Suttle/Cross - TB Flashcards
1
Q
What is BCG also used for?
A
To treat bladder cancer
2
Q
What are the risk factors for TB?
A
- Prison (crowded conditions)
- Immigrant from high burden country
- Malnourished
- Alcoholism
- Poverty
- Debilitating illness
- AIDS
- Elderly
-
Certain diseases: DM, Hodgkin lymphoma, CKD, malnutrition, immunosuppression
1. RA on TNF alpha antagonists
3
Q
What are the basic TB tx regimens (chart: preferred and alternatives)?
A
- Summary: 2-4 drugs taken for at least 26 weeks on different dosing schedules
- NOTE: a continuation phase of once-weekly INH/RPT can be used for HIV- patients who do NOT have cavities on chest film AND who have (-) acid-fast bacilli (AFB) smears at the completion of the initial phase
4
Q
What is this?
A
- MTB acid-fast stain
-
Acid fast bacillus, obligate aerobe
1. Ability to retain carbolfuchsin stain due to high lipid content in waxy cell wall (mycolic acid)
2. Grows very slowly (doubling time of 18 hours) - Cultures held for 6-8 weeks before being finalized
- Stained poorly by the dyes used in gram stain
5
Q
What are the 2 main side effects for INH?
A
- Neuropathy for slow acetylators
- Hepatotoxicity for fast acetylators
6
Q
What is the MOA of Ethambutol?
A
- Inhibition of RNA synthesis
-
Disrupts cell wall synthesis: INH arabinosyl transferase -> mycolic acids usually attach to 5’-hydroxyl groups of D-arabinose residues of arabinogalactan and form mycolyl-arabinogalactyl-peptidoglycan complex in cell wall
1. Disrupts arabinogalactan synthesis (necessary for synthesis of peptidoglycan units of cell wall)
2. Results in increased cell wall permeability - Static effect: possible -cidal at high levels
- Bacilli must be actively dividing
- Slow devo of resistance; no cross resistance
7
Q
What are the first-line and alternative agents for treating TB?
A
-
First-line:
1. Isoniazid (INH) + Rifampin (RIF) + Pyrazinamide (PZA) + Ethambutol (EMB) or Streptomycin -
Alternative:
1. Ofloxacin; cycloserine; capreomycin; kanamycin; amikacin; ethionamide; clofazimine; para-aminosalicyclic acid - NOTE: in HIV+, Rifabutin (instead of Rifampin) can DEC drug interaxns w/PI’s and NNRTI’s
8
Q
Why is the IGRA test important?
A
- IFN-gamma assay (IGRA) can be used for diagnosis of TB, and is specific only to MTB
- Will also not get a false (+) for people who have received the BCG vaccine
9
Q
What is the difference between TB infection and active disease?
A
- Most infections acquired from active case to susceptible host – this is primary infection
- In most cases, primary infections are asymptomatic (only 5% develop clinically significant disease -> peeps with impaired cell-mediated immunity)
1. Only evidence of infection is fibrocalcific nodule at site of infection
2. Viable organisms can remain dormant for years and reactivate to produce 2o infection (active disease)
3. 2o infection usually involves apices of lungs -> cavitation occurs frequently
4. Erosion of cavities into airway is source of infection –> person is expectorating organisms
10
Q
What are some of the new TB drugs in devo (image)?
A
Probably don’t need to know these
11
Q
How is TB related to HIV?
A
- All stages of HIV associated w/INC risk of TB, even with HAART -> but, low CD4 count important risk factor
- Variable pulmonary manifestations (see attached image; others with bilateral infiltrates, pleural effusion)
1. Increased frequency of false negative sputum smears, absence of granulomas in tissues -> may see TB infection in the lower lobes of the lungs - Cavitation/bronchial damage more severe in immuno-competent individuals due to robust immune response
1. With reduced immune response as in HIV, there is no bronchial damage and few AFB in sputum
12
Q
What are the AE’s of Isoniazid?
A
-
Peripheral neuropathy: dose-relsated burning, prickling sensation in hands and feet (stocking-glove)
1. Competition bt INH and pyridoxal phosphate -> corrected w/Vit. B6 supplementation (10-50mg daily)
2. More freq. in malnourished, diabetics, and alcoholics -
Hepatotoxicity: dose-related
1. Major toxic rxn (hepatitis) in 2% due to toxic metabolite from acetylation of INH
2. INC liver enzymes in up to 20% of pts (caution if admin w/other hepatotoxic drugs, like RIF) - Allergic rxns: not dose-related
13
Q
Why is TB difficult to diagnose in HIV+ patients?
A
- Not as much expectoration of bacteria (can’t rely as much on these tests)
- PPD may be (-) because the patient’s immune system is so compromised
14
Q
Briefly describe the MOA’s of the 4 first-line anti-TB drugs (image).
A
- Isoniazid: inhibits cell wall synthesis
- Ethambutol: inhibits cell wall synthesis
- Pyrazinimide: exact target unclear, but 1) disrupts plasma membrane and 2) disrupts energy metabolism
- Rifampin: inhibits RNA synthesis
15
Q
What is the critical cytokine for the control of TB?
A
- TNF from macros is critical to help control TB infection (this is why RA pts on TNF-alpha inhibitors are at an increased risk)
- TNF is important to keep granulomas from falling apart
1. IFN-gamma also critical because if you have mutations in this receptor, you won’t form granulomas at all
16
Q
What are the treatment options for latent TB infection? Which tx is more frequently completed?
A
- 3-mo tx with INH-RPT with DOT is effective and more frequently completed than US standard of INH w/o DOT
- NOTE: due to reports of severe liver injury and death, the CDC recommends that the combo of RIF and PZA should generally NOT be offered for tx of latent TB infection
17
Q
What are the MOA, resistance, and spectrum of Rifampin?
A
-
MOA: inhibition of RNA synthesis via binding of beta subunit of the Mb RNA polymerase (mammalian RNA polymerase not as sensitive, so unaffected except at supra-clinical doses)
1. Bactericidal -
Resistance: DNA-dependent RNA polymerase does not bind drug (becoming widespread)
1. Never give as a single agent bc resistance emerges rapidly - Spectrum: IC and EC mycobacteria
- NOTE: RIF is the most commonly used of the Rafamycins
18
Q
What is resistant TB? What is the main risk factor?
A
- MDR TB: resistance to INH and RIF most common -> AIDS patients
-
XDR TB: resistance to INH, RIF, flouroquinolone, at least one additional drug
1. Emerged in 2005 in south Africa. -
Noncompliance is risk factor for devo of resistance
1. Directly observed therapy (DOT) is used in Shelby County and many other places to prevent this
19
Q
What should you do before treating patients for latent TB?
A
Make sure patients do not have active disease -> get a CXR
20
Q
What are some of the clinical manifestations of miliary/disseminated TB? CXR?
A
- Lymphohematogenous dissemination following 1o inf can result in miliary/disseminated TB (HIV patients at high risk)
-
CXR can look like a bunch of seeds all over (millet seeds)
1. Dyspnea, cough -
Other organ involvement: liver (RUQ pain, nausea and vomiting), bone marrow, spleen
1. Meningitis, Pott’s disease (vertebral osteomyelitis), GI (nausea/vomiting/diarrha), urinary tract (sterile pyuria, hematuria, proteinuria)
2. Adrenal insufficiency, epididymitis (highly convoluted duct behind the testis, along which sperm passes to the vas deferens), prostatitis
21
Q
How is Isoniazid absorbed, distributed, metabolized, and excreted?
A
- Absorption: rapidly from GI tract with oral dose, or IM
-
Distribution: all tissues and fluids
1. W/inflamed meninges, therapeutic levels in CSF
2. Crosses placenta; distributed in breast milk -
Metabolism: acetylated via N-acetyl transferase
1. 2-3x lower plasma conc in fast acetylators vs. slow (half-lives vary from 1-4 hours)
2. Chronic liver disease affects metabolism (DEC dose)
3. Induces CYP -> can influence concurrent CYP substrate therapy - Excretion: drug, inactive metabolites (75%) out in urine
22
Q
How do you diagnose latent TB?
A
-
PPD (purified protein derivative): intradermal injection of tuberculin material stimulates delayed-type hypersensitivity rxn mediated by T lymphos -> induration in 48-72 hours
1. BCG immunization can cause false (+) test -> wanes over time and clinically ignore the fact that someone got the BCG (adults at least; up to 20% will still be (+) 10 yrs or more from time of vaccination)
2. Infection with nontuberculous mycobacteria can also cause false positive results -
IGRA (Quantiferon gold, Quan-TB, T-spot): blood cells from the pt exposed to Ags from MTB -> amt of IFN-gamma released from cells is measured
1. No false positives with BCG or NTM infections - HIV+ patients: false negatives in both tests can occur due to lack of immune response, sometimes called anergy
23
Q
How are Rifabutine and RPT related to RIF?
A
- Rifabutine and RPT are derivatives of RIF
1. Rifabutine: <potent></potent>
<p>2. <u>RPT</u>: longer half-life than Rifabutine and RIF, so it can be given only once weekly (intermediate to RIF and Rifabutine as a CYP inducer) </p>
</potent>
24
Q
What is the main toxicity associated with Ethambutol?
A
Ocular toxicity
25
Q
What are some of the possible clinical manifestations of TB (image)?
A
26
Q
How do you treat TB?
A
-
Secondary/primary pulmonary TB
1. If suspicion is high, don’t wait for confirmed dx -> start treatment
2. 4-drug treatment required initially:
a. INH, Rifampin, Pyrazinimide, Ethambutol (RIPE)
b. Once susceptibility is known, and if susceptible, can stop Ethambutol
c. After 2 months of RIPE/RIP, can stop PZA and continue INH/Rifampin for 4-7 more months to complete 6-9 months of therapy - Miliary TB: 9-12 months -> all 4 drugs
33
Q
What is PknG?
A
- MTB can grow intracellularly in macros -> effective means of evading the immune system
1. Ab’s and complement are ineffective - Once MTB is phagocytosed, it can inhibit phagosome-lysosome fusion via the protein PknG (see attached image)
34
Q
How do you diagnose TB?
A
-
Acid fast stain on sputum initial test (see attached image) -> culture should be done at the same time
1. Lowenstein-Jensen agar required -> substances to enrich growth and inhibit other flora
2. 3-6 wks to grow on solid agar (doubling time 18 hrs)
3. Will not grow on blood agar - Culture in liquid media can show results in 2 weeks
-
PCR, or nucleic acid amplification even more rapid
1. Better on smear-positive specimens (initially sputum will come back smear-positive or negative)
39
Q
What is this?
A
Miliary/disseminated TB
44
Q
What is MDR-TB? What are the possible effective treatments?
A
- MDR TB is a form of drug-resistant TB in which TB bacteria can no longer be killed by at least the two best antibiotics, isoniazid (INH) and rifampin (RIF), most commonly used to cure TB
- As a result, this form of the disease is more difficult to treat than ordinary TB and requires up to 2 additional drugs?
48
Q
What is XDR-TB? What are some tx options?
A
- Less common form of MDR-TB in which TB bac have changed enough to circumvent the 2 best AB’s, INH and RIF, as well as most of the alternative drugs for MDR-TB
1. These second-line drugs incl. any fluoroquinolone, and at least one of the other three injectable anti-TB drugs: amikacin or kanamycin (aminoglycosides), or capreomycin - As a result, XDR TB needs up to 2 years of extensive drug treatment, and is the most challenging to treat.
51
Q
What is the pathogenesis of TB?
A
- Doesn’t have classic bacterial virulence factors, like toxins, capsules and fimbriae
- Cell wall contains many waxy-like substances that make it impermeable to many host defense systems: 1) mycolic acids, 2) glycolipids, 3) arabinogalactans, 4) free lipids
-
Virulence factors:
1. Cord factor: virulent strains grow in characteristic cord-like pattern, avirulent strains do not -> inhibits macro maturation and induces TNF-alpha release
2. Sulfatides (surface glycolipids): once phagocytosed, inhibits phago-lysosomal fusion (protein PknG), allowing the bacteria to replicate - Can grow IC in macros: effective means of evading the immune system -> Ab’s and complement are ineffective
-
IFN-γ: critical mediator allowing macros to contain the infection -> released by TH1 (after MTB enters macro via endocytosis)
1. Th1 response leads to granuloma formation and caseous necrosis (IL-12 released by macros to call Th1)
2. Activated macros secrete TNF and cytokines that recruit more monocytes - TNF-α extremely important –> RA patients on antagonists at increased risk for TB
57
Q
What is a positive PPD?
A
- >15 mm: no known risk factors
- 10-15 mm: homeless, IVDU, nursing home resident, recent immigrant, children less than 4 years of age
- 5-10 mm: HIV, recent contact of someone with TB, person with fibrotic changes on CXR consistent with prior TB, organ transplants, immunosuppressed (prednisone, TNF alpha antagonists)
