TB Flashcards
Mycobacteria
There are more than 170 species in the Mycobacterium genus.
Environmental organisms found in soil and water.
120 can cause opportunistic, non-tubercular lung disease.
Some can be serious pathogenssuch as Mycobacterium leprae and Mycobacterium tuberculosis.
Mortality from infectious disease
TB was the leading cause of death from a single infectious disease agent and one of the top 10 causes of death worldwide, until 2020.
1.2 million deaths due to TB every year (2018)
TB facts- incidence and deaths
~ 1.3 million TB related deaths:
1.1 million died from TB and an additional 0.2 million died of TB-HIV co-infection.
~ 10.4 million new TB cases:
1.2 million, HIV positive: 60% occurred in 6 countries, India, Indonesia, China, Nigeria, Pakistan, and South Africa.
~ 490,000 new MDR-TB cases
MDR-TB
multidrug-resistant tuberculosis (defined
as TB caused by strains of Mycobacterium tuberculosis
that are resistant to at least isoniazid and rifampicin).
XDR-TB
extensively drug-resistant tuberculosis (de-
fined as MDR-TB plus resistance to a fluoroquinolone
and at least one second-line injectable agent:
amikacin, kanamycin and/or capreomycin).
Treating MDR-TB
still responds to second line drugs, successful treatment requires up to two years of therapy, and often involves drug administration on an in-patient basis.
The cost of drugs alone for treating the average MDR-TB patient is 50 to 200 times higher than for treating a drug-susceptible TB patient
High risk for developing TB
-Those who have been recently infected
-Those with clinical conditions that increase their risk of progressing from latent TB to TB disease
Clinical conditions that increase risk of TB disease
HIV infected persons
Those with history of prior, untreated TB
Underweight or malnourished persons
Injection drug use
Those receiving TNF-a antagonists for treatment of rheumatoid arthritis or Crohn’s disease
TB- primary infection
90-95% of cases begin with pulmonary focus
usually a SINGLE focus
hypersensitivity develops 2 to 6 weeks
- until then, focus may grow larger
- hypersensitivity brings caseation
Primary tuberculosis
Brief acute inflammation
5-6 days invoke granuloma formation.
2 to 8 weeks – healing – Ghon focus (+ lymph node Ghon’s complex)
Develop immunity – Mantoux positive
Ghon’s complex
Primary tuberculosis is the pattern seen with initial infection with tuberculosis in children.
Reactivation, or secondary tuberculosis, is more typically seen in adults.
Primary infection- lympho-haematogenous spread
8-14 weeks after onset of TB
Mantoux positive during this phase
bodywide seeding occurs during this phase
- bone, kidney, meninges etc.
- 3% of children develop calcifications in lung apices (SIMON FOCI)
Miliary disease
Generalised Haematogenous Tuberculosis
generalised dissemination through bloodstream
caseous focus ruptures into blood vessel
growth of tubercle within the blood vessel
may be acute, occult or chronic
uniformly fatal if not treated
rare
usually occurs in the first 4 months after primary infection
TB pathogenesis
Infects CD4+ macro phage cells
Formation of a granule a starts in the lung
Morphology of granuloma
Rounded tight collection of chronic inflammatory cells.
Central caseous necrosis.
Active macrophages - epithelioid cells.
Outer layer of lymphocytes, plasma cells & fibroblasts.
Langerhans giant cells – joined epithelioid cells.
Secondary tuberculosis
Reactivation occurs in 10-15% of patients.
Most commonly males 30-50 years
Slowly Progressive (several months)
Cough, sputum, Low grade fever, night sweats, fatigue and weight loss.
Hemoptysis or pleuritic pain = severe disease
TB drug regimen
two drugs were necessary to prevent treatment failure
streptomycin (STR) is an aminoglycoside that interferes with translation of messenger RNA (mRNA) transcripts in Mycobacterium tuberculosis. STR binds to a ribosomal protein (S12) that is a component of the 30S subunit of the ribosome complex
Treatment
always use at least 2 drugs:
– natural incidence of spontaneous resistance to any
1 drug = 1 in 10(4-5)
– natural resistance spontaneously to
2 drugs = 1 in 10(10)
prolonged 6-9 months depending on regimen
• Directly Observed Therapy
Drug treatment
Include two of the four 1st-line drugs in initial regimen
Isoniazid (INH)
Rifampin (RIF)
Pyrazinamide (PZA)
Ethambutol (EMB)
Second line drugs
INJECTABLES:
STREPTOMYCIN AMIKACIN KANAMYCIN CAPREOMYCIN
– • ORAL AGENTS
QUINOLONES: LEVOFLOXACIN OR MOXIFLOXACIN CYCLOSERINE ETHIONAMIDE P-aminosalicylic acid (PAS)
Injectables
AMIKACIN: NEPHROTOXIC
• STREPTOMYCIN: NEUROTOXIC TO VIII NERVE
-Both auditory and vestibular ototoxicity
-Partial or total irreversible deafness may continue to develop after drug is stopped
-Other features of neurotoxicity include paresthesia, twitching, and seizures.
-Teratogenic: Contra-indicated during pregnancy
• KANAMYCIN: SIMILAR TO STREPTOMYCIN
• CAPREOMYCIN
Cell wall of TB
3x normal thickness
Large layer of fatty acids- means that bacterium does not take up many chemicals
Why is TB treatment so long
Very slow growth
Difficult to get drugs into TB
Mechanism of action of isoniazid
inhibits synthesis of mycolic acids, the essential component of TB cell wall
• INH is bacteriocidal against actively growing intracellular and extracellular organisms
• INH resistant M. tuberculosis develop with INH monotherapy
interferes with cell wall biosynthesis in Mycobacterium tuberculosis. INH is a prodrug and is converted to an active form by catalase peroxidase (KatG). Activated INH inhibits the action of enoyl-acyl carrier protein reductase (InhA). InhA is an important enzyme component of the fatty acid synthetase II (FAS-II) complex. FAS-II is involved in the synthesis of long-chain mycolic acids. Mycolic acids are essential structural components of the mycobacterial cell wall and are attached to the arabinogalactan layer.
