorate bronchoscopy for biopsy & BAL. Biopsy if suspicious lesion in liver, LN, bone marrow. • TB PCR: rapid id of rifampicin resistance.

  10. Histology: caseating granulomata TB

  11. CXR = consolidation, cavitation, fibrosis & calcification in pulmonary TB, usually upper lobes Radiology

  12. Immunological • Tuberculin skin test/Mantoux: tuberculin purified protein derivative (PPD) injected intradermally & cell-mediated response at 48-72h . +ve 5-14mm induration, strongly +ve >15mm • +ve test indicated immunity (may be previous exposure, BCG) Strong +ve test = active infxn. False neg tests in immunosuppression (miliary TB, sarcoid, AIDS, lymphoma)

  13. Treatment of pulmonary TB • NB of compliance (helps cure pt & prevents spread of resistance) • Before tx baseline FBC, LFTs (incl alt), RP • Isoniazid, rifampicin & pyrazinamide all hepatotoxic • Test colour vision (Ishihara chart) & acuity (Snellen chart) before & after tx (ethambutol may cause (reversible) ocular toxicity • TB treated in 2 phases – initial phase using at least 3-4 drugs & continuation phase using 2 drugs in fully sensitive cases

  14. Treatment of pulmonary TB • Initial phase (2/12 on 3-4 drugs) – designed to ↓bacterial population asap & prevent resistance. • Rifampicin: MOA - Inhibits bacterial RNA synthesis by binding to the beta subunit of RNA polymerase, blocking RNA transcription. • Isoniazid: MOA - Unknown, but may include the inhibition of myocolic acid synthesis resulting in disruption of the bacterial cell wall. Most effective Bactericidal agent • Pyrazinamide (bactericidal active against intracellular dividing forms of M. tuberculosis, main effect only in 1st 2/12, useful in TB meningitis as good meningeal penetration) [Combination=RIFATER] • If resistance likely add ethambutol (if previous TB, immunosuppressed, in contact with organism likely to be drug resistant) • Streptomycin rarely used (given if resistance to isoniazid established)

  15. Treatment of pulmonary TB • Continuation phase (4/12 on 2 drugs) • Rifampicin + isoniazid. [Combination RIFINAH] If resistance problem use ethambutol. • Drugs best given as combination preparations unless one of components cannot be given (resistance/intolerance) • Monitor LFTs. If pre-existing liver disease/alcohol abuse need frequent LFTs esp in initial phase. If no liver problem further checks necessary only if sx fever, malaise, n&v, jaundice, deterioration. • If AST/ALT 2 times normal monitor LFTs until normal • If AST/ALT 5 times normal or bilirubin ↑ stop anti-TB meds -if pt not unwell & non-infectious TB no tx until LFTs normal -if pt unwell/smear positive need inpt tx until LFTs normal, eg with streptomycin/ethambutol -once LFTs normal challenge doses of original drugs sequentially in order: isoniazid, rifampicin, pyrazinamide with monitoring pts clinical condition & LFTs

  16. Treatment of pulmonary TB • RP checked prior to tx. Streptomycin & ethambutol best avoided if renal impairment, but if used need to ↓ dose & monitor drug levels. • If +ve culture for M. tuberculosis but susceptibility results not available after 2/12 then tx with pyrazinamide (& ethambutol if appropriate) should continue until susceptibilities confirmed • Longer tx for meningitis (~ 12 mths) & resistant organisms • NB Give pyridoxine 10 mg OD (Vit B6 ) throughout tx in high risk pts • Steroids indicated in meningeal & pericardial disease • Relapse uncommon if good compliance with tx

  17. Recommended dosage for standard unsupervised 6-mth tx of Pulmonary TB • Rifater [rifampicin, isoniazid, pyrazinamide] ( for 2/12 initial phase) Adults <40kg 3 tablets/d 40-49kg 4 tablets/d 50-64kg 5 tablets/d >65kg 6 tablets/d • Ethambutol (for 2/12 initial phase) 15mg/kg OD • Rifinah/Rimactazid [rifampicin & isoniazid] (for 4/12 continuation phase following initial tx with Rifater) Adults <50kg 3 tablets/d of Rifinah-150 50kg+ 2 tablets/d of Rifinah-300 or Rimactazid-300 Standard regimen may be used in pregnancy & BF. Streptomycin CI in pregnancy (ototoxic to fetus)

  18. DOT of Pulmonary TB • DOT in pts who can’t 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 Recommended dosage for intermittent supervised 6-mth tx Isoniazid (for initial 2/12 & 4/12 continuation phases) Adult & child: 15mg/kg (max 900 mg) 3 times/wk Rifampicin (for initial 2/12 & 4/12 continuation phase) Adult 600-900mg 3 times/wk; child 15mg/kg (max 900mg) 3 times/wk Pyrazinamide (for 2/12 initial phase only) Adult <50 kg 2g 3 times/wk, 50kg+ 2.5g 3 times/wk; child 50mg/kg 3 times/wk Ethambutol (for 2/12 initial phase only) Adult & child 30mg/kg 3 times/wk

  19. S/E of drugs used in tx of pulmonary TB • Need specialist advice in renal/liver failure, pregnancy.

  20. NB Interactions Rifampicin = hepatic enzyme p450 inducer (therefore ↓ level of) – affects OCP( NB to warn pt of ↓ effectiveness) corticosteroids protease inhibitors phenytoin sulphonylureas anticoagulants methadone Isoniazid = hepatic enzyme inhibitor (therefore ↑ level of) -affects phenytoin carbamazepine anticoagulants

  21. MDR-TB & TB in pts with HIV/AIDS • DOT aims to prevent MDR-TB • TB is common, serious but treatable complication of HIV infxn. Estimated that 30-50% of pts with AIDS in developing world have concurrent TB. • Interactions of HIV & TB • Mantoux may be –ve in HIV +ve pt with TB • Increased reactivation of latent TB • Atypical presentation & findings on CXR (lobar/bibasal pneumonia, hilar LN) • Previous BCG doesn’t prevent infxn • Smears may be –ve for AFB. NB to culture organism & assess drug sensitivities/resistance • 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 • Extrapulmonary & disseminated disease more common • 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, IRIS)

  22. MDR-TB & TB in pts with HIV/AIDs • Isolation necessary if TB pts near HIV+ve 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

  23. Preventing TB in HIV +ve pts • Primary prophylaxis against TB indicated in some HIV +ve pts ( if no BCG + mantoux >5mm, if BCG + mantoux >10mm, if recent exposure to active TB) Isoniazid (e.g. 300mg/d PO, children 5mg/kg, max 300mg given with pyroxidine) for 9 mths. If known isoniazid-resistant TB contact give rifampicin

  24. Chemoprophylaxis for asymptomatic TB infxn • Immigrant/contact screening may id pts with no symptoms/no CXR findings, but +mantoux • In LTBI ~10% will go onto develop active disease • Chemoprophylaxis useful to kill organisms & prevent disease progression • Chemoprophylaxis may be required in latent disease & receiving tx with immunosuppressants (eg cytotoxics, TNF blockers, long term tx with steroids) • 1 or 2 anti-TB agents used for shorter period than with symptomatic disease (e.g. rifampicin 600mg OD PO & isoniazid 300mg OD PO [Rifinah] for 4 mths or isoniazid 300mg OD PO alone for 9 mths) • Standard anti-TB tx should be initiated once any evidence active disease (clinical/radiological)

  25. BCG vaccine • BCG is live attenuated strain derived from M. bovis → stimulates development of hypersensitivity to M. tuberculosis • 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 > 40/100,000 • Infants with parent/grandparent born in country with incidence of TB >40/100,000 • Contacts of pts with active pulmonary TB • Health care staff • Veterinary staff • Prison staff • If intending to stay for >1 mth in country with high incidence TB

  26. 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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