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.► FARMACOLOGIA CLÍNICA - JP > Antifungal Drug Questions > Flashcards

Antifungal Drug Questions Flashcards

1
Q

What do most pathogenic fungi need to cause infection?

A
  • most are opportunistic

- require a compromised host or disrupted barrier to cause infections

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2
Q

What is the term for treatment of fungal infections?

A

Medical mycology

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3
Q

What two forms do microscopic fungi exist in?

A
  • yeasts

- molds

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4
Q

What are yeasts?

A

Unicellular forms of fungi

  • reproduce by budding
  • have moist, shiny appearance when left to grow in colonies
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5
Q

What are molds?

A

Multicellular fungi

  • consist of many branching hyphae
  • can reproduce either by translocation of existing hyphae to a new area

Or

  • through spore formation and spread (one bad apple really does spoil a bunch)
  • have familiar fuzzy appearance (Rhizopus seen on bread)
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6
Q

What are dimorphic fungi?

A

Can exist in either form

  • often mold-like at room temperature
  • yeast-like at body temperature
  • referred to as endemic fungi (cause infections endemic to certain regions of the world)

Valley fever

  • caused by Coccidioides immitis
  • found in SW USA and central California
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7
Q

What type of fungus has become a leading cause of nosocomial bloodstream infections?

A

Yeasts

-particularly Candida species

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8
Q

Why are invasive Candida infections hard to diagnose?

A
  • presence of Candida in a culture might represent colonization not infection (colonization of urinary catheters)
  • deep-seated Candida infections frequently not detected by standard methods and sometimes only found on autopsy
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9
Q

In what patient population do molds generally cause invasive infections?

A

Immunocompromised hosts

-should be considered in patients with various levels of immunosuppression

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10
Q

What types of infection do dimorphic fungi cause?

A
  • usually cause mild self-limited disease

- can cause fatal disseminated disease (especially in patients with suppressed immunity)

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11
Q

Describe fungal cultures.

A

Pathogens can be more difficult to isolate on culture than bacterial organisms

  • prompt initiation of empiric therapy important when invasive fungal infections suspected
  • prophylaxis used in highly susceptible populations to prevent development of fungal infections
  • most centers do not conduct antifungal susceptibility testing
  • clinician must guess at most likely susceptibility patterns
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12
Q

How do the capabilities of the host affect the likelihood of success in invasive fungal infections?

A

For neutropenic patients with mycoses:

  • neutrophil recovery a significant predictor of success
  • patients with prolonged immunocompromised status have a much worse prognosis
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13
Q

What are examples of patient-specific factors that increase the likelihood of success?

A
  • need to remove a central venous catheter

- decrease doses of immunosuppressants

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14
Q

Describe selective toxicity in regards to antifungals?

A

Selective toxicity more difficult to achieve with eukaryotic fungi than with prokaryotic fungi

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15
Q

What type of fungus is Candida?

A

Yeast

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16
Q

What type of fungus is Cryptococcus?

A

Yeast

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17
Q

What type of fungus is Histoplasma?

A

Dimorphic fungi

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18
Q

What type of fungus is Blastomyces?

A

Dimorphic fungi

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19
Q

What type of fungus is Coccidioides?

A

Dimorphic fungi

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20
Q

What type of fungus is Paracoccidioides?

A

Dimorphic fungi

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21
Q

What type of fungus is Aspergillus?

A

Mold

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22
Q

What type of fungus is Fusarium?

A

Mold

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23
Q

What type of fungus is Scedosporium?

A

Mold

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24
Q

What type of fungus is Mucorales?

A

Mold

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25
Q

Name the polyenes.

A
  • amphotericin B

- nystatin (topical)

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26
Q

What toxicities is amphotericin B most notable for?

A
  • nephrotoxicity

- infusion-related reactions

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27
Q

What are the lipid forms of amphotericin B?

A
  • amphotericin B colloidal dispersion (ABCD)
  • amphotericin B lipid complex (ABLC)
  • liposomal amphotericin B (LAmB)
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28
Q

Why is amphotericin B still used?

A
  • activity against yeasts and many molds
  • proven efficacy in understudied disease states
  • long history of use
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29
Q

What is the MOA of polyenes?

A

Bind to ergosterol in the fungal cell membrane

  • forms pores in the membrane
  • leads to leakage of cellular contents
  • eventual cell death
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30
Q

What organisms does amphotericin B have GOOD activity against?

A
  • most species of Candida
  • most species of Aspergillus
  • Cryptococcus neoformans
  • dimorphic fungi
  • many molds
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31
Q

What organisms does amphotericin B have MODERATE activity against?

A

Mucorales

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32
Q

What organisms does amphotericin B have POOR activity against?

A
  • Candida lusitaniae

- Aspergillus terreus

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33
Q

Describe amphotericin B infusion related reactions.

A

Can be impressive

  • fevers
  • chills
  • rigors
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34
Q

How can the incidence and severity of amphotericin B infusion-related reactions be attenuated?

A

Pre-medicating with:

  • acetaminophen
  • diphenhydramine
  • hydrocortisone
  • sometimes other medications
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35
Q

Which amphotericin B lipid formulation has the LOWEST incidence of infusion-related reactions?

A

Liposomal amphotericin B (LAmB)

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36
Q

Which amphotericin B lipid formulation has the HIGHEST incidence of infusion-related reactions?

A

Amphotericin B colloidal dispersion (ABCD)

37
Q

Describe amphotericin B nephrotoxicity.

A

Common

Direct effects:

-on the distal tubule

Indirect effects:

-vasoconstriction of the afferent arteriole

38
Q

What does amphotericin B nephrotoxicity lead to?

A

Wasting of magnesium and potassium

-patients frequently need supplementation

39
Q

Which amphotericin B formulation has the lowest incidence of nephrotoxicity?

A

All the lipid formulations have less than conventional amphotericin B deoxycholate

-liposomal amphotericin B has the least (LAmB)

40
Q

What are some other adverse effects of amphotericin B products?

A
  • increased transaminases

- rash

41
Q

What is amphotericin B deoxycholate generally dosed at?

A

Between 0.5 and 1.5 mg/kg/day

42
Q

What are the amphotericin B lipid formulations generally dosed at?

A

Between 3 and 6 mg/kg/day

  • most clinicians dose them as if they are equivalent (debatable)
  • fatal overdoses can occur if lipid dosing used for the conventional dosage form
43
Q

What is one strategy used to decrease amphotericin B nephrotoxicity?

A

Sodium loading

  • administer boluses of normal saline before and after the amphotericin infusion
  • inexpensive and easy way to protect the kidneys
44
Q

Why is meperidine sometimes given to patients on amphotericin B?

A

Often given to treat rigors when they develop

45
Q

Why should one be wary of using meperidine in patients who develop renal dysfunction?

A
  • it has a neurotoxic metabolite

- eliminated renally

46
Q

Why is nystatin only used topically?

A

Poor tolerance when given systemically

47
Q

What is one very important thing to double check before dispensing amphotericin B?

A

Double check the dose

-which formulation is being used?

48
Q

What is amphotericin B good for?

A

Drugs of choice for

-cryptococcal meningitis

-serious forms of some other fungal infections
(dimorphic fungi; some molds)

Are broad spectrum

-reasonable choice if fungal infection suspected but infecting organism not known (febrile neutropenia)

49
Q

In which infections has amphotericin B use declined due to availability of newer safer agents?

A
  • candidiasis

- aspergillosis

50
Q

Name an antifungal antimetabolite.

A

Flucytosine (5-FC)

  • is fluorouracil for fungi
  • originally investigated as oncology drug
  • found to be more active against fungi than human cancer cells
51
Q

What is flucytosine’s primary role?

A

In combination therapy with amphotericin B for cryptococcal disease

52
Q

Why is flucytosine rarely used for other infections?

A
  • toxicity

- relative lack of efficacy

53
Q

What is flucytosine’s MOA?

A

Is deaminated inside fungal cells to 5-fluorouracil

  • further converted into metabolites
  • interfere with both protein and DNA synthesis
54
Q

What organisms does flucytosine have GOOD activity against?

A

In combination with amphotericin B

  • Cryptococcus neoformans
  • most species of Candida
55
Q

What organisms does flucytosine have MODERATE activity against?

A

Monotherapy

  • Cryptococcus neoformans
  • most species of Candida
56
Q

What organisms does flucytosine have POOR activity against?

A
  • molds

- Candida krusei

57
Q

How selective is flucytosine for fungi?

A

Only relatively selective

-can cause considerable bone marrow suppression (higher doses or prolonged courses)

58
Q

What are more common complaints with flucytosine?

A

GI complaints

-more common but less severe

59
Q

How is drug concentration monitoring used for flucytosine?

A
  • check peak concentration about 2 hours after dose is given
  • in most hospitals it is a sendout lab
  • can take up to a week to be resulted
  • most common therapy duration is 2 weeks so the practical utility of monitoring flucytosine levels is limited
60
Q

What is more important than drug concentrations when monitoring for toxicity?

A

Hematology values

61
Q

Should flucytosine be used as monotherapy for invasive candidiasis?

A

Generally not

-potential emergence of resistance in vivo

62
Q

What is the not common use for flucytosine?

A

In combination with amphotericin B for cryptococcal meningitis

  • the combination is recommended in guidelines and very common
  • some clinicians have questioned the value of flucytosine
  • in early clinical trial: flucytosine use associated with more rapid sterility of CSF cultures but showed no obvious clinical benefit
  • more recent studies have shown survival benefit with its use
  • is difficult to obtain or afford in resource poor countries where HIV infection is highly endemic
63
Q

What are the abbreviations for flucytosine and fluorouracil?

A

Flucytosine: 5-FC

Fluorouracil: 5-FU (more toxic)

64
Q

What is flucytosine good for?

A

In combination with amphotericin B for cryptococcal meningitis

This combination can also be used for

  • other forms of cryptococcal infection
  • Candida infection (uncommon)

May be acceptable option for

  • clearance of candiduria in patients who cannot receive fluconazole (because of allergy or resistance)
  • number of patients who require this therapy is small
65
Q

What value is important to monitor for flucytosine therapy?

A

Follow cell counts closely

-consider dose modification or discontinuation if hematologic toxicity develops

66
Q

Name the echinocandins.

A
  • caspofungin
  • micafungin
  • anidulafungin
67
Q

Describe the echinocandins.

A
  • virtually indistinguishable spectra between the three
  • very well tolerated
  • considerably fewer drug interactions than the azoles
  • safer than polyenes
  • excellent activity against Candida
  • have great activity against fluconazole resistant yeasts
68
Q

What is a major PK setback of the echinocandins?

A

Lack of an oral formulation

69
Q

What is the MOA of echinocandins?

A

Inhibit beta-1,3-D-glucan synthase

  • is responsible for the production of beta-1,3-D-glucan (vital component of the cell wall of many fungi)
  • only active against fungi that are dependent on this type of glucan
70
Q

What organisms do the echinocandins have GOOD activity against?

A
  • Candida albicans
  • Candida glabrata
  • Candida lusitaniae
  • Candida parapsilosis
  • Candida tropicalis
  • Candida krusei
  • Aspergillus species
71
Q

What organisms do the echinocandins have MODERATE activity against?

A
  • Candida parapsilosis
  • some dimorphic fungi
  • Mucorales (in combination with amphotericin B)
72
Q

What organisms do the echinocandins have POOR activity against?

A
  • most non-Aspergillus molds

- Cryptococcus neoformans

73
Q

Generally describe the safety profile of echinocandins.

A

Excellent

74
Q

Describe the adverse effects of echinocandins.

A
  • can cause mild histamine-mediated infusion-related reactions (not common; can be ameliorated by slowing the infusion rate)
  • hepatotoxicity (possible but not common)
75
Q

How are caspofungin and micafungin eliminated?

A

Hepatically

-noncytochrome P450 metabolism

76
Q

How is anidulafungin metabolized?

A

Degrades in the plasma

  • avoids hepatic metabolism
  • NOT completely devoid of hepatotoxicity
77
Q

What kind of activity do echinocandins have against Candida?

A

Excellent fungicidal activity

78
Q

What kind of activity do echinocandins have against Aspergillus?

A

Activity that is neither classically cidal nor static

-cause aberrant nonfunctional hyphae to be formed by the actively growing mold

79
Q

How effective are echinocandins against molds?

A

Modestly active

-appear to substantially enhance the effects of other antifungals against these pathogens

80
Q

What did a trial of voriconazole with/out anidulafungin in invasive aspergillosis show?

A

Trend toward reduced mortality with combination therapy

  • p=0.07
  • echinocandins have low toxicity so many clinicians advocate for combination therapy
81
Q

Echinocandins may enhance the efficacy of liposomal amphotericin B against what type of infection?

A

Mucorales

-based on in vitro and limited clinical data

82
Q

With what drugs do echinocandins have interactions with?

A

Interactions are minor

  • cyclosporine (caspofungin)
  • sirolimus (micafungin)
83
Q

What are echinocandins the drugs of choice for?

A

Invasive candidiasis

-particularly in patients who are clinically unstable or risk of azole resistant species

84
Q

What infection are echinocandins useful for?

A

Treatment of invasive aspergillosis

-do not have level of support of data that voriconazole and polyenes have for this indication

85
Q

What are all echinocandins used for?

A

Esophageal candidiasis

86
Q

What are some echinocandins used for?

A

Prophylaxis or empiric therapy of fungal infections in neutropenic patients

87
Q

When are echinocandins used as combination therapy?

A

Some clinicians use it to increase likelihood of cure for some infections

  • Aspergillus (with voriconazole)
  • Mucorales (with amphotericin B)
88
Q

When and why should echinocandins be transitioned?

A

Expensive and IV therapy can be inconvenient

-after using as empiric therapy, consider transition to fluconazole if susceptible strain of Candida and no contraindications

.► FARMACOLOGIA CLÍNICA - JP (50 decks)

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