Mycobacterium Tuberculosis

Mycobacterium Tuberculosis

1. Epidemiology

   • RIsk Factors
     • Birth/travel to endemic country
     • Homlessness
     • Incarceration
     • IVDU
     • Alcoholism
     • Immunosuppression
     • TNFa antagonists (infliximab), corticosteroids)
     • Exposure
   • !/3 of world population infected
   • Developing countries
   • HIV correlation

2. Transmission

   • Respiratory droplets
   • Close, prolonged contact
   • Sputum +ve more infectious
   • unpasturized milk - bovine TB

3. Pathogenesis

   • Bacilli inhaled into resp tract
   • Engulfed by macrophages
   • T cell inflammatory mediators (TNFa) activate macrophages
   • Bacilli walled off = granuloma: die or remain dormant
   • Pathogenicity
     • evade macrophage induced killing
     • induce delayed Type IV hypersensitivity response
   • Virulence factors (cell wall components)
     • Cord factor: granuloma production
     • Sulfatides: prevent phagosome-lysosome fusion
     • LAM: inhibit mac activation; induce TNFa and IL10 mac production
     • Heat shock rptoein: AI rxns

4. Clinical features

   • Fever, night sweats, malaise, fatigue, weight loss (many TNFa mediated)
   • Pulmonary: cough sputum, haemoptysis, pleuritic pain, unresolving LRTI not responding to abx
   • Extra pulmonary
     • headache, confusion
     • local swelling, pain
     • DIscharging lesion
   • Radiology
     • Apical: 80-90%
     • infiltrates, cavitation
     • Atyoical: mid/lower lobes, hilar effusion, hilar adenopathy
     • CXR normal in 5%
   • Macroscopic
     • Subpleural Ghon focus + enlarged hilar LNs
     • Cavitary fibrocaseous disease = erosion into a bronchiole + cavity lined by yellow-grey caseous material
   • Microscopic
     • Caseating granuloma

5. Lab Diagnosis

   • Mantoux test
     • Tuberculin PDD intradermally
     • Read induration at 48-72hrs
     • Previous exposure - anergy, BCG
   • Microscopy
     • LM: ZN stain
     • Fluorescent: auramine-rhodamine stain
     • +ve = suggestive of TB
   • Culture
     • Lowenstein-Jensen
       • Rough, tough, buff colonies
     • automated culture systems
     • decontaiminate non sterile specimens
     • Incubate at 35-37C for up to 8w
   • PCR
     • ID organisms from culture
     • DIrectly on AFB+ specimens
     • MTB complex
     • Rifampicin resistance (rpoB gene)

6. Treatment

   • FIrst line treatment
     • Isoniazid
       • limited to TB tx
       • Hydrazide of isonicotinic acid (INH)
       • cteriostatic (resting), bacteriocidal (active)
       • MOA
         • inhibit mycolic acid synthesis; combines with a MB enzyme leading to disorganisation of the metabolism of the cell
       • resistance:
         • mutation in MTB catalase-peroxidase enxyme
         • Reduced penetration
         • overexpression of carrier proteins
       • PK
         • p.o. admin
         • good absorption
         • wide distribution (BBB; caseous lesions)
         • acetylation
         • renal excretion
       • Side effects
         • allergic skin rxn, SLE
         • CNS - memory loss, seizures
         • peripheral neuropathy - competition for apotryptophanase = decreased pyridoxine
         • Hepatotoxicity
         • decreased metabolism of AEDs
     • Rifampicin:
       • Bactericidal
       • MOA: binds B subunit of bacterial DNA dependent RNA polymerase
       • Resistance
         • tions in defined region of RNA polymerase subunit: rpoB gene
         • Ribosylation: degradative mechanism
       • PK
         • PO admin
         • CSF in meningitis
         • deacytlation in liver; EH recycling
         • bile and urine excretion
       • Side effects
         • Orange secretions
         • Cholestatic Jaundice
         • induce CYP450
     • Ethambutol
       • inhibits transferases involved in cell wall synthesis
       • BBB if meninges inflamed
       • resistance with overexpression and structural changes of arabinosyl transferases
       • Dose related optic neuritis (RG colour blindess, decreased acuity)
     • Pyrazinamide
       • Nicotinamide family
       • gout- hyperuricaemia
       • pH lowering
       • Resistance in mutations of pyrazinamidase
   • Second line tx
     • Capreomycin (AG)
       • protein synthesis inhibitor
     • Cycloserine
       • cell wall synthesis inhibitor
     • Amikacin (AG)
       • protein synthesis inhibitor
     • Ciprofloxacin (FQ)
       • nucleic acid synthesis inhibitor
   • DR/MDR/XDR TB
     • MD = isonizid + rifampicin
   • 4 drugs/2m + 2 drugs/4m (longer if more severe disease/resistance)

7. Prevention and management

   • isolation of open cases(-ve pressure)
   • PH notifications and contact tracing
   • BCG vaccination

8. Natural history

   • 1. Immediate clearance of the organism
   • 2. Primary disease
     • Pulmonary - replication of bacilli in lung tissue and LNs = Ghon focus
     • Extra pulmonary (kidney, brain, spine)
     • Disseminated (miliary TB)
       • severe impairment of host resistance
     • Ghon complex = Ghon Focus + Hilar LN adenopathy
     • T CMI after 2-3w (Mantoux +)
     • CD4+ Th cells
       • IFNy: iNOS production
       • epithelioid cell granulomas
     • CD8+ suppressor T cell
       • Caseating granulomas
       • acidic, anaerobic nectoric centre
     • Foci of scarring may harbour bacilli
   • 3. latent infection
     • 5-10% reactivate
   • 4. Reactivation/reinfection disease
     • post primary disease = previously sensitised host
     • usually pulmonary = 90% apical
     • Open TB = erosion through bronchial wall and cavity formation (sputum +)
     • Caseating granulomas
     • Dissemination is unusual

9. Tuberculosis: Infectious disease caused by tubercle bacilli and characterised by the formation of granulomata in the lungs and other tissues of the body - caused by M.TB complex and atypical mycobacterial sp (more difficult to treat)