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.► FARMACOLOGIA CLÍNICA - JP > Antimycobacterials Questions > Flashcards

Antimycobacterials Questions Flashcards

1
Q

What is tuberculosis caused by?

A

Mycobacterium tuberculosis

-formidable infection

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2
Q

How do mycobacteria replicate compared to “typical bacteria”?

A

Replicate more slowly

  • pharmacotherapy more difficult
  • rapidly dividing cells are most metabolically active and therefore susceptible to antibiotic therapy
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3
Q

What state can mycobacteria exist in?

A

Dormant state

-makes them resistant to nearly all antibiotics

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4
Q

Where do mycobacteria live in the host?

A

Inside human cells

-antimicrobials that have poor intracellular penetration are ineffective

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5
Q

What does the outermost layer of mycobacteria consist of?

A

Phospholipids and mycolic acids

  • make a waxy layer
  • resists penetration from antibiotics
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6
Q

What are components of the mycobacterial cell wall?

A

Arabinogalactan and peptidoglycan

  • are polysaccharide components of the cell wall
  • peptidoglycan not accessible to beta-lactams: are poorly active
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7
Q

Why are combinations of drugs always given for active mycobacterial disease?

A
  • minimize the development of resistance

- shorten the duration of therapy

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8
Q

What is one common characteristic of mycobacterial drugs?

A

Pharmacokinetic drug interactions

-many immunocompromised patients are very susceptible to mycobacterial disease and are usually on drugs with many interactions

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9
Q

How long does standard susceptibility testing take for mycobacteria?

A

Takes weeks instead of days

  • mycobacteria grow slowly
  • empiric regimens often given for extended durations
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10
Q

What is the standard of care for active tuberculosis?

A

Four drug regimen

  • compliance important
  • careful monitoring for drug interactions
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11
Q

Which antibacterials also have antimycobacterial properties?

A
  • fluoroquinolones (moxifloxacin is particularly active)
  • macrolides
  • AMG
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12
Q

Name the rifamycins.

A
  • Rifampin (known as rifampicin in Europe)
  • Rifabutin
  • rifapentine
  • rifaximin
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13
Q

Which rifamycin is not used for mycobacterial disease?

A

Rifaximin

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14
Q

What diseases are rifamycins the cornerstones of therapy for?

A
  • tuberculosis

- Mycobacterium avium-intracellulare complex (MAC)

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15
Q

What are rifamycins?

A

Protein synthesis inhibitors

-inhibit transcription of DNA to bacterial mRNA

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16
Q

How do rifamycins affect the cytochrome P450 system?

A

Are potent inducers

-patients receiving them should always be screened for drug interactions

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17
Q

Besides mycobacteria, what are rifamycins also active against?

A

Active against many “typical” bacteria

-sometimes added to other therapies (particularly to treat difficult MRSA infections)

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18
Q

What is the MOA of rifamycins?

A

Protein synthesis inhibitors

  • inhibit RNA polymerase
  • prevent transcription by blocking the production of mRNA
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19
Q

How are rifamycins different from other protein synthesis inhibitors?

A

Others inhibit translation

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20
Q

What organisms do rifamycins have GOOD activity against?

A

-most mycobacteria

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21
Q

What organisms do rifamycins have MODERATE activity against?

A
  • Staphylococcus
  • Acinetobacter
  • Enterobacteriaceae
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22
Q

What organisms do rifamycins have POOR activity against?

A
  • “typical” bacteria as monotherapy

- some very rare mycobacteria

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23
Q

How are rifamycins tolerated?

A

Generally well-tolerated

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24
Q

What are rifamycins most notorious for?

A

Potent CYP450-inducing effects

  • anticonvulsants (loss of seizure control)
  • organ rejection (antirejection agents)
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25
Q

What adverse effect of rifampin do patients appreciate knowing about?

A

Characteristically colors secretions orange-red

  • urine
  • tears
  • can stain contact lenses (do not wear during rifampin therapy)
  • is nonpermanent and not harmful
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26
Q

What are some other adverse effects of rifamycins?

A
  • rash
  • nausea
  • vomiting
  • hypersensitivity (often fever)
  • can cause hepatotoxicity
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27
Q

Which rifamycin is preferred for tuberculosis?

A

Rifampin

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28
Q

Which rifamycin is preferred for MAC? Why?

A

Rifabutin

  • MAC most common in HIV patients
  • rifabutin has somewhat less-potent CYP450 inducing effects than rifampin (antiretroviral therapy often metabolized by CYP450)
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29
Q

Which rifamycin has somewhat less potent CYP450-inducing effects than rifampin?

A

Rifabutin

-still a potent inducer

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30
Q

What are the two most important drugs for tuberculosis?

A
  • rifampin (or rifabutin)
  • isoniazid

If an isolate of M. tuberculosis is resistant to rifampin, more complicated regimens must be used for longer durations

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31
Q

Which rifamycins induce CYP450 enzymes?

A

All of them

  • can induce the metabolism of drugs through other hepatic pathways as well
  • always screen for drug interactions
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32
Q

What is rifapentine?

A

A second line rifamycin

  • given once weekly
  • if an isolate is resistant to other rifamycins, it is resistant to rifapentine as well
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33
Q

When is rifapentine used?

A

In combination with isoniazid for latent tuberculosis

-given once weekly

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34
Q

What is rifaximin used for?

A

Treatment or prevention of GI conditions

-is a nonabsorbed rifamycin

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35
Q

Is rifaximin used for mycobacterial diseases?

A

No

36
Q

Can rifamycins be used as monotherapy for tuberculosis?

A

NOT for treatment of active tuberculosis

37
Q

When can rifampin be used as monotherapy?

A

To treat latent tuberculosis

38
Q

What are rifamycins good for?

A

In combination with other agents for treatment of:

  • active tuberculosis
  • MAC

Latent tuberculosis

Selected bacterial infections:

-most notably bacterial infections involving prosthetic material (in combination with standard antibacterials): ex: artificial hip or heart valve

39
Q

What side effect of rifamycins may be a surprise to most patients?

A

Urine and other secretions may turn orange or red

40
Q

What type of mycobacteria is isoniazid active against?

A

Both active growing and dormant

-used in treatment of both active and latent tuberculosis

41
Q

What mycobacteria is isoniazid active against?

A

Only:

  • M. tuberculosis
  • M. kansasii
42
Q

What is the MOA of isoniazid?

A

Prevents the synthesis of mycolic acids in the cell wall

-inhibits enzymes that catalyze their production

43
Q

What adverse effect does isoniazid share with several other antituberculosis medications?

A

Hepatotoxicity

44
Q

Describe isoniazid hepatotoxicity.

A

Early in therapy

  • many patients will experience asymptomatic elevations in liver transaminases
  • will resolve on their own in most cases and patient can complete therapy
45
Q

When does isoniazid need to be stopped to prevent severe liver damage?

A

Enzyme levels are many times the ULN

and/or

Patient experiences symptoms of hepatitis

  • nausea
  • abdominal pain
  • jaundice
46
Q

What is isoniazid’s characteristic adverse effect?

A

Peripheral neuropathy

47
Q

How can isoniazid-induced peripheral neuropathy be prevented?

A

By administering pyridoxine (vitamin B6)

48
Q

For which patients is pyridoxine recommended while on isoniazid?

A

Those at risk for developing neuropathy

  • diabetic
  • pregnant women
  • alcohol abusers

There’s no downside to recommending it to all patients receiving isoniazid

49
Q

What are other neurotoxicities of isoniazid?

A
  • optic neuritis (less common)

- seizures (rarely)

50
Q

What possible adverse effect of isoniazid abates with cessation of therapy?

A

Drug-induced lupus

51
Q

How does isoniazid hypersensitivity present?

A

Can be seen most commonly as:

  • rash
  • drug fever
52
Q

List the categories of isoniazid toxicities.

A
  • hepatotoxicity
  • peripheral neuropathy
  • other neurotoxicities
  • drug-induced lupus
  • hypersensitivity
53
Q

What is a drug of choice for treatment of latent tuberculosis?

A

Isoniazid

54
Q

Which form of tuberculosis as isoniazid be used as monotherapy?

A

Latent

-burden of organisms is much lower than in active

55
Q

Can isoniazid be used as monotherapy for active tuberculosis?

A

NO

-resistance can develop

56
Q

Which tuberculosis drug has variable pharmacogenomic metabolism?

A

Isoniazid

57
Q

Describe isoniazid variable pharmacogenomic metabolism.

A
  • rapid acetylators metabolize it more quickly than slow acetylators
  • clinical significance is unknown
  • genetic testing before starting therapy is NOT routinely performed
58
Q

Is isoniazid bactericidal or bacteriostatic?

A
  • bactericidal against growing mycobacteria

- bacteriostatic against dormant mycobacteria

59
Q

What should patients avoid while on isoniazid?

A

Do not drink alcohol while on therapy

  • to prevent additive risk of hepatotoxicity
  • myth: alcohol decreases antibiotic effectiveness
60
Q

What is isoniazid good for?

A

Drug of choice for:

  • active TB (must be combined with other drugs)
  • latent TB
61
Q

What drugs are recommended for the consolidation phase of non-MDR-TB?

A

Combination of:

-isoniazid

and

-rifampin

62
Q

Which drug allows the overall duration of TB therapy to be shortened from 9 months to 6 months?

A

Pyrazinamide

63
Q

What does the initial four drug regimen for active TB consist of?

A

RIPE

  • rifampin
  • isoniazid
  • pyrazinamide
  • ethambutol
64
Q

What type of activity does pyrazinamide have against M. tuberculosis?

A

Bactericidal

-even against slow growing M. tuberculosis

65
Q

During what part of TB therapy is pyrazinamide used?

A

Generally only during the first 2 months of therapy

66
Q

What is the MOA of pyrazinamide?

A

Pro-drug; unclear MOA

In its active form, thought to:

  • prevents production of mycolic acids
  • inhibits the enzyme fatty acid synthetase 1
  • likely has other effects as well
67
Q

What organisms is pyrazinamide active against?

A

Only:

-M. tuberculosis

68
Q

What are the key adverse effects for pyrazinamide?

A
  • hyperuricemia

- hepatotoxicity

69
Q

Describe pyrazinamide hepatotoxicity.

A
  • chiefly hepatitis
  • dose dependent
  • less common at the lower doses given today than higher ones previously used
70
Q

Describe pyrazinamide hyperuricemia.

A
  • predictable
  • can precipitate gout (rarely)
  • leads to withdrawal from regimen and extension of duration of TB therapy
71
Q

What is another adverse effect of pyrazinamide?

A

Arthralgias can occur

  • separate from hyperuricemia
  • can be managed with OTC pain medications
72
Q

In what environment is pyrazinamide active in?

A

Active only in acidic environments

  • pH < 6
  • would be problematic for some disease states
  • perfect for the caseous granulomas that active TB forms

Also works intracellularly in phagocytes

73
Q

Which two drugs with similar names should not be confused for active TB?

A
  • pyrazinamide

- pyridoxine

74
Q

What is pyrazinamide good for?

A

Only use:

-initial phase of active TB treatment

75
Q

What symptoms should patients report while on pyrazinamide or any first line TB therapy?

A

Any signs of hepatitis

  • dark urine
  • abdominal pain
  • loss of appetite
76
Q

What is ethambutol?

A

EMB

  • first line drug for both active TB and MAC infections
  • used in initial four drug phase of active TB
  • given for the duration of MAC therapy
77
Q

What is the MOA of ethambutol?

A

Inhibits the enzyme aribinosyl transferase III

  • blocks production of arabinogalactan
  • arabinogalactan is a component of the cell wall of mycobacteria but not “typical” bacteria
  • so activity limited to mycobacteria
78
Q

What is the spectrum of activity of ethambutol?

A
  • M. tuberculosis
  • M. avium-intracellularare complex
  • M. kansasii
79
Q

What is the characteristic adverse effect of ethambutol?

A

Optic neuritis

  • often manifests as decreased visual activity or inability to differentiate red from green
  • dependent on both dose and duration of therapy
  • generally reversible
  • monitoring required
80
Q

Why is ethambutol NOT recommended in children younger than 5 years old?

A

Generally not able to reliably perform the vision tests needed for monitoring

81
Q

What adverse effects occur uncommonly with ethambutol?

A
  • rash

- drug fever

82
Q

Which TB drug is not associated with hepatotoxicity?

A

Ethambutol

83
Q

Which drug can be used as a substitute for rifampin in patients unable to take it during the continuation phase (after 2 months) of active TB?

A

Ethambutol

-duration has to be extended relative to what it would be with rifampin and isoniazid

84
Q

What drug is a primary first line drug for treating MAC infections?

A

Ethambutol

-along with a macrolide and rifabutin

85
Q

What is ethambutol good for 1st line?

A
  • active TB

- MAC

86
Q

What is ethambutol good for 2nd line?

A

In patients unable to tolerate rifampin during the continuation phase

87
Q

What organ system does Ethambutol affect?

A

Eyes

-optic neuritis

.► FARMACOLOGIA CLÍNICA - JP (50 decks)

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