Flashcards in Treatment of TB Deck (58):
1
1st line drugs for TB
-Isoniazid
-Rifampin
-Pyrazinamide
-Ethambutol
-Rifabutin, Rifapentine
2
Pyridoxine can be added adjectively to TB treatments. Why?
TO prevent drug-induced neuropathy
3
What are the majors organs affected by TB?
-lungs
-nodes, pleura, bones, and joints
4
How is TB spread?
inhalation of infectious droplet nuclei aerosolized by pulmonary TB
5
What is MDR TB?
resistant to isoniazid and rifampin.
6
What is XDR TB?
resistant to isoniazid and rifampin plus a fluoroquinolone and one of the three second line drugs
7
Describe the mycobacterial cell wall
The mycobacterial cell wall consists of an inner layer and an
outer layer that surround the plasma membrane
8
How is the inner layer of the mycobacterial wall constructed?
The inner compartment consists of peptidoglycan (PG), arabinogalactan (AG), and mycolic acids (MA) covalently linked
together to form a complex known as the MA-AG-PG complex that extends from the
plasma membrane outward in layers, starting with PG and ending with MAs
This
complex is insoluble and referred to as the essential core of the mycobacterial cell
wall.
9
While multidrug resistance has recently grabbed headlines, mycobacteria are
inherently resistant to numerous antibiotics. Why?
Mycobacteria have unusually impermeable cell walls that are thought to be advantageous in stressful conditions of osmotic shock or desiccation as well as
contributing to their considerable resistance to many drugs.
10
T or F. Lipophilic drugs, such as fluoroquinolones or rifamycins, pass more easily through the lipid-rich cell wall and
thus are more active.
T.
11
What is another reason for resistance to antibiotics in Mycoplasma TB?
TB forms caseous granulomas, which is composed of macrophages (where the TB resides), neutrophils, and a cuff of lymphocytes
Poor penetrative ability of the drugs into the granuloma, coupled with the hypoxic centre and fibrotic ring can all impact drug
effectiveness.
12
Other possible resistance mechanisms to drugs?
efflux pumps, antibiotic-modifying or -degrading enzymes such as β-lactamase, target-modifying
enzymes, and decoys that mimic the drug target.
13
What is the most common cause of TB treatment failure?
poor adherence (leads to resistance!)
14
T or F. TB infection can be latent or active
T.
15
Are those with latent infection likely to spread TB?
No, with a latent infection, the patient is
initially asymptomatic (this may progress, as shown) and is not a public health risk.
16
How could you ID a latent TB infection?
A
chest X-ray would appear normal, however, a TB skin test would yield a positive
result.
17
T or F. The majority of patients who become infected do not go on to experience
active TB
T; their immune systems can intervene. However, the risk of active disease
development is clearly greater in immunocompromised patients.
18
What are the symptoms of active TB?
-cough (progressing to productive), chest pain, SOB
-flu like symptoms, fever
-weight loss, fatigue
19
Before beginning immuosuppressants like TNF-alpha inhibitors, a TB test should be performed to avoid allowing latent TB to become active. What should be done if the assay shows a positive result?
Anti-tubercular drug treatment should
be initiated. What is not resolved is whether or not this prolonged treatment regimen needs to be completed before the immunosuppressive drugs can be initiated.
20
Rules for reading a TB test
-measure rxn within 48-72hrs
-measure induration, not erythema
-record rxn in millimeters, NOT positive/negative
21
What is the preferred drug regimen for HIV patients, children 2-11 yoa, pregnant women with pyridoxine/vitamin B6 supplementation with LATENT TB?
Isoniazid 1x daily for 9 months
22
What is the preferred drug regimen for persons over 12 yoa with LATENT TB?
Isoniazid + Rifapentine 1x weekly for 3 months
23
When is Isoniazid + Rifapentine 1x weekly for 12 weeks contraindicated?
-Under 2 yoa
-With concurrent anti-retrovirals
-Women expecting to be pregnant
24
How to manage patients that miss treatment?
Extend or re-start treatment and use DOT
25
What is the preferred drug regimen for ACTIVE TB initial phase?
Daily INH, RIF, PZA, and EMB for 56 doses
26
What is the preferred drug regimen for ACTIVE TB continuation phase?
Daily INH and RIF for 126 doses (18 weeks) or twice-weekly INH and RIF for 36 doses (18 weeks)
27
What is the purpose of the initiation phase of TB treatment?
Kill most of the bacilli (but some can survive longer)
28
T or F. The initial phase of TB treatment determines the ultimate effectiveness of the regimen
T.
29
What is the purpose of the continuation phase of TB treatment?
finishes killing TB
30
How is the treatment of active TB in HIV patients different?
Initial phase is the same and the continuation phase consists of INH and a rifamycin for 4 months
31
What is dose intensity based on for TB in HUV patients?
CD4 counts, 2x/week for greater than 100CD4/ul and daily or 3x/week for less than 100CD4/ul
32
What is something to be cautious of in Active TB HIV patients?
DD interactions with some PIs and NNRTIs
33
How is isoniazid changed one inside the body?
it is a pro-drug that acetylated by NAT2 isoforms to its principal metabolite,
34
How is N-acetyl isoniazid excreted?
renal
35
How is N-acetyl isoniazid activated?
diffuses into mycoplasma and is activated by KatG (oxidase/peroxidase) to the nicrotinoyl radial, which reacts with NAD+ or NADP+ to produce adducts that inhibit cell-wall (enoyl-acyl carrier reductase) and nucleus acid synthesis
36
Specifically, how does isoniazid inhibit nucleic acid synthesis?
dihydrofolate reductase inhibitor
37
What is the significance of isoniazid in drug dosing?
humans vary in their acetylating capacity (called 'status')
38
What ethnicities are typically fast acetylators?
Asians (may require higher doses)
39
What is a risk for slow acetylators?
drug accumulation giving rise to lupus-like AEs
40
What endogenous molecule does isonazid deplete?
vitamin B6 (so pyridoxine supplements are often given)
41
How does isoniazid deplete vitamin B6?
CYP2E1 products bind and inactivate pyridoxine species and inhibits pyridoxine phosphokinase
42
What are some possible toxicities isoniazid?
-Hepatitis
-Peripheral neuropathy (Give vitamin B6)
-Seizures in epileptic patients (reduction of GABA)
43
Hemolysis is a possible AE of isoniazid in ____ patients
G6PD deficient
44
Isoniazid inhibits which CYP?
2C19
45
DD interactions of Isoniazid?
-Antidepressants
-PPIs
-Phenyotin
46
What are the member of the rifamycin family of drugs?
-Rifampin
-Rifabutin
-Rifapentine
47
How do rifamycin drugs work?
They inhibit bacterial RNA synthesis by forming a stable complex with DNA-dependent RNA polymerase (rpoB)
48
How are rifamycins metabolized?
via deacetylation and CYP3A hydrolysis
49
What is one thing to remember about Rifamycins?
they are CYP1A2 2C9, 2C19, and 3A4 INDUCERS (Rifampin the most) by promoting protein synthesis in the liver
50
AEs of rifamycins?
-red-man syndrome
-rare hepatotoxicity
-discoloration of contact lens
51
How does Pyrazinamide enter mycobacteria?
processed by initial
deamination within the mycobacterium and is effluxed, only to re-enter the bacillus
by simple diffusion in an acidic environment.
52
How does pyrazinamide kill TB?
1) Inhibition of fatty acid synthase type 1 inhibiting mycelia acid synthesis
2) reduction of intracellular pH
3) disruption of membrane transport by HPOA
53
Toxicities of Pyrazinamide?
-Hepatotoxicity
-Inhibition of urate excretion, causing hyperuricemia in nearly all patients
-May cause gout
54
T or F. Pyrazinamide is allowed during pregnancy
F.
55
How does Ethambutol work?
The final one of the principal drugs to consider is ethambutol. Activity is limited to
mycobacteria where it seems to work by inhibiting mycobacterial cell wall production
by inhibiting arabinosyl transferase enzyme activity.
56
AEs of Ethambutol?
-dose-related optic neuropathy (change in acuity or red-green blindness)
-hyperuricemia and elevated LFTs
57
2nd line options for TB
-Fluoroquinolones
-Amikacin, Kanamycin
-Linezolid
-many others
58