Antifungal Agents Flashcards
(158 cards)
1
Q
Amphotericin A and B are antifungal antibiotics produced by
A
Streptomyces nodosus.
2
Q
Amphotericin B is an?
A
amphoteric polyene macrolide (polyene =
containing many double bonds; macrolide = containing a large
lactone ring of 12 or more atoms)
3
Q
Amphotericin B is nearly insoluble in water
and is therefore prepared as a?
A
colloidal suspension of amphotericin B and sodium desoxycholate for intravenous injection
4
Q
New formulation of Amphotericin B
A
packaged in a lipid-associated delivery system
5
Q
Most expensive lipid formulation of amphotericin B
A
AmBisome
6
Q
lipid formulation of amphotericin B with 3 - 5 dosing
A
AmBisome
7
Q
Lipid formulation of amphotericin B with highest Cmax
A
AmBisome
8
Q
Lipid formulation of Amphotericin B with infusional toxicity
A
Amphotec
9
Q
Oral amphotericin B is thus effective only on?
A
fungi within
the lumen of the tract and cannot be used for treatment of systemic
disease because it is poorly absorbed from the GIT
10
Q
amphotericin B is excreted slowly in the ____ over a period of several days
A
urine
11
Q
Dose adjustment is required in amphotericin B. True or false?
A
False
12
Q
How many % of the blood level of amphotericin B is reached in the CSF, necessisating intrathecal therapy for fungal meningitis?
A
2 - 3%
13
Q
Amphotericin B is selective in its fungicidal effect because?
A
It only targets fungal cell membrane, Ergosterol
14
Q
Amphotericin B binds to ergosterol and alters the permeability of the cell by forming?
A
amphotericin B-associated pores in the cell membrane
15
Q
Amphipathic characteristic of Amphotericin B binds with ergosterol along the _____ of its structure and associates with water molecules along the _____
A
double bond-rich side (around outside the pore)
hydroxyl-rich side (lining the inside)
16
Q
MOA of amphotericin B
A
Formation of pores on the cell membrane bilayer, allowing leakage of intracellular ions and molecules
17
Q
2 mechanisms of resistance/impairing ergosterol binding by amphotericin B
A
- Decreasing the membrane concentration of ergosterol
2. Modifying the sterol target molecule to reduce its affinity for the drug
18
Q
Antifungal agent with the broadest spectrum of activity.
A
Amphotericin B
19
Q
With intrinsic amphotericin B resistance
A
Candida lusitaniae and Pseudallescheria boydii
20
Q
Useful agent for all life-threatening mycotic infections
A
Amphotericin B
21
Q
Often used as the initial induction regimen to rapidly reduce fungal burden
A
amphotericin B
22
Q
Used for immunosuppressed patients and those with severe fungal pneumonia, severe cryptococcal meningitis or disseminated infections with endemic mycoses such as histoplasmosis or coccidiodomycosis
A
Amphotericin B
23
Q
Once initial therapy with amphotericin B is used, what med is used as maintenance therapy?
A
-azoles
24
Q
For treatment of systemic fungal disease. amphotericin B is given by?
A
Slow IV infusion at 0.5 - 1 mg/kg/day
25
Amphotericin B is continued to a defined total dose rather than a defined time span. True or false?
True
26
Which remains an option in cases of fungal CNS infections that have not responded to other agents?
Intrathecal amphotericin B though it is poorly tolerated and CSF access is difficult
27
Mycotic corneal ulcers and keratitis may be cured with what kind of amphotericin B formulations/method of administration?
topical drops and direct subconjuctival injection
28
Type of amphotericin B toxicty that manifests as fever, chills, muscle spasms, vomiting, headache, and hypotension
Infusion-Related Toxicity
29
How to treat Infusion-Related Toxicity of amphotericin B?
by slowing the infusion rate or
| decreasing the daily dose
30
Premids for amphotericin B
antipyretics, antihistamines, meperidine, or corticosteroids
31
When starting amphotericin B , what should be done to gauge the severity of the reaction?
administer a test dose of 1 mg intravenously to serve as a guide to an initial dosing regimen and premedication
strategy
32
occurs in nearly all patients treated with clinically significant doses of amphotericin
Renal damage
33
A reversible component of amphotericin B renal damage that is associated with a form of prerenal renal
failure
decreased renal perfusion
34
results from renal tubular
| injury and subsequent dysfunction in amphotericin B toxicity
Irreversible renal damage
35
The irreversible form of
| amphotericin nephrotoxicity usually occurs in the setting of?
prolonged administration (> 4 g cumulative dose)
36
Renal toxicity in amphotericin B use is commonly manifested as?
renal tubular acidosis and severe potassium
| and magnesium wasting
37
It is common practice to administer daily doses of amphotericin B with _____ to attenuate prerenal component of cumulative toxicity
normal saline infusions
38
After intrathecal therapy with amphotericin, _____ may develop,
often with serious neurologic sequelae.
seizures and a chemical arachnoiditis
39
Other occasionally seen AEs of amphotericin B
Abnormalities of liver function tests
Reduced erythropoietin production
by damaged renal tubular cells
40
MOA of Flucytosine (5-FC)
Inhibition of RNA and DNA synthesis
41
water-soluble pyrimidine analog related to the
| chemotherapeutic agent 5-fluorouracil (5-FU)
Flucytosine (5-FC)
42
Which has a narrower spectrum of activity, 5-FU or amphotericin B?
5-FU
43
5-FU is well absorbed (> 90%), with serum
| concentrations peaking ___ after oral dose
1–2 hours
44
5-FU is poorly protein bound. True or false?
True
45
5-FU can penetrate CSF. True or False?
True
46
5-FU is eliminated by?
eliminated by glomerular
| filtration with a half-life of 3–4 hours and is removed by hemodialysis
47
5-Fu toxicity is more likely to occur in?
AIDS patients
| and those with renal insufficiency
48
Peak serum concentrations of 5-FU
should be measured periodically in patients with renal insufficiency
and maintained between?
between 50 and 100 mcg/mL
49
Flucytosine is taken up by fungal cells via the enzyme?
cytosine permease
50
MOA of flucytosine
It is converted intracellularly first to 5-FU and then to
5-fluorodeoxyuridine monophosphate (FdUMP) and fluorouridine
triphosphate (FUTP), which inhibit DNA and RNA synthesis,
respectively
51
in 5-FU, human cells are unable to convert the
| parent drug to its active metabolites, resulting in selective toxicity. True or false?
True
52
5-FC is synergistic with which drug?
amphotericin B
53
Resistance to 5-FU is via?
altered metabolism
| of flucytosine develops rapidly in monotherapy
54
The spectrum of activity of flucytosine is restricted to?
C neoformans, some Candida sp, and the dematiaceous molds that cause
chromoblastomycosis
55
Clinical use of 5-FC
confined to combination therapy:
+ AmpB = cryptococcal meningitis
+ itraconazole = chromoblastomycosis
56
The adverse effects of flucytosine result from metabolism
| (possibly by intestinal flora) to the toxic antineoplastic compound?
fluorouracil
57
most common adverse effects of flucytosine
Bone marrow toxicity with anemia, leukopenia, and thrombocytopenia with
derangement of liver enzymes occurring less frequently; toxic enterocolitis can occur
58
Azoles are synthetic compounds that can be classified as either
imidazoles or triazoles according to the number of?
nitrogen atoms in the five-membered azole ring
59
Azoles now used only in topical therapy?
miconazole, and clotrimazole
60
The triazoles include?
itraconazole, fluconazole, voriconazole, and posaconazol
61
The antifungal activity of azole drugs results from?
the reduction of
ergosterol synthesis by inhibition of fungal cytochrome P450
enzymes
62
Which has a lesser degree of selectivity accounting for their higher incidence of drug
interactions and adverse effects?
Imidazoles vs triazoles
63
azole drugs with high water solubility
Fluconazole
| Voriconazole
64
azole drugs with high variable absorption
Ketoconazole
| Itraconazole
65
azole drug with highest (>0.7) CSF: Serum
| Concentration Ratio
Fluconazole
66
azole drug with longest t1/2
Itraconazole 24–42 hours
67
Only azole drug excreted renally
fluconazole
68
Azole drugs available only in oral forms
ketoconazole
| Posaconazole
69
The spectrum of action of azole medications is broad, including many species of Candida, C neoformans , the endemic mycoses
(blastomycosis, coccidioidomycosis, histoplasmosis), the dermatophytes,
and, in the case of ____ and ____, even
Aspergillus infections.
itraconazole and voriconazole
70
As a group, the azoles are relatively nontoxic. The most common
adverse reaction is relatively?
minor gastrointestinal upset
71
All azoles have been reported to cause abnormalities in?
liver enzymes and, very rarely, clinical hepatitis
72
First oral azole introduced
Ketoconazole
73
It is distinguished from triazoles by its greater propensity to inhibit mammalian cytochrome P450 enzymes
Ketoconazole
74
It is available in oral and intravenous formulations and is used at a dosage of 100–400 mg/d.
Itraconazole
75
Drug absorption of itraconazole is increased by?
food and by low gastric pH
76
An important drug interaction is
| reduced bioavailability of itraconazole when taken with?
rifamycins
77
Newer formulations of itraconzaole, including an oral liquid and an intravenous preparation,
have utilized ____ as a carrier molecule to enhance solubility
and bioavailability.
cyclodextran
78
Azole that penetrates
| poorly into the cerebrospinal fluid
ketoconazole, itraconazole
79
azole of
choice for treatment of disease due to the dimorphic fungi
Histoplasma, Blastomyces , and Sporothrix.
Itraconazole
80
Itraconazole has activity
against Aspergillus sp, but it has been replaced by ____ as
the azole of choice for aspergillosis
voriconazole
81
Itraconazole is used extensively in the treatment of?
dermatophytoses and onychomycosis
82
Azole that displays a high degree of water solubility and good cerebrospinal fluid penetration.
Fluconazole
83
Azole that has the least effect of all the azoles
| on hepatic microsomal enzymes.
fluconazole
84
Azole that has the widest therapeutic index of the azoles because of fewer hepatic enzyme
interactions and better gastrointestinal tolerance
fluconazole
85
Azole available in oral and intravenous formulations and is used at a dosage of
100–800 mg/d.
fluconazole
86
azole of choice in the treatment and secondary
| prophylaxis of cryptococcal meningitis.
Fluconazole
87
has been shown to be equivalent to amphotericin B in
treatment of candidemia in ICU patients with normal white blood
cell counts
Fluconazole
88
agent most commonly used for the
| treatment of mucocutaneous candidiasis.
Fluconazole
89
Fluconazole activity dimorphic fungi is limited to?
coccidioidal disease, and in particular for meningitis
90
Fluconazole displays no
| activity against?
Aspergillus or other filamentous fungi
91
Prophylactic use of fluconazole has been demonstrated to
| reduce fungal disease in?
bone marrow transplant recipients and AIDS patients
92
Voriconazole is available in intravenous and oral formulations. The recommended dosage is?
400 mg/d
93
The azole drug that is well absorbed orally, with a bioavailability exceeding 90%, and it exhibits less
protein binding than itraconazole.
Voriconazole
94
A clinically relevant inhibitor of mammalian
CYP3A4, and dose reduction of a number of medications is
required when this is started
Voriconazole
95
Drugs affected by voriconazole
cyclosporine, tacrolimus, and HMG-CoA reductase inhibitors
96
Observed toxicities in voriconazole use include
rash and elevated hepatic enzymes
97
Visual disturbances
| are common, occurring in up to 30% of patients receiving?
intravenous voriconazole
98
Visual disturbance with intravenous voriconazole include?
blurring and changes in
| color vision or brightness
99
Visual disturbance with intravenous voriconazole resolve within?
30 minutes
100
commonly observed in
| patients receiving chronic oral therapy of voriconazole
photosensitivity dermatitis
101
Voriconazole is similar to itraconazole in its spectrum of action,
having excellent activity against?
```
Candida sp (including fluconazoleresistant
species such as Candida krusei ) and the dimorphic fungi
```
102
is less toxic than amphotericin B and is the treatment
| of choice for invasive aspergillosis
Voriconazole
103
Azole that is the newest triazole to be licensed in the USA. It is available only in a liquid oral formulation and is used at a dosage of 800 mg/d, divided into two or three doses.
Posaconazole
104
Absorption of Posaconazole is improved when taken with?
meals high in fat
105
Azole that is rapidly
distributed to the tissues, resulting in high tissue levels but
relatively low blood levels.
Posaconazole
106
drug interactions with increased levels of CYP3A4 substrates
| such as tacrolimus and cyclosporine have been documented
Posaconazole
107
broadest spectrum member of the azole
| family, with activity against most species of Candida and Aspergillus
Posaconazole
108
It is the only azole with significant activity against the agents of
mucormycosis.
Posaconazole
109
currently licensed for salvage therapy in invasive aspergillosis
Posaconazole
110
It is currently licensed for prophylaxis of fungal infections during
induction chemotherapy for leukemia
Posaconazole
111
It is currently licensed for allogeneic bone
| marrow transplant patients with graft-versus-host disease
Posaconazole
112
```
newest class of antifungal agents to be
developed.
```
Echinocandins
113
They are large cyclic peptides linked to a long-chain fatty acid.
Echinocandins
114
These agents are active against Candida and Aspergillus, but not C neoformans or the agents of zygomycosis and mucormycosis.
Echinocandins
115
Echinocandins are available only in?
intravenous formulations
116
Caspofungin is administered as a single loading dose of?
Caspofungin is administered as a single loading dose of 70 mg,
followed by a daily dose of 50 mg.
117
The half-life of caspofungin is __, and the metabolites are excreted by the ____.
9–11 hours
| kidneys and gastrointestinal tract
118
Dosage adjustments of caspofungin are required only in the presence of?
severe hepatic insufficiency
119
Echinocandin that displays similar properties with caspofungin with
a half-life of 11–15 hours and is used at a dose of 150 mg/d for
treatment of esophageal candidiasis
Micafungin
120
Micafungin 100 mg/d for treatment of?
candidemia
121
Micafungin 50 mg/d is for?
prophylaxis of fungal infections
122
Echinocandin that has a half-life of 24–48 hours. For esophageal
candidiasis, it is administered intravenously at 100 mg on the first
day and 50 mg/d thereafter for 14 days.
Anidulafungin
123
loading
dose of 200 mg is recommended with 100 mg/d thereafter for at
least 14 days after the last positive blood culture in which echinocandin?
Anidulafungin
124
Echinocandins act at the level of the fungal cell wall by?
by inhibiting
| the synthesis of β(1–3)-glucan
125
currently licensed for disseminated and mucocutaneous
| candidal infections
caspofungin
126
Echinocandin for empiric antifungal therapy
| during febrile neutropenia.
Caspofungin
127
largely replaced amphotericin B for the antifungal therapy
| during febrile neutropenia
Caspofungin
128
Licensed for use
in invasive aspergillosis only as salvage therapy in patients who have
failed to respond to amphotericin B, and not as primary therapy.
Caspofungin
129
Licensed for mucocutaneous candidiasis, candidemia,
and prophylaxis of candidal infections in bone marrow transplant
patients
Micafungin
130
approved for use in esophageal candidiasis
| and invasive candidiasis, including candidemia
Anidulafungin
131
Echinocandin agents are extremely well tolerated, with_____ reported infrequently.
minor gastrointestinal side effects and flushing
132
Elevated liver enzymes have been noted in several patients receiving caspofungin in combination with?
cyclosporine
133
Micafungin has been shown to increase
| levels of?
nifedipine, cyclosporine, and sirolimus
134
Anidulafungin does not seem to have significant drug interactions, but ____ release may occur during intravenous infusion.
histamine
135
a very insoluble fungistatic drug derived from a species of penicillium
Griseofulvin
136
Griseofulvin only use is in the systemic treatment of?
dermatophytosis
137
It is administered in a microcrystalline form at a dosage of 1 g/d.
Griseofulvin
138
Absorption of griseofulvin is improved when?
given with fatty foods
139
Griseofulvin’s mechanism of action at the cellular level is unclear, but it is deposited in?
deposited in newly forming
| skin where it binds to keratin, protecting the skin from new infection
140
Because its action is to prevent infection of these new skin structures, griseofulvin must be administered for?
administered for 2–6 weeks for
skin and hair infections to allow the replacement of infected keratin
by the resistant structures
141
Also used for nail infections for months to allow regrowth of the new protected nail and is often followed by relapse
Griseofulvin
142
AEs of Griseofulvin
allergic syndrome
| much like serum sickness, hepatitis
143
Griseofulvin has drug interactions with?
warfarin and phenobarbital
144
synthetic allylamine that is available in an oral
| formulation and is used at a dosage of 250 mg/d
Terbinafine
145
used in the
| treatment of dermatophytoses, especially onychomycosis
Terbinafine
146
Similarity and difference of griseofulvin with terbinafine
Like griseofulvin, terbinafine is a keratophilic medication
| Unlike griseofulvin, terbinafine is fungicidal
147
Rather than interacting with the P450 system, terbinafine inhibits the fungal ?enzyme
squalene epoxidase
148
One tablet given daily for 12 weeks achieves a cure rate of up to 90% for onychomycosis and is more effective than griseofulvin
or itraconazole.
terbinafine
149
AEs of terbinafine
gastrointestinal upset and headache
150
A polyene macrolide much like amphotericin B. It is too
| toxic for parenteral administration and is only used topically.
Nystatin
151
It is not absorbed to a significant degree from skin, mucous membranes,
or the gastrointestinal tract.
nystatin
152
As a result, nystatin has little
| toxicity, although oral use is often limited by the?
unpleasant taste
153
common indications of nystatin include?
oropharyngeal thrush, vaginal candidiasis,
| and intertriginous candidal infections
154
The two azoles most commonly used topically are?
clotrimazole and
| miconazole
155
clotrimazole and miconazole are available over-the-counter and are often used for?
vulvovaginal
| candidiasis
156
Oral clotrimazole troches are available for treatment of oral thrush and are advantageous over nystatin because?
it is a pleasant-tasting alternative
157
Useful for dermatophytic
infections, including tinea corporis, tinea pedis, and tinea cruris.
Absorption is negligible, and adverse effects are rare.
clotrimazole and
| miconazole
158
Allylamines available as topical creams that are effective for treatment of tinea cruris and tinea corporis.
terbinafine and naftifine
