Exam 5: Chemistry of Antimycobacterial Agents/ Tuberculosis

Question 1

What is the most common infection in the world?

Answer 1

Tuberculosis

Question 2

What organism causes tuberculosis?

Answer 2

Mycobacterium tuberculosis

Question 3

What kind of bacteria is Mycobacterium tuberculosis?

Answer 3

Slow-growing
Aerobic

Question 4

What are some characteristics of a tuberculosis infection?

Answer 4

Can be dormant for a long period of time
-cause both latent and active infections

Forms granulomas (tubercles) in the lungs

*neither Gram + nor Gram -

*Is an acid-fast bacteria

Question 5

What is an acid-fast bacteria

Answer 5

A bacteria than cannot be discolorized by an acid wash after staining with Neelsen stain (stays red)

*these have a lipid rich cell wall that contains mycolic acids and is impermeable to many drugs

Question 6

How does the cell wall of an acid fast bacteria differ from Gram + and
Gram - cells?

Answer 6

It has a thick mycolic acid rich layer

It also has an arabinogalactan layer not present in the other cell types

Question 7

What is the most common treatment for TB?

Answer 7

Rifampin
+
Isoniazid
+
Pyrazinamide
+
Ethambutol

Question 8

What is an alternative therapy option for TB?

Answer 8

Rifapentine
+
Isoniazid
+
Pyrazinamide
+
Moxifloxacin

Question 9

What form of TB is Isoniazid active against?

Answer 9

Specific for M. tb only

Only active against growing form of TB

Question 10

Is Isoniazid bactericidal or bacteriostatic?

Answer 10

Bactericidal

Question 11

What is an important clinical pearl about Isoniazid?

Answer 11

It is a prodrug

Question 12

What activates Isoniazid?

Answer 12

KatG

Question 13

What is the MOA of isoniazid?

Answer 13

Gets activated by KatG

Forms adducts with NAD+ and NADP+

Inhibits enzymes that use NAD+ and NADP+

Activated drug inhibits InhA
-a component of FAS II (fatty acid synthase)
-this is responsible for catalyzing the HADH-dependent reduction of fatty acids bound to acyl carrier proteins

-Inhibits mycolic acid synthesis leading to defective cell wall

Question 14

What is the purpose of the arabinogalactan layer in TB cells?

Answer 14

The mycolic acid layer is assembled by attaching it to this layer

Question 15

How does resistance to isoniazid occur?

Answer 15

Over-expression of InhA

Mutations in KatG leading to the drug not getting activated

Question 16

How is isoniazid metabolized?

Answer 16

Acetylation in the liver by N-acetyltransferase (NAT2)

-different forms of the gene that people have determine if they are slow or fast metabolizers

Question 17

What are the side effects of isoniazid?

Answer 17

Hepatitis*
-must stop treatment if this occurs

Peripheral neuropathy

Drug-induced syndrome resembling lupus

Peripheral neuropathy

Question 18

What is the mechanism of toxicity for isoniazid?

Answer 18

Acetylisoniazid can be converted to acetylhydrazine

CYP2E1 converts acetylhydrazine to hepatotoxic metabolites

NAT2 can acetylate acetylhydrazine to nontoxic diacetylhydrazine
(normal metabolism mechanism)

-Slower acetylators or induction of CYP2E1 with lead to more toxic metabolites

Question 19

Which drug induces CYP2E1, potentiating isoniazid hepatotoxicity?

Answer 19

Rifampin

Question 20

How does isoniazid cause peripheral neuropathy?

Answer 20

It resembles pyridoxine (Vitamin B6)
and competitively inhibits pyridoxine phosphokinase

-can reverse by giving pyridoxine

Question 21

What affect did Pyrazinamide have on TB treatment?

Answer 21

Shortened therapy to 6 months

Question 22

What kind of TB is Pyrazinamide active against?

Answer 22

Sterilizing agent against residual intracellular bacteria

-predominantly used for persister bacteria also called nonreplicating, persistent bacilli (NRPB)

Question 23

Pyrazinamide is structurally similar to what?

Answer 23

Nicotinamide

Question 24

The activity of Pyrazinamide is dependent on what?

Answer 24

pH

-activated by low pH
-inactive at neutral pH

Question 25

How is Pyrazinamide activated?

Answer 25

Prodrug Requires conversion to pyrazinoic acid by pncA

Question 26

The MOA of pyrazinamide is not fully known. What is the current best guess?

Answer 26

Inhibits panD leading to inhibition of Coenzyme A synthesis note that panD binding affinity is low but accumulation in granuloma offsets this

Question 27

What is the primary mechanism of resistance to Pyrazinamide?

Answer 27

Mutations in pncA

Question 28

What are the SE of Pyrazinamide?

Answer 28

Joint pain -most common Hepatitis -most dangerous *pyrazinamide is the main drug in TB therapy that causes this

Question 29

Before treatment with pyrazinamide, patients need to do what?

Answer 29

Undergo studies of hepatic function

Question 30

Is ethambutol bacteriocidal or bacteriostatic?

Answer 30

Bacteriostatic

Question 31

What is the MOA of ethambutol?

Answer 31

Inhibits mycobacterial arabinosyl transferases -these are enzymes involved in making the arabinogalactan layer -involved in polymerization of arabinogalactan Arabinan builds up (precursor to layer)

Question 32

Ethambutol is synergistic with which drug?

Answer 32

Rifampin -increases penetration into cell since it weakens the cell wall

Question 33

What is the mechanism of resistance against ethambutol?

Answer 33

Over-expression of/ mutations in arabinosyl transferase

Question 34

What is the most important side effect of ethambutol?

Answer 34

Optic neuritis -must d/c treatment or it may not reverse

Question 35

What product is rifampin a derivative of?

Answer 35

Rifamycin B (natural product)

Question 36

What effect did rifampin have on treatment duration?

Answer 36

Reduced length of therapy from 18 to 9 months

Question 37

What is the most effective first-line agent for TB?

Answer 37

Rifampin

Question 38

What forms of TB is rifampin active against?

Answer 38

BOTH growing and non-dividing (stationary) forms

Question 39

Is rifampin bactericidal or bacteriostatic?

Answer 39

Bactericidal

Question 40

What is rifapentin?

Answer 40

Derivative of rifampin -has a five-sided ring attached to its structure that makes it more lipophilic and gives it a longer half life

Question 41

What is the moa of rifampin?

Answer 41

Binds to RNA polymerase deep within the DNA/RNA channel -blocks elongation of RNA *binds distant from the active site

Question 42

What are the side effects of rifampin?

Answer 42

Colors urine, tears, and sweat orange Can permanently stain contact lenses Potent inducer of CYP450

Question 43

Ethambutol may be replaced by what drug in the alternative TB therapy?

Answer 43

Moxifloxacin

Question 44

What is the MOA of moxifloxacin?

Answer 44

Traps gyrase (Topo II) on DNA as a ternary complex -blocks activity of gyrase, cannot repair cleaved DNA, cannot resolve supercoils -disrupts DNA replication

Question 45

Is moxifloxacin bactericidal or bacteriostatic?

Answer 45

Bactericidal

Question 46

Which TB drugs cause hepatitis?

Answer 46

Isoniazid Pyrazinamide Rifampin

Question 47

Which TB drug causes eye damage?

Answer 47

Ethambutol *think e*

Question 48

Which TB drug causes urine discoloration?

Answer 48

Rifampin

Question 49

How often should patients be monitored for adverse effects?

Answer 49

Monthly

Question 50

BPaL is a newly approved TB regimen, what drugs does it contain?

Answer 50

Bedaquiline Pretomanid Linezolid

Question 51

When would we use the BPaL regimen for TB treatment?

Answer 51

Extensively drug-resistant TB

Question 52

What kind of TB does Bedaquiline treat?

Answer 52

Both actively growing and dormant

Question 53

Is bedaquiline bactericidal or bacteriostatic?

Answer 53

Bactericidal

Question 54

What is the MOA of bedaquiline?

Answer 54

Inhibits ATP synthase -not able to make ATP, is toxic

Question 55

What is the mechanism of resistance to bedaquiline?

Answer 55

Mutations in atpE

Question 56

How is Pretomanid activated?

Answer 56

Prodrug -activated by Ddn

Question 57

What is the MOA of Pretomanid?

Answer 57

Aerobic: -Forms reactive intermediate metabolites that inhibit mycolic acid production Anaerobic, Nonreplicating, Persistent bacilli: -Generates reactive nitrogen species -Directly poisons the respiratory complex leading to *ATP depletion*

Question 58

What are the second-line agents for TB?

Answer 58

Streptomycin Ethionamide Para-aminosalicylic acid Cycloserine Capreomycin

Question 59

What is the most important part of TB therapy?

Answer 59

ADHERENCE

Question 60

What is a TST test?

Answer 60

Tuberculosis skin test

Question 61

What is another name for the TST test?

Answer 61

PPD

Question 62

What is a downside to using the TST tuberculosis test?

Answer 62

Delayed immune response, takes 2-3 days to read

Question 63

When will the TST test come back positive?

Answer 63

Infection eliminated with acquired immune response Latent TB Subclinical disease Active TB ****will be positive for everything except elimination of infection with the innate immune system

Question 64

What is the IGRA?

Answer 64

TB test that gives immediate results

Question 65

What is another name for the IGRA tuberculosis test?

Answer 65

QuantiFERON

Question 66

When does the IGRA tuberculosis test come back positive?

Answer 66

For everything except elimination of infection by the innate immune system (same as TST test)

Question 67

When will a TB culture come back positive?

Answer 67

May only be positive with subclinical disease (intermittently positive) or Active TB disease -not for eliminated infections or latent infections

Question 68

What is the initial screening strategy for TB?

Answer 68

Sputum smear

Question 69

How many sputum smears need to be done before we can rule out TB?

Answer 69

3

Question 70

When will a sputum smear come back positive?

Answer 70

Normally only with active TB disease -this may still give a false negative

Question 71

When is TB considered infectious?

Answer 71

Sporadically when it is subclinical disease Active disease *not when it is latent or eliminated by the immune system

Question 72

When will patients experience TB symptoms?

Answer 72

Mild or no symptoms with subclinical disease Active disease

Question 73

During what stages would we start TB treatment in a patient?

Answer 73

Infection eliminated by innate or acquired immune response: NO Latent TB infection: Preventative therapy Subclinical disease: Multidrug therapy Active disease: Multidrug therapy

Question 74

TB is killed by what besides medications?

Answer 74

Sunlight

Question 75

Which medication would you typically want to avoid or be cautious with in patients living with HIV?

Answer 75

Rifampin

Question 76

How long do symptoms from a rifampin interaction take to appear?

Answer 76

A few days to a week

Question 77

*What is drug-susceptible TB?

Answer 77

TB strains that are sensitive to the standard first-line TB agents

Question 78

What is monoresistant TB?

Answer 78

TB strains that are SENSITIVE to only one anti-TB drug

Question 79

What is polyresistant TB?

Answer 79

TB strains that are resistant to more than one anti-TB drug BUT NOT: INH (isoniazid) or RIF

Question 80

*What is multidrug resistant (MDR) TB?*

Answer 80

TB strains that are resistant to both RIF and INH (isoniazid)

Question 81

What is Extensively drug-resistant (XDR) TB?

Answer 81

TB strains that are resistant to RIF and INH (isoniazid) AND at least one injectable agent (amikacin, kanamycin, capreomycin) AND any of the fluoroquinolones

Question 82

How does resistance occur in TB?

Answer 82

Mycobacterial particles have a spontaneous rate of mutation *TB does not transmit mutations to each other like other bacteria do, mutations only occur spontaneously and at pre-determined mathematical rates

Question 83

What is the mutation rate of Rifampin?

Answer 83

10^(-8)

Question 84

What is the mutation rate of BOTH Isoniazid and Pyrazinamide?

Answer 84

10^(-6)

Question 85

Which TB therapy option is our 6-month therapy?

Answer 85

Standard regimen of: -Rifampin -Isoniazid -Ethambutol -Pyrazinamide "RIPE"

Question 86

Which TB therapy option is our 4-moth therapy?

Answer 86

New regimen: -Rifapentine -Isoniazid -Moxifloxacin -Pyrazinamide "RIPM"