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
2
Q
What is the term for treatment of fungal infections?
A
Medical mycology
3
Q
What two forms do microscopic fungi exist in?
A
- yeasts
- molds
4
Q
What are yeasts?
A
Unicellular forms of fungi
- reproduce by budding
- have moist, shiny appearance when left to grow in colonies
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)
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
7
Q
What type of fungus has become a leading cause of nosocomial bloodstream infections?
A
Yeasts
-particularly Candida species
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
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
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)
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
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
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
14
Q
Describe selective toxicity in regards to antifungals?
A
Selective toxicity more difficult to achieve with eukaryotic fungi than with prokaryotic fungi
15
Q
What type of fungus is Candida?
A
Yeast
16
Q
What type of fungus is Cryptococcus?
A
Yeast
17
Q
What type of fungus is Histoplasma?
A
Dimorphic fungi
18
Q
What type of fungus is Blastomyces?
A
Dimorphic fungi
19
Q
What type of fungus is Coccidioides?
A
Dimorphic fungi
20
Q
What type of fungus is Paracoccidioides?
A
Dimorphic fungi
21
Q
What type of fungus is Aspergillus?
A
Mold
22
Q
What type of fungus is Fusarium?
A
Mold
23
Q
What type of fungus is Scedosporium?
A
Mold
24
Q
What type of fungus is Mucorales?
A
Mold
25
Name the polyenes.
- amphotericin B
| - nystatin (topical)
26
What toxicities is amphotericin B most notable for?
- nephrotoxicity
| - infusion-related reactions
27
What are the lipid forms of amphotericin B?
- amphotericin B colloidal dispersion (ABCD)
- amphotericin B lipid complex (ABLC)
- liposomal amphotericin B (LAmB)
28
Why is amphotericin B still used?
- activity against yeasts and many molds
- proven efficacy in understudied disease states
- long history of use
29
What is the MOA of polyenes?
Bind to ergosterol in the fungal cell membrane
- forms pores in the membrane
- leads to leakage of cellular contents
- eventual cell death
30
What organisms does amphotericin B have GOOD activity against?
- most species of Candida
- most species of Aspergillus
- Cryptococcus neoformans
- dimorphic fungi
- many molds
31
What organisms does amphotericin B have MODERATE activity against?
Mucorales
32
What organisms does amphotericin B have POOR activity against?
- Candida lusitaniae
| - Aspergillus terreus
33
Describe amphotericin B infusion related reactions.
Can be impressive
- fevers
- chills
- rigors
34
How can the incidence and severity of amphotericin B infusion-related reactions be attenuated?
Pre-medicating with:
- acetaminophen
- diphenhydramine
- hydrocortisone
- sometimes other medications
35
Which amphotericin B lipid formulation has the LOWEST incidence of infusion-related reactions?
Liposomal amphotericin B (LAmB)
36
Which amphotericin B lipid formulation has the HIGHEST incidence of infusion-related reactions?
Amphotericin B colloidal dispersion (ABCD)
37
Describe amphotericin B nephrotoxicity.
Common
Direct effects:
-on the distal tubule
Indirect effects:
-vasoconstriction of the afferent arteriole
38
What does amphotericin B nephrotoxicity lead to?
Wasting of magnesium and potassium
-patients frequently need supplementation
39
Which amphotericin B formulation has the lowest incidence of nephrotoxicity?
All the lipid formulations have less than conventional amphotericin B deoxycholate
-liposomal amphotericin B has the least (LAmB)
40
What are some other adverse effects of amphotericin B products?
- increased transaminases
| - rash
41
What is amphotericin B deoxycholate generally dosed at?
Between 0.5 and 1.5 mg/kg/day
42
What are the amphotericin B lipid formulations generally dosed at?
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
What is one strategy used to decrease amphotericin B nephrotoxicity?
Sodium loading
- administer boluses of normal saline before and after the amphotericin infusion
- inexpensive and easy way to protect the kidneys
44
Why is meperidine sometimes given to patients on amphotericin B?
Often given to treat rigors when they develop
45
Why should one be wary of using meperidine in patients who develop renal dysfunction?
- it has a neurotoxic metabolite
| - eliminated renally
46
Why is nystatin only used topically?
Poor tolerance when given systemically
47
What is one very important thing to double check before dispensing amphotericin B?
Double check the dose
-which formulation is being used?
48
What is amphotericin B good for?
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
In which infections has amphotericin B use declined due to availability of newer safer agents?
- candidiasis
| - aspergillosis
50
Name an antifungal antimetabolite.
Flucytosine (5-FC)
- is fluorouracil for fungi
- originally investigated as oncology drug
- found to be more active against fungi than human cancer cells
51
What is flucytosine's primary role?
In combination therapy with amphotericin B for cryptococcal disease
52
Why is flucytosine rarely used for other infections?
- toxicity
| - relative lack of efficacy
53
What is flucytosine's MOA?
Is deaminated inside fungal cells to 5-fluorouracil
- further converted into metabolites
- interfere with both protein and DNA synthesis
54
What organisms does flucytosine have GOOD activity against?
In combination with amphotericin B
- Cryptococcus neoformans
- most species of Candida
55
What organisms does flucytosine have MODERATE activity against?
Monotherapy
- Cryptococcus neoformans
- most species of Candida
56
What organisms does flucytosine have POOR activity against?
- molds
| - Candida krusei
57
How selective is flucytosine for fungi?
Only relatively selective
-can cause considerable bone marrow suppression (higher doses or prolonged courses)
58
What are more common complaints with flucytosine?
GI complaints
-more common but less severe
59
How is drug concentration monitoring used for flucytosine?
- 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
What is more important than drug concentrations when monitoring for toxicity?
Hematology values
61
Should flucytosine be used as monotherapy for invasive candidiasis?
Generally not
-potential emergence of resistance in vivo
62
What is the not common use for flucytosine?
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
What are the abbreviations for flucytosine and fluorouracil?
Flucytosine: 5-FC
Fluorouracil: 5-FU (more toxic)
64
What is flucytosine good for?
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
What value is important to monitor for flucytosine therapy?
Follow cell counts closely
-consider dose modification or discontinuation if hematologic toxicity develops
66
Name the echinocandins.
- caspofungin
- micafungin
- anidulafungin
67
Describe the echinocandins.
- 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
What is a major PK setback of the echinocandins?
Lack of an oral formulation
69
What is the MOA of echinocandins?
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
What organisms do the echinocandins have GOOD activity against?
- Candida albicans
- Candida glabrata
- Candida lusitaniae
- Candida parapsilosis
- Candida tropicalis
- Candida krusei
- Aspergillus species
71
What organisms do the echinocandins have MODERATE activity against?
- Candida parapsilosis
- some dimorphic fungi
- Mucorales (in combination with amphotericin B)
72
What organisms do the echinocandins have POOR activity against?
- most non-Aspergillus molds
| - Cryptococcus neoformans
73
Generally describe the safety profile of echinocandins.
Excellent
74
Describe the adverse effects of echinocandins.
- can cause mild histamine-mediated infusion-related reactions (not common; can be ameliorated by slowing the infusion rate)
- hepatotoxicity (possible but not common)
75
How are caspofungin and micafungin eliminated?
Hepatically
-noncytochrome P450 metabolism
76
How is anidulafungin metabolized?
Degrades in the plasma
- avoids hepatic metabolism
- NOT completely devoid of hepatotoxicity
77
What kind of activity do echinocandins have against Candida?
Excellent fungicidal activity
78
What kind of activity do echinocandins have against Aspergillus?
Activity that is neither classically cidal nor static
-cause aberrant nonfunctional hyphae to be formed by the actively growing mold
79
How effective are echinocandins against molds?
Modestly active
-appear to substantially enhance the effects of other antifungals against these pathogens
80
What did a trial of voriconazole with/out anidulafungin in invasive aspergillosis show?
Trend toward reduced mortality with combination therapy
- p=0.07
- echinocandins have low toxicity so many clinicians advocate for combination therapy
81
Echinocandins may enhance the efficacy of liposomal amphotericin B against what type of infection?
Mucorales
-based on in vitro and limited clinical data
82
With what drugs do echinocandins have interactions with?
Interactions are minor
- cyclosporine (caspofungin)
- sirolimus (micafungin)
83
What are echinocandins the drugs of choice for?
Invasive candidiasis
-particularly in patients who are clinically unstable or risk of azole resistant species
84
What infection are echinocandins useful for?
Treatment of invasive aspergillosis
-do not have level of support of data that voriconazole and polyenes have for this indication
85
What are all echinocandins used for?
Esophageal candidiasis
86
What are some echinocandins used for?
Prophylaxis or empiric therapy of fungal infections in neutropenic patients
87
When are echinocandins used as combination therapy?
Some clinicians use it to increase likelihood of cure for some infections
- Aspergillus (with voriconazole)
- Mucorales (with amphotericin B)
88
When and why should echinocandins be transitioned?
Expensive and IV therapy can be inconvenient
-after using as empiric therapy, consider transition to fluconazole if susceptible strain of Candida and no contraindications
