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Antibiotics > Azole Questions > Flashcards

Azole Questions Flashcards

1
Q

How do azoles work?

A

Inhibit fungal cytochrome P450

-decreases ergosterol production

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2
Q

What idea needs to be remembered about drug interactions?

A
  • most drug interactions can be successfully dealt with by dose adjustment but not all
  • any dose adjustments made while a patient is receiving an interacting drug needs to be readjusted when therapy with the interactor is finished
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3
Q

When was fluconazole introduced?

A

1990

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4
Q

What are the benefits of fluconazole?

A
  • highly bioavailable
  • available in both IV and PO (converting from IV to oral is simple)
  • highly active against many species of Candida
  • low incidence of serious adverse reactions
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5
Q

What factor has affected the use of fluconazole?

A

Shift toward non-albicans species of Candida

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6
Q

What is the MOA of azoles?

A

Inhibit fungal cytochrome P450 14-alpha demethylase

-inhibits conversion of lanosterol into ergosterol (it is a component of the fungal cell membrane)

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7
Q

What organisms does fluconazole have GOOD activity against?

A
  • Candida albicans
  • Candida tropicalis
  • Candida parapsilosis
  • Candida lusitaniae
  • Cryptococcus neoformans
  • Coccidioides immitis
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8
Q

What organisms does fluconazole have MODERATE activity against?

A
  • Candida glabrata
  • can be:
  • susceptible
  • dose-dependent
  • resistant
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9
Q

What organisms does fluconazole have POOR activity against?

A
  • molds
  • many dimorphic fungi
  • Candida krusei
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10
Q

What are the adverse effects of fluconazole?

A

Generally well tolerated

Can cause

  • hepatotoxicity
  • rash
  • QTc prolongation possible
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11
Q

What is fluconazole’s propensity for serious drug interactions compared to many other azoles?

A

Lower propensity for serious interactions

-interactions still occur

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12
Q

How does fluconazole dosing change for some systemic fungal infections?

A

May be escalated

-particularly for treatment of Candida glabrata infections

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13
Q

How is fluconazole eliminated?

A

Through the urine

-adjust dosing with regard to renal function

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14
Q

What is the dose for vulvovaginal candidiasis for fluconazole?

A

One time dose of 150mg

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15
Q

What organisms is fluconazole poorly active against?

A
  • all Candida krusei

- some Candida glabrata

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16
Q

What are some factors to consider when treating Candida glabrata with fluconazole?

A
  • best to check susceptibility (if lab does not do testing for fungi, consider an alternative such as echinocandin)
  • give 800mg/day after a loading dose
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17
Q

When is fluconazole used as prophylaxis?

A

Often against Candida infections in susceptible patients

  • ICU patients
  • patients with some cancers
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18
Q

If patient was receiving fluconazole prophylaxis and now has yeast in the blood, what should be tried?

A

Patient may have fluconazole resistant Candida

-try echinocandin instead

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19
Q

As patient begins to tolerate oral therapy, what is an excellent therapy to transition to?

A

Fluconazole

-has high oral bioavailability

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20
Q

What is fluconazole good for?

A

Drug of choice for many susceptible fungal infections

  • invasive and noninvasive candidiasis
  • cryptococcal disease

Some dimorphic fungal infections

-coccidioidomycosis

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21
Q

Are all species of Candida fluconazole-susceptible?

A

No

-check patient’s isolate before committing to a definitive course of therapy

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22
Q

How does itraconazole compare to fluconazole?

A

Broader spectrum azole

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23
Q

Why doesn’t itraconazole have a bigger place in therapy?

A

PK issues

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24
Q

What activity does itraconazole have?

A

Against

  • Aspergillus
  • other mold species
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25
Q

What was itraconazole once commonly used for?

A

Step down therapy in aspergillosis

-use has declined because of voriconazole

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26
Q

What organisms does itraconazole have GOOD activity against?

A
  • Candida albicans
  • Candida tropicalis
  • Candida parapsilosis
  • Candida lusitaniae
  • Cryptococcus neoformans
  • Aspergillus species
  • many dimorphic fungi
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27
Q

What organisms does itraconazole have MODERATE activity against?

A
  • Candida glabrata

- Candida krusei

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28
Q

What organisms does itraconazole have POOR activity against?

A
  • Mucorales

- many other molds

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29
Q

How does itraconazole’s adverse effect profile compare with fluconazole?

A

Causes more concerns

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30
Q

In what patients is itraconazole contraindicated?

A

Patients with heart failure

-negative ionotrope

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31
Q

What is the itraconazole oral solution associated with?

A

Diarrhea

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32
Q

What is the strength of itraconazole drug interaction compared with fluconazole?

A

Stronger inhibitor

-many drug interactions

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33
Q

What other adverse effects are associated with itraconazole?

A
  • hepatotoxicity

- QTc prolongation

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34
Q

Which dosage form of itraconazole has worse bioavailability?

A

Capsules have lower bioavailability compared to solution

-less preferred for systemic fungal infections

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35
Q

How should itraconazole oral capsules be taken?

A

Always be taken with a full meal

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36
Q

How should itraconazole oral solution be taken?

A

Always on an empty stomach

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37
Q

How does pH affect itraconazole absorption?

A

Absorption can be lowered by agents that decrease gastric acidity

  • such as PPIs
  • try taking with a soda
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38
Q

Are itraconazole concentrations monitored?

A

Yes

-absorption is so erratic and unpredictable

Consider checking a trough concentration if

  • taking for a serious fungal infection
  • and/or a long time
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39
Q

Is itraconazole available as an IV formulation?

A

Not anymore

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40
Q

What is itraconazole good for?

A

Drug of choice for some dimorphic fungal infections

-ex: histoplasmosis

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41
Q

For what infections has voriconazole largely replaced itraconazole?

A

Management and prophylaxis of

  • aspergillosis
  • other mold infections
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42
Q

What are itraconazole capsules used for?

A

Treatment of onychomycosis

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43
Q

What did the introduction of voriconazole represent a significant improvement in?

A

Treatment of mold infections

44
Q

How does voriconazole differ from itraconazole?

A
  • well absorbed

- available in highly bioavailable oral formulations and IV admixture

45
Q

What is voriconazole active against?

A

Broad spectrum antifungal

Good activity against

  • Candida species
  • many molds
46
Q

How does voriconazole compare to amphotericin B deoxycholate?

A

Superior for invasive aspergillosis and now is the drug of choice

47
Q

What are some limitations of voriconazole?

A
  • highly variable PK

- long term adverse effects

48
Q

What organisms does voriconazole have GOOD activity against?

A
  • Candida albicans
  • Candida lusitaniae
  • Candida parapsilosis
  • Candida tropicalis
  • Candida krusei
  • Cryptococcus neoformans
  • Aspergillus species
  • many other molds
49
Q

What organisms does voriconazole have MODERATE activity against?

A
  • Candida glabrata
  • fluconazole-resistant Candida albicans
  • Fusarium species
50
Q

What organisms does voriconazole have POOR activity against?

A

Mucorales

51
Q

What are common class adverse effects of azoles?

A
  • hepatotoxicity
  • rash
  • drug interactions
52
Q

What are the categories of adverse effects of voriconazole?

A
  • renal
  • visual effects
  • CNS effects
  • dermatologic
53
Q

Why is voriconazole associated with nephrotoxicity?

A

The cyclodextrin solubilizer in IV voriconazole accumulates in renal dysfunction

  • thought to be nephrotoxic
  • almost certainly less toxic than amphotericin B
  • risk/reward consideration in renally insufficient patients
54
Q

Describe voriconazole visual effects.

A

-seeing wavy lines

or

  • halos around bright lights
  • very common
  • dose-related
  • tend to go away with continued use
55
Q

Describe voriconazole CNS effects.

A

Sometimes experience visual and auditory hallucinations

  • are distinct from the common visual effects
  • not permanent
56
Q

When do voriconazole CNS effects tend to occur?

A

At higher voriconazole levels

-especially during peak concentration periods

57
Q

Describe voriconazole dermatologic effects.

A

Sun sensitivity

  • use sunscreen
  • avoid excessive sun exposure

Some studies suggest association between prolonged use and certain skin cancers

-reducing sun exposure is so important

58
Q

Describe voriconazole PK.

A
  • highly variable interpatient PK
  • nonlinear elimination
  • difficult to dose correctly
59
Q

How is voriconazole monitored?

A

Serum drug concentrations

  • usually a trough level
  • no official consensus; (2-5 mg/L usually considered to be in the therapeutic window)
60
Q

Is voriconazole active against fluconazole-resistant strains of C. albicans?

A

Against some

  • less active than against fluconazole-susceptible strains
  • consider susceptibility testing if you need to use it as oral option
  • echinocandin is a better choice
61
Q

Does voriconazole inhibit other drugs?

A

Potent inhibitor and substrate of P450

  • long and varied drug interaction list
  • some contraindicated (ex: rifampin)
  • some require dose adjustments (calcineurin inhibitors: ex: cyclosporine)
  • many patients who are immunosuppressed require voriconazole (be alert for drug interactions)
62
Q

When is IV voriconazole contraindicated?

A

In patients with severe renal dysfunction

  • (CrCL < 50 mL/min)
  • IV form contains cyclodextrin (accumulates in renal dysfunction and is nephrotoxic)
  • oral forms avoid this issue
63
Q

How is voriconazole eliminated?

A

Hepatically

-unlikely to be useful in treatment of candiduria

64
Q

What is voriconazole good for?

A

Drug of choice for

-invasive aspergillosis

Frequently used in treatment of infections caused by other molds

Can be used for candidiasis

-fluconazole and echinocandins more frequently used for these infections

Some clinicians use it for

-empiric treatment of febrile neutropenia

65
Q

What are two important points to think about when using voriconazole?

A
  • watch for drug interactions

- consider checking drug concentrations if using for extended course of therapy

66
Q

What is posaconazole?

A

Analog of itraconazole

-substantially more active against many fungi

67
Q

What is posaconazole indicated for?

A

Prophylaxis of

-fungal infections in high risk patients

Treatment of

-oropharyngeal candidiasis

68
Q

What is the first azole with good activity against Mucorales?

A

Posaconazole

-Mucorales is a difficult to treat order of molds that most antifungals do not treat

69
Q

What organisms does posaconazole have GOOD activity against?

A
  • Candida albicans
  • Candida lusitaniae
  • Candida parapsilosis
  • Candida tropicalis
  • Candida krusei
  • Aspergillus species
  • Mucorales
  • many other molds
  • dimorphic fungi
70
Q

What organisms does posaconazole have MODERATE activity against?

A
  • Fusarium species

- C. glabrata

71
Q

What is something to consider about posaconazole’s spectrum of activity?

A

Though it is active against these organisms, comparative clinical trial data are lacking for many of them

72
Q

Describe posaconazole’s adverse reactions.

A

-seems to be well tolerated

Can cause

  • hepatotoxicity
  • nausea
  • rash
73
Q

How does posaconazole’s propensity to cause drug interactions compare with other azoles?

A

Similar

74
Q

What was a key limitation to posaconazole’s use?

A

Initial availability only as oral suspension

-absorption is limited and variable even under the best circumstances

75
Q

What is required to take with the posaconazole suspension?

A

Administration with food to increase absorption

  • foods with high fat concentration
  • nutritional supplements containing fat
  • low-pH beverages like soda
76
Q

What dosage forms of posaconazole exist?

A
  • oral suspension
  • delayed-release tablet
  • IV
77
Q

What are some facts about the posaconazole delayed-release tablet?

A
  • achieves much higher and more reliable concentrations compared to the oral suspension
  • cannot be crushed or chewed
78
Q

What is a consideration with posaconazole prophylactic use?

A

Many of these patients are on immunosuppressants

  • watch for drug interactions
  • monitor drug concentrations
  • same as for voriconazole
79
Q

Why are clinicians hesitant to use posaconazole first line against Aspergillus?

A

In vitro activity against Aspergillus is generally similar to voriconazole and it is better tolerated but:

-lacks clinical trial data comparing it to voriconazole (or even amphotericin)

80
Q

What is a consideration with the posaconazole oral suspension?

A

Issues with absorption

  • high fat meals and acidic beverages boost absorption substantially (may be required for adequate absorption in some patients)
  • proton pump inhibitors lower absorption (administering with soda will not overcome this factor)
81
Q

When should posaconazole concentrations be monitored?

A
  • patients with questionable absorption

- if used for treatment of invasive infections

82
Q

What is posaconazole most commonly used for?

A

Prophylaxis against fungal infections in susceptible hosts

83
Q

What can posaconazole be used for?

A
  • mucormycosis
  • oropharyngeal candidiasis
  • fungal infections refractory to other agents
84
Q

What is posaconazole’s major limitation to more widespread use?

A

Lack of clinical trial data

85
Q

Which two azoles have very different dosing and administration with their oral formulations (capsules/tablets and suspension)?

A
  • itraconazole

- posaconazole

86
Q

What is the newest azole?

A

Isavuconazole

87
Q

How is isavuconazole similar to posaconazole?

A
  • expanded spectrum of activity (includes: Candida, Aspergillus, Mucorales)
  • available as IV and oral formulations
  • has P450-mediated drug interactions
  • toxicity profile most concerning for hepatic effects
88
Q

How is isavuconazole different than posaconazole?

A
  • isavuconazole’s FDA approval based on clinical trials in invasive aspergillosis and mucormycosis (posaconazole lacks clinical trial data for these)
  • posaconazole has more extensive clinical use
89
Q

What organisms does isavuconazole have GOOD activity against?

A
  • Candida species
  • Aspergillus species
  • Mucorales
  • some other molds
  • some dimorphic fungi
90
Q

What organisms does isavuconazole have MODERATE activity against?

A

Candida glabrata

91
Q

What organisms does isavuconazole have POOR activity against?

A

Fusarium species

92
Q

How does isavuconazole hepatotoxicity compare with other azoles?

A

Similar level to other azoles is anticipated

-may be somewhat less frequent than with voriconazole

93
Q

Other azoles prolong the QT interval. What effect does isavuconazole have?

A

Shortens it

  • may affect patients with congenitally short QT intervals
  • may allow for use in patients with prolonged QT intervals who would be at risk for arrhythmia if prescribed a different azole
94
Q

Describe the bioavailability of isavuconazole’s oral formulation (capsule)?

A

Excellent

  • not affected by food or gastric acidity
  • capsules are hard
  • not designed to be opened, crushed, or chewed (limits administration in patients with feeding tubes or swallowing issues)
95
Q

What is isavuconazole’s half life?

A

Very long

-requires loading dose

96
Q

Why does isavuconazole have a loading dose?

A

To attain therapeutic levels more rapidly (due to very long half)

97
Q

Describe isavuconazole’s extensive loading dose regimen.

A

Administration every 8 hours for six doses (48 hours)

Then transition to a once daily maintenance regimen

98
Q

How is isavuconazole supplied?

A

As a prodrug (isavucazonium sulfate)

-hydrolyzed to isavuconazole after administration

372mg of isavucazonium yields 200mg of isavuconazole

-leads to potential for confusion in ordering doses

99
Q

How does isavuconazole’s in vitro activity against Candida species compare to voriconazole and posaconazole?

A

Similar

100
Q

What type of candidiasis is posaconazole FDA approved for?

A

The less severe oropharyngeal candidiasis

-not studied in invasive candidiasis

101
Q

What type of candidiasis is voriconazole FDA approved for?

A

Invasive candidiasis

  • based on the results of a study comparing it to conventional amphotericin B followed by fluconazole
  • echinocandins may be more effective than the above combination
102
Q

How does isavuconazole compare to the echinocandins in invasive candidiasis?

A

Not noninferior

103
Q

What drugs should be used for invasive candidiasis?

A
  • echinocandins (most effective)

- fluconazole (balance of efficacy and convenience)

104
Q

How does isavuconazole’s PK compare to voriconazole and possibly posaconazole?

A

More predictable

105
Q

How do clinicians feel reassured when using azoles?

A

By demonstrating adequate serum drug levels

-fewer labs offer isavuconazole levels than voriconazole or posaconazole currently

106
Q

What is isavuconazole good for?

A

Not extensive experience with it yet; trial data shows it to be a good option in

-invasive mold infections

107
Q

What is an important fact to remember about isavuconazole?

A

Give the correct dose as well as full loading regimen

-otherwise will take a week to get to a subtherapeutic steady state

Antibiotics (63 decks)

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