Lecture 29 + 30 Tuberculosis and Antitubercular Agents Flashcards
Who discovered the tubercle bacillus and when?
Robert Koch in 1882
How is tuberculosis transmitted?
inhalation of droplets containing M. tuberculosis from infectious pt
1-5 micron droplets formed when coughing, sneezing, talking ⇒ small enough to implant in alveoli
droplets remain suspended in air for hours, contain 3-10 tubercle bacilli, each untreated person with active TB can be expected to infect 10-15 people in 1 year
Probability of transmission increases with: bacterial burden, cavitary and upper lung zone disease or laryngeal disease, amount and severity of cough, duration of exposure, indoor rather than outdoor, delays in diagnosis and/or effective tx, susceptibility of exposed person
Who are the high risk groups for transmission of TB?
close contacts of pt with infectious TB (ex. household), immunocompromised, children (less than 5 years of age)
congregate settings: homeless shelters, institutional facilities, correctional institutions, continuing care facilities
What is involved in the immune response for TB?
alveolar macrophages ingest TB - primary infection will heal if host has healthy immune system
when macrophages unable to destroy the TB they multiply until macrophage bursts attracting new macrophages to engulf released TB and cycle continues
T-lymphocytes respond within 3-8 weeks, they migrate to site of infection to surround macrophages
inflammatory responses produces granuloma ⇒ some bacilli remain alive encapsulated in scars in apices of lungs (termed TB infection)
What is a ‘latent’ TB infection?
pt has inhaled M. tuberculosis but it is walled off by immune system
bacilli have ability to produce enzymes enabling them to live in anaerobic environment
these organisms may stay in place for many years until the pt immune system begins to fail ⇒ ex. old age, transplant, immunosuppression, etc ⇒ at this time TB may reactivate
What is primary and reactivation TB, how often do they occur relative to cases?
Primary (5%): recently infected but unable to contain infection despite stimulation of cell-mediated immunity, progress to disease in matter of months, likely to occur in young children and immunocompromised
Reactivation (5%): progression of TB infection to disease, may occur many decades after initial infection, usually presents as pulmonary disease, more likely to occur in immunocompromised, may disseminate resulting in extrapulmonary TB
Who are the high risk groups for progression of TB infection to disease?
pt with Hx of untreated or inadequately treated pulmonary TB - ex. elderly infected with TB in youth
pt with ‘high risk’ lung scar on chest radiograph
foreign born from areas of high prevalence - especially within first 2 years of arrival
immunocompromised - biologics, transplant, long term corticosteroid use, cancer, HIV, stage IV/V CKD
How is a TB infection (‘latent’ TB) diagnosed, and why is it done?
Goal: to see those at risk of developing TB disease and would benefit from preventative meds
Tests: tuberculin skin test (TST) and interferon gamma release assay (IGRA) - both surrogate markers of TB infection and indicate cellular immune response
neither test can separate infection from disease or be used to monitor tx response
IGRA more specific in pt vaccinated with Bacille Calmette-Guerin (BCG)
neither highly accurate for prediction of TB disease
What is a tuberculin skin test (TST)?
aka Mantoux test,, tests T-cell mediated response (delayed response) to purified protein derivative (PPD)
0.1 mL containing 5 TU injected intradermally
read at 48-72 hours after injection, diameter of area of induration read (not area of redness)
a + result indicates contact with TB (TB infection, disease, previous TB or TB vaccine (BCG))
Results: 10 mm or more SIGNIFICANT in all
5-9 mm induration SIGNIFICANT IN: pt with HIV or stage IV/V CKD, close recent contact of person with infectious TB disease, pt whose chest radiograph suggests previous TB, prior to organ transplant or biologics
What is the Bacille Calmette-Guerin (BCG) vaccine?
it is a live attenuated vaccine derived from M. bovis
variable efficacy 0-80%, highest in children <2 and lower in adults
meta-analysis showed overall protective effect around 50%, higher against meningeal and miliary TB
in Canada currently only used in infants in high incidence settings typically given at birth
CONTRA in those with immune deficiency diseases or those with + TST result
may interfere with Mantoux test BUT NOT IGRA
What is an Interferon Gamma Release Assay (IGRA)?
quantiferon-TB Gold Plus assay used in Alberta,, not meant for active disease diagnosis
measures T-cell release of this after stimulation by antigens specific to M. tuberculosis
may offer increased specificity for TB vs TST
Results: positive, negative, indeterminate - inadequate or excessive mitogen, invalid - incorrect processing or collection
How is TB disease diagnosed?
S&S: persistent cough (>2-3 weeks) - initially dry, usually productive after several weeks to months
sputum production, occasionally hemoptysis often seen as bright red streaks, chest pain (TB pleurisy), fever/chills, night sweats, weight loss (consumption)/anorexia/loss of appetite, fatigue
check medical Hx (demographics, previous infection, risk fx)
physical exam (bronchial breathing, rales, lymphadenopathy)
chest radiograph
sputum smear microscopy
nucleic acid amplification tests (NAATs)
mycobacterial culture is gold standard in diagnosis of TB disease
What are the treatment regimens for preventative TB treatment?
1st Line: Rifampin 600 mg QD self-admin F4M
Isoniazid and Rifapentine both 900 mg once weekly directly observed tx F12W
Others: Isoniazid 300 mg QD self admin F9M
Isoniazid and Rifapentine 300 mg and 600 mg QD self admin F1M
Rifapentine 600 mg QD self admin F6W
Rifampin 20 mg/kg QD self admin F2M
What is rifampin (MOA, AE)
semisynthetic derived from Streptomyces mediterranei found in soil from pine forest on French Riviera in 1957
most potent anti-TB drug available
also active against S. aureus, S. pneumoniae, N/ meningitidis (only as adjunct or prophylaxis)
MOA: inhibits mycobacterial RNApol
AE: hepatotoxicity (alcoholics with pre-existing disease more susceptible), elevated bilirubin, alkaline phosphatase
flushing, rash, pruritis, thrombocytopenia, neutropenia, interstitial nephritis and renal failure, systemic flu like illness +/- thrombocytopenia with intermittent tx, reddish-orange colour in urine and tears, may stain contact lenses
What are some drug intx with rifampin and why?
induces number of metabolizers ⇒ CYP3A4 and 2C9 as well as P-gp,, more than 100 intx described
Anticoagulants: warfarin, DOACs
Anticonvulsants: carbamazepine, phenytoin, lamotrigine,, Antifungals
Antihypertensives: CCBs, BBs
Antiretrovirals: protease inhibitors, NNRTIs, integrase inhibitors
Hormonals: estrogen, oral contraceptives, glucocorticoids
Others: opioid agonists, immunosuppressives, antidepressants, Synthroid
Treatment phases for TB disease
Initial Intensive Phase: 2 months given QD or 5x weekly
start with 4 drugs ⇒ once susceptibilities known can drop to 3 that organism is susceptible to
leads to rapid bacteriologic sputum conversion and decreasing clinical sx
Continuation Phase: usually 2 drugs for 4 months (standard), may be given as high dose 3x weekly, may also be for 7 months
intended to kill less metabolically active and intermittently replicating
Duration may be extended if: pyrazinamide wasn’t used in intensive, more than one site involved, drug resistant strain, persistent cavity on CXR at 2 months, positive smear culture after 2 months of tx
What are the antitubercular drugs and their MOAs?
First Line: (superior efficacy and acceptable toxicity), isoniazid (INH) ⇒ inhibits synthesis of mycolic acid
rifampin (RIF) ⇒ inhibits mycobacterial RNApol
ethambutol (EMB) ⇒ impairs mycobacterial cell wall synthesis
pyrazinamide (PZA) ⇒ converts to pyrazinoic acid which lowers pH
2nd Line: fluoroquinolones (moxifloxacin (MOXI), levofloxacin (LEVO)), linezolid, SAP (bedaquiline, delamanid, clofazimine, cycloserine, ethionamide), injectables (amikacin (AMIK))
What is isoniazid (MOA, PK, AE, Intx)?
first intro in 1952
antitubercular drug first line agent
highly effective in killing rapidly dividing bacteria but bacteriostatic for slowly dividing
for TB if this isn’t given for full tx, the tx should be prolonged to 9-12 months
MOA: inhibits synthesis of mycolic acid
PK: metabolized in liver by N-acetyltransferase, can have rapid or slow acetylators
diminished acetylation cap correlated with higher risk of hepatotoxicity, while rapid acetylators at risk of tx failure and acquired drug resistance
AE: hepatotoxicity (increase risk in alcoholics, pregnancy, combo with acetaminophen, malnutrition, pre-existing liver disease (Hep C)) - usually reverses with discontinuation
neurotoxicity (peripheral 17%, risk fx: slow acetylator, alcoholism, DM, uremia) - it increases B6 excretion so can supplement with 25 mg B6 QD in those with risk fx, renal failure, malnutrition, substance abuse, seizures, pregnancy or breast feeding
rash, skin eruptions, N/V, fatigue, H/A, rarely systemic lupus, B6 deficiency related anemia
Intx: acetaminophen - increases toxic metabolites,, phenytoin and carbamazepine and valproic acid - increases levels
What is pyrazinamide (MOA, PK, AE)?
used as component of standard TB tx, first line agent
bactericidal but appears to provide benefit ONLY IN FIRST 2 MONTHS of tx (INTENSIVE), shortens duration of tx from 9 to 6 months if used in intensive phase
MOA: converts to pyrazinoic acid and lowers pH
PK: t1/2 of 12 hr, metabolized by liver, metabolites excreted in urine requiring dose mods in renal failure
AE: N/V most common
hepatotoxicity - this > INH > RIF, 15% with past higher doses (40-50 mg/kg), 20-25 mg/kg much safer
rash, arthralgias, elevation of serum uric acid (caution in gout hx)
What is ethambutol?
discovered in 1961
least effective first line agent in TB for bactericidal activity
used to prevent drug resistance in intensive phase of TB tx
once susceptibilities are known it can be discontinued if sensitive to other agents
MOA: impairs mycobacterial cell wall synthesis
PK: 25% metabolized by liver, 80% remains excreted unchanged in urine, requires dose mod in renal failure
AE: neuropathy and visual loss (most commonly retrobulbar neuritis, peripheral uncommon) - results in bilateral blurry vision, impaired visual acuity, red-green colour vision, more common with high dose 25 mg/kg/day than 15 but visual loss has occurred rarely in elderly with 15, pt should be monitored and report reduced acuity promptly and d/c drug until tests done
GI, hyperuricemia, hypersensitivity
What is the risk of hepatotoxicity with anti-TB drugs, as in which drugs have the highest risk?
pyrazinamide (PZA) > isoniazid (INH) > rifampin (RIF)
