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Drug treatment of Pulmonary Tuberculosis

Drug treatment of Pulmonary Tuberculosis. 4 th medical year Pharmacology. Tuberculosis. Kills ~ 3 million/yr worldwide In UK ~ 10% drug resistance. Tuberculosis.

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Drug treatment of Pulmonary Tuberculosis

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  1. Drug treatment of Pulmonary Tuberculosis 4th medical year Pharmacology

  2. Tuberculosis • Kills ~ 3 million/yr worldwide • In UK ~ 10% drug resistance

  3. 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.

  4. 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, 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

  5. Tuberculosis • 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)

  6. 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

  7. 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 >/= 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)

  8. First Line Antituberculous drugs • Isoniazid • Rifampicin • Pyrazinamide • Ethambutol • Streptomycin

  9. 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)

  10. 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

  11. 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) - n&v

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. Directly Observed Therapy 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

  20. 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 doesn’t prevent infection • Atypical presentation & findings • Extrapulmonary & disseminated disease more common

  21. 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)

  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 given with pyroxidine for 9 months If known isoniazid-resistant TB contact give rifampicin

  24. 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)

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

  26. 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 > 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

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

  28. BTS Guidelines • http://www.brit-thoracic.org.uk/c2/uploads/Chemotherapy.pdf • http://www.brit-thoracic.org.uk/c2/uploads/TB.pdf

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