Antifungals (Kays) Flashcards
1
Q
What is amphotericin B’s mechanism of action?
A
binds ergosterol and increases cell permeability, leading to leakage of Na/K/cellular constituents and ultimately cell death
2
Q
What is flucytosine’s mechanism of action?
A
deaminates to 5-FU, when converts to 5-fluorodeoxyuridylic acid monophosphate and inhibits thymidylate synthetase, ultimately interfering with DNA synthesis
3
Q
What is the azole drugs’ mechanism of action?
A
inhibits ergosterol synthesis via inhibition of lanosterol 14-α-demethylase (damages cell membrane, causes cytoplasmic leakage, and inhibits growth)
4
Q
Are azole antifungals fungicidal or -static?
A
fungistatic
5
Q
What is the echinocandins’ mechanism of action?
A
inhibits glucan synthesis, leading to noncompetitive inhibition of 1,3-β-D-glucan (nothing can bind to chitin to help provide cell wall structure)
6
Q
Are the echinocandins fungicidal or -static?
A
fungicidal
7
Q
What is ibrexafungerp’s mechanism of action?
A
inhibits glucan synthesis, leading to noncompetitive inhibition of 1,3-β-D-glucan (nothing can bind to chitin to help provide cell wall structure)
8
Q
Which antifungal covers Pneumocystis jirovecii?
A
ibrexafungerp
9
Q
What antifungal(s) cover Fusarium?
A
voriconazole and echinocandins (limited)
10
Q
What antifungal covers Scedosporium apiospermum?
A
voriconazole
11
Q
What antifungal covers Sporothrix schenckii?
A
itraconazole
12
Q
What antifungal(s) cover Coccidioides immitis?
A
- amphotericin B
- itraconazole
- fluconazole
- posaconazole
“AND IT FUCKS PUSSIES” (cocc sounds like cock)
13
Q
What antifungal(s) cover Blastomyces?
A
- amphotericin B
- itraconazole
- fluconazole
- voriconazole
“AWAY IT FLIES VERTICALLY” (blast=fireworks)
14
Q
What antifungal(s) cover Histoplasma capsulatum?
A
- amphotericin B
- ketoconazole
- itraconazole
- fluconazole
- voriconazole
- posaconazole
- echinocandins (limited)
“ANIMALS KEEP INTENTIONALLY FLYING VERY POOR ENVIRONMENTS” (bats spread histoplasma)
15
Q
What antifungal(s) cover Mucor?
A
- amphotericin B
- posaconazole
- isavuconazole
- echinocandins (limited)
“ALLERGIES PROBABLY, IT’S EXHAUSTING” (Mucor = mucus)
16
Q
What antifungal covers Absidia?
A
amphotericin B
17
Q
What antifungal(s) cover Rhizopus?
A
- amphotericin B
- isavuconazole
18
Q
What antifungal(s) cover Cryptococcus neoformans?
A
- amphotericin B
- flucytosine
- ketoconazole
- itraconazole
- fluconazole
- voriconazole
- posaconazole
- echinocandins (limited)
everything except for isavuconazole and ibrexafungerp
19
Q
What antifungal(s) cover Aspergillus?
A
- amphotericin B
- itraconazole
- voriconazole
- posaconazole
- isavuconazole
- echinocandins
- ibrexafungerp
“ASPARAGUS IS VERY POPULAR IN ENTREES INTERNATIONALLY” (Aspergillus = asparagus)
20
Q
What antifungal(s) cover Candida?
A
- amphotericin B
- flucytosine
- ketoconazole
- itraconazole
- fluconazole
- voriconazole
- posaconazole
- echinocandins
- ibrexafungerp
everything covers Candida on some level, except isavuconazole
21
Q
What happens with amphotericin B in low concentrations?
A
K+ channel activity is increased
22
Q
What happens with amphotericin B in higher concentrations?
A
pores are formed in the fungal cell membrane
23
Q
Amphotericin B’s onset can be described as __________.
A
rapid
24
Q
Through which two routes could resistance to amphotericin B develop?
A
- decreased ergosterol biosynthesis
- alternative sterol synthesis
25
What is the pharmacodynamic parameter for amphotericin B?
peak/MIC
26
Which *Candida* type is not covered by amphotericin B?
*C. lusitaniae*
27
Amphotericin B has reduced activity against which *Aspergillus*?
*A. terreus*
28
Describe amphotericin B deoxycholate's oral absorption.
poor
29
Describe amphotericin B deoxycholate's intramuscular absorption.
poor
30
Although amphotericin B deoxycholate widely distributes into tissues, where does it primary deposit?
reticuloendothelial tissues (liver, spleen, bone marrow)
31
Describe amphotericin B deoxycholate's CSF penetration.
poor, even with inflamed meninges
32
Amphotericin B deoxycholate is highly protein-bound, mainly to \_\_\_\_\_\_\_\_\_\_\_\_\_.
β-lipoproteins
33
Describe amphotericin B deoxycholate's metabolism.
not appreciably metabolized (most of the drug is degraded in situ)
34
Amphotericin B deoxycholate's elimination pattern can best be described as \_\_\_\_\_\_\_\_\_\_\_\_\_\_.
tri-exponential
35
Amphotericin B deoxycholate can be detected in serum concentrations for at least ___________ after the end of therapy.
7 weeks
36
Does amphotericin B deoxycholate need to be renally/hepatically dose-adjusted?
no
37
True or false: all lipid-associated formulations of amphotericin B have similar PK patterns.
false
38
What are the clinical uses for amphotericin B?
* disseminated candidiasis
* cryptococcosis
* aspergillosis
* histoplasmosis
* blastomycosis
* coccidioidomycosis
* mucormycosis
39
Should you pre-medicate when giving a test dose of amphotericin B deoxycholate?
no
40
What are the dosing rules for amphotericin B deoxycholate?
* test dose of 0.1 mg/kg or 1 mg over 20-30 minutes
* total daily dose of 0.3-1.0 mg/kg/day over 4-6 h (generally)
41
What can happen if amphotericin B deoxycholate is too rapidly infused in a patient with severely compromised renal function?
* acute hyperkalemia
* ventricular fibrillation
42
Data suggest that there are significantly fewer adverse events if amphotericin B deoxycholate is administered as a continuous infusion over \_\_\_\_\_\_\_\_\_\_\_.
24 hours
43
How should you administer intrathecal/intraventricular amphotericin B deoxycholate?
start with 0.1 mg and gradually increase to max 0.5 mg q48-72 h
44
How should liposomal amphotericin B be dosed/administered?
1.5-6 mg/kg daily, infused over 2 h
45
What is the recommended daily dose for ABLC?
5 mg/kg
46
Which patient weight should be used for dosing amphotericin B?
ideal body weight (or adjusted body weight)
47
What infusion-related adverse reactions can occur with amphotericin B deoxycholate?
* headache
* fever/chills
* arthralgias/myalgias
* N/V
* tachypnea
* hypotension
* thrombophlebitis
48
What should be used to pre-treat infusion-related reactions from amphotericin B deoxycholate?
* APAP or aspirin
* antihistamines
* meperidine
* phenothiazine
49
What can be used to combat thrombophlebitis reactions from amphotericin B deoxycholate?
add heparin 500-1000 units to infusion bag
50
What can be used to combat the non-thrombophlebitic infusion-related reactions from amphotericin B deoxycholate?
add hydrocortisone 25-50 mg to the infusion bag
51
What non-infusion-related adverse reactions are associated with amphotericin B deoxycholate?
* **nephrotoxicity (inreased SCr and BUN)**
* **HYPOkalemia**
* **HYPOmagnesemia**
* bicarbonate wasting
* anemia
52
How can we attempt to prevent thrombophlebitis from amphotericin B deoxycholate?
* infuse slowly (4-6 h)
* rotate infusion sites
* use in-line filters (\>0.22 micron)
53
Through what mechanism does amphotericin B deoxycholate produce nephrotoxic effects?
direct vasocontriction of afferent renal arterioles resulting in cortical ischemia and decrease in GFR
54
Is amphotericin B deoxycholate nephrotoxicity reversible?
no; permanent loss of renal function related to total dose
55
How can we prevent/manage nephrotoxicity associated with amphotericin B deoxycholate?
* sodium repletion (0.5-1 L NS 30 minutes before and after completion)
* hydration
* adjustment of daily dose
56
Is amophotericin B deoxycholate-associated anemia reversible?
yes
57
What adverse reactions can happen when amphotericin B deoxycholate is intrathecally administered?
* peripheral nerve pain
* headache
* vomiting
* paresthesias
* paraplegia
* seizures
* difficulty voiding
* impaired vision
58
True or false: lipid-associated amphotericin B formulations generally cause more nephrotoxicity and infusion-related toxicities.
false; less nephrotoxicity and infusion-related toxicities
59
High-dose liposomal amphotericin (7.5 mg/kg/d) is associated with high _______________ rates.
nephrotoxicity
60
How should we manage infusion-related reactions from liposomal amphotericin B?
diphenhydramine
61
Amphotericin B can interact with what drugs?
* other nephrotoxic drugs
* digoxin
* skeletal muscle reactions
* flucytosine (used together for cryptococcal meningitis)
62
Describe flucytosine's oral absorption.
well-absorbed orally
63
Does flucytosine penetrate the CSF adequately?
yes
64
How is flucytosine affected by hemodialysis and peripheral dialysis?
removed by HD and PD
65
What is flucytosine's primary clinical use?
in combination with amphotericin B for cryptococcal meningitis
66
What adverse reactions are associated with flucytosine?
* **Hematologic (bone marrow suppression)**
* GI (N/V/D, abdominal pain, enterocolitis)
67
What is the recommended dose range for flucytosine in patients with normal renal function?
25-37.5 mg/kg q6h
68
Should flucytosine be renally/hepatically dose adjusted?
yes for renal, no for hepatic
69
How should flucytosine be renally dose adjusted?
as ClCr worsens, continue to double the dosing interval
70
Which patient weight is used to dose flucytosine?
IBW if non-severe, AdjBW if severe
71
What baseline parameters should be monitored in patients taking flucytosine?
* CBC
* platelets
* SCr
* BUN
72
What is the goal peak concentration for flucytosine?
70-80 μg/mL (drawn 2 hours post-dose after 3-5 days)
73
At what peak concentration is flucytosine associated with increased toxicity?
\> 100 μg/mL
74
What trough concentration range is recommended to prevent rapid selection of resistance in yeast for patients taking flucytosine?
20-40 μg/mL
75
Describe ketoconazole's oral absorption.
well-absorbed orally; inversely-related to gastric pH
76
Does ketoconazole penetrate the CSF?
no; negligible CSF penetration
77
Ketoconazole is extensively metabolized in the \_\_\_\_\_\_\_\_.
liver
78
The major excretory route of ketoconazole is \_\_\_\_\_\_\_\_\_\_\_\_.
enterohepatic
79
Ketoconazole's elimination pattern can best be described as \_\_\_\_\_\_\_\_\_\_\_\_\_.
biphasic
80
Does ketoconazole need to be renally/hepatically dose adjusted?
doesn't need to be renally adjusted, contraindicated in acute/chronic liver disease
81
When should ketoconazole be used 1st line for fungal infection?
NEVER! This is due to risk of hepatotoxicity and drug interactions.
82
What are the clinical uses of ketoconazole?
* chronic mucocutaneous candidiasis
* histoplasmosis (in immunocompetent hosts)
83
What adverse reactions are associated with ketoconazole?
* GI (N/V/D, anorexia, abdominal pain)
* **hepatotoxicity**
* **endocrine (gynecomastia, decreased libido, oligospermia, hair loss, menstrual irregularities)**
84
Ketoconazole is a VERY potent inhibitor of CYP\_\_\_\_.
3A4
85
What drugs may interact with ketoconazole?
* drugs that affect gastric pH
* anticoagulants
* rifampin
* cyclosporine/tacrolimus/sirolimus
* phenytoin
86
Describe itraconazole's oral absorption.
good and **dependent on gastric acidity**
87
Which formulation of itraconazole is better absorbed in a fasting state?
oral solution
88
Which formulation of itraconazole is better absorbed when taken with a meal or acidic cola beverage?
capsules
89
Which formulation of itraconazole is better absorbed: oral solution or capsules?
oral solution
90
Is SUBA-itraconazole affected by gastric acidity?
no; may be given **with** or without food
91
Describe itraconazole's CSF penetration.
poor
92
What is the active metabolite of itraconazole?
hydroxyitraconazole
93
Does itraconazole need to be renally/hepatically dose adjusted?
no
94
What are the clinical uses for itraconazole?
* **histoplasmosis (DOC)**
* aspergillosis
* blastomycosis
* life-threatening infections
* onychomycosis
95
What is the goal serum trough itraconazole concentration associated with efficacy?
\> 0.5-1 μg/mL
96
What itraconazole serum concentration is associated with increased adverse events?
\> 3 μg/mL
97
What adverse events are associated with itraconazole?
* **hepatotoxicity**
* **CHF (boxed warning)**
* **QTc prolongation**
* peripheral neuropathy
* GI (nausea, abdominal discomfort)
* rash
98
In what groups is itraconazole contraindicated?
* ventricular dysfunction (CHF)
* history of CHF
* pregnancy
* nursing
99
What is the drug of choice for histoplasmosis?
**itraconazole** 200 mg PO TID x 3 days, then 200 mg PO BID
100
What drugs will interact with itraconazole capsules to decrease their absorption?
* H2 antagonists
* PPIs
* antacids
101
Itraconazole is a potent inhibitor of CYP\_\_\_.
3A4
102
What drugs' concentrations will be increased in administered with itraconazole?
* digoxin
* quinidine
* benzodiazepines
* HMG-CoA reductase inhibitors (not pravastatin)
* rifabutin
* cyclosporin/tacrolimus/sirolimus
* protease inhibitors (ritonavir, indinavir, saquinavir)
103
What drugs' concentrations will be decreased if given with itraconazole?
* carbamazepine
* phenytoin
* phenobarbital
* rifampin
* rifabutin
* nevirapine
104
What drugs can increase the concentration of itraconazole?
* clarithromycin
* indinavir
* ritonavir
105
What *Candida* is fluconazole NOT active against?
*C. krusei*
106
Describe fluconazole's oral absorption.
well-absorbed orally; **independent of gastric activity**
107
Describe fluconazole's CSF penetration.
good
108
Does fluconazole need to be renally/hepatically dose adjusted?
yes for renal, no for hepatic
109
What are the clinical uses for fluconazole?
* non-invasive candidiasis (OPC, EC, vaginal)
* invasive candidiasis
* bone marrow transplant prophylaxis
* *Candida* UTI
* cryptococcal meningitis (inferior for induction, **okay for consolidation and maintenance**)
110
What patient weight should be used for fluconazole dosing?
TBW (total body weight)
111
What adverse reactions are associated with fluconazole?
* **QTc prolongation**
* headache
* nausea
* anorexia
* torsades de pointes
* elevation of hepatic transaminases
112
Fluconazole is a potent inhibitor of CYP\_\_\_\_ and a moderate inhibitor of CYP\_\_\_\_.
2C9; 3A4
113
Describe voriconazole's oral bioavailability.
good; **NOT affected by H2 antagonists, PPIs, antacids**
114
What key counseling point should be included when telling patients about voriconazole administration?
tablets and PO suspensions should be taken 1 hour before or after meals
115
Voriconazole is significantly metabolized by \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_.
**CYP2C19, 2C9, 3A4**
116
Voriconazole's metabolism is ______________ and its pharmacokinetics are \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_.
**saturable; non-linear**
117
Does voriconazole need to be renally/hepatically dose adjusted?
for renal, avoid IV voriconazole in ClCr \< 50 (PO is okay)
decrease PO maintenance dose in hepatic cirrhosis
118
What are the clinical uses for voriconazole?
* invasive aspergillosis
* candidemia in nonneutropenic patients and other deep-tissue *Candida* infections
* esophageal candidiasis
* scedosporiosis and fusariosis
119
Adults who weigh \< 40 kg should receive _______ of the oral maintenance dose of voriconazole.
half
120
What patient weight should be used when dosing voriconazole?
IBW or adjusted body weight
121
What adverse reactions are associated with voriconazole?
* **visual disturbances**
* **elevated LFTs**
* **QTc prolongation**
* CNS (cognitive difficulties, memory loss)
* peripheral neuropathy
* phototoxic skin reactions
* periostitis secondary to excess fluoride
122
What voriconazole trough range is associated with clinical response?
\> 1-1.5 μg/mL
123
What voriconazole trough range is associated with a higher incidence of CNS adverse events?
\> 5-6 μg/mL
124
What drug class can decrease the oral absorption of posaconazole suspension?
PPIs (absorption affected by gastric pH)
125
What is the preferred oral formulation of posaconazole?
DR tablets (absorption not affected by gastric pH)
126
Most of posaconazole is recovered in \_\_\_\_\_\_\_\_.
feces
127
At what CrCl should IV posaconazole be avoided?
\< 50 mL/min (IV formulation contains cyclodextrin)
128
What are the clinical uses of posaconazole?
* invasive *Candida* or *Aspergillus* prophylaxis in immunocompromised patients
* oropharyngeal candidiasis (+ refractory to fluconazole/itraconazole)
* may be used as salvage therapy for aspergillosis or *Mucor* infections
129
What posaconazole trough concentration is associated with higher incidence of breakthrough fungal infections during prophylaxis with suspension?
\> 0.7 μg/mL
130
What posaconazole trough concentration is associated with treatment response for invasive aspergillosis?
\> 1 μg/mL
131
Posaconazole is a strong inhibitor of CYP\_\_\_.
3A4
132
What drug is CONTRAINDICATED with posaconazole?
sirolimus
133
What adverse events are associated with posaconazole?
* **QTc prolongation**
* elevated LFTs
* hypokalemia
* GI (N/V/D, abdominal pain)
* rash
134
Isavuconazole has __________ pharmacokinetics.
linear
135
Describe isavuconazole's oral absorption.
well-absorbed orally
136
Does isavuconazole need to be renally/hepatically dose adjusted?
no
137
Does the isavuconazole IV formulation contain cyclodextrin?
no
138
What are the clinical uses for isavuconazole?
* invasive aspergillosis in patients 18+
* invasive mucormycosis in patients 18+
139
What administration tip would you give to a patient taking isavuconazole oral capsules?
swallow whole; do not crush/chew/dissolve/open
140
What adverse effects are associated with isavuconazole?
* GI (N/V/D)
* headache
* increased LFTs
* infusion-related reactions (hypotension, dyspnea, chills, dizziness, paresthesias, hypoesthesia); discontinue if these occur
* HYPOkalemia
* hypersensitivity and severe skin reactions (anaphylaxis, Stevens Johnson)
141
Does isavuconazole cause QTc prolongation?
no
142
Isavuconazole is a substrate for CYP\_\_\_.
3A4
143
Isavuconazole is a mild inhibitor of \_\_\_\_\_\_\_\_\_\_\_.
P-glycoprotein
144
When is isavuconazole contraindicated?
* strong CYP3A4 inhibitors (e.g. ketoconazole, high-dose ritonavir)
* strong CYP3A4 inducers (e.g. rifampin, carbamazepine, St. John's wort, long-acting barbiturates)
* familial short QT syndrome
145
What genes encode for glucan synthase expression?
FKS1 and FKS2
146
Describe the echinocandins' oral bioavailability.
poor (administered IV)
147
Caspofungin plasma concentration declines in a _________ manner.
polyphasic
148
Caspofungin is slowly metabolized by __________ and \_\_\_\_\_\_\_\_\_\_.
hydrolysis; N-acetylation
149
Does caspofungin need to be renally/hepatically dose adjusted?
no for renal, only dose-adjust for severe hepatic dysfunction
150
What is caspofungin indicated for?
* candidemia
* esophageal candidiasis
* empiric therapy of presumed fungal infections in febrile neutropenia
* invasive aspergillosis in patients who are refractory to or intolerant to other therapies
151
Does caspofungin induce or inhibit any CYP450s?
no
152
What drug interactions can occur with caspofungin?
* tacrolimus
* cycosporine
* inducers of drug clearance (efavirenz, nelfinavir, nevirapine, phenytoin, rifampin, carbamazepine)
153
What adverse reactions are associated with caspofungin?
* histamine-mediated symptoms (rash, face swelling, pruritus, flushing)
* fever
* phlebitis at infection site
* N/V
* headache
* increased liver transaminases
* decreased potassium
* eosinophilia
* increase in urine protein and RBCs
* decreased hemoglobin/hematocrit
154
Micafungin is metabolized by the \_\_\_\_\_\_\_\_\_.
liver
155
Does micafungin need to be renally/hepatically dose adjusted?
no
156
What are the clinical uses for micafungin?
* EC and OPC
* candidemia
* aspergillosis
* *Candida* prophylaxis in HSCT
157
Is micafungin metabolized by any CYP450s?
no
158
What adverse reactions are associated with micafungin?
* hyperbilirubinemia
* N/D
* eosinophilia
* rash, pruritus, urticaria (rare)
159
How is anidulafungin eliminated?
through slow chemical degradation
160
Should anidulafungin be renally/hepatically dose adjusted?
no
161
What are the clinical uses for anidulafungin?
* candidemia and other *Candida* infections (peritonitis, intra-abdominal abscess)
* EC
162
What drug interactions are of concern with anidulafungin?
none; not a substrate/inducer/inhibitor of CYP450
163
What adverse reactions are associated with anidulafungin?
* histamine-mediated symptoms (rash, urticaria, flushing, pruritus, hypotension)
* diarrhea
* increased LFTs
* hypokalemia
164
Describe ibrexafungerp's oral absorption.
good; **dependent on gastric acid and better absorbed with food**
165
How is ibrexafungerp's CSF penetration?
poor
166
91% of ibrexafungerp is recovered in \_\_\_\_\_\_\_.
feces
167
What are the clinical uses for ibrexafungerp?
VVC in adults and post-menarchal pediatric females
168
In what patient group is ibrexafungerp contraindicated?
pregnancy; **use effective contraception during and for 4 days after treatment**
169
What adverse reactions are associated with ibrexafungerp?
* GI (N/V/D, abdominal pain)
* dizziness
170
Does ibrexafungerp cause QTc prolongation?
no
171
Ibrexafungerp is a weak inhibitor of CYP\_\_\_\_\_ and \_\_\_\_\_.
3A4; 2C8
172
What drug type should be avoided with ibrexafungerp?
strong/moderate CYP3A4 inducers
173
What adverse reactions are associated with anidulafungin?
* histamine-mediated symptoms (rash, urticaria, flushing, pruritus, hypotension)
* diarrhea
* increased LFTs
* hypokalemia
