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Flashcards in Antifungals Deck (133):
1

TRUE/FALSE
 

Terbinafine is a tricyclic antifungal

FALSE

Terbinafine is an allyamine antifungal

2

What type of antifungal is Flucytosine?

Fluorinated pyrimidine

3

Name two inhibitors of chitin synthesis and cell wall synthesis

Lufenuron

Caspofungin

4

Can you label this diagram?

Q image thumb

5

Know this

Q image thumb

6

Azoles are broken down into two categories. What are they?

Imidazoles - ketoconazole, miconazole, econazole, enilconazole

Triazoles – Itraconazole, fluconazole, voriconazole, posaconazole, ravuconazole

7

What is the primary target of azole antifungals?

Primary target of azoles is the heme protein which catalyzes cytochrome p450-dependent 14a-demethylation of lanosterol.

Inhibition of  14a-demethylase leads to depletion of ergosterol and accumulation of sterol precursors including 14a-methylated sterols (eg. lanosterol)

Results in formation of a plasma membrane with altered structure and function

8

Do we use Ketoconazole in cats?

Not really - high incidence of s/e

9

TRUE/FALSE

Ketoconazole has activity against: 

Microsporum, Trichophyton, Malassezia, Blastomycosis, Candida (resistance documented), Coccidioides, Cryptococcus, Histoplasma (higher dose), Aspergillus (some efficacy 43%), Sporothrix (higher doses)

TRUE

Ketoconazole has activity against: 

Microsporum, Trichophyton, Malassezia, Blastomycosis, Candida (resistance documented), Coccidioides, Cryptococcus, Histoplasma (higher dose), Aspergillus (some efficacy 43%), Sporothrix (higher doses)

10

How does ketoconazole block ergosterol synthesis?

Blocks fungal ergosterol synthesis by blocking cytochrome p450 enzyme lanosterol 14-demethylase

11

How long does it take for ketoconazole to establish steady state and effective concentrations in the skin?

10-14 days 

12

Ketoconazole has known anti-inflammatory/immune modulating activity. What is the proposed mechanism of this?

Inhibition of 5-lipooxygenase 

Suppresses T-lymphocytes

13

Is ketoconazole fungistatic or fungicidal?

Fungistatic! 

But - it is fungicidal at high doses for long periods of time!

14

Ketoconazole inhibits __________ which blocks deoxycorticosterone to corticosterone.

Ketoconazole inhibits 11-hydroxylase which blocks deoxycorticosterone to corticosterone.

15

Ketoconazole is metabolized in the _________. 

Ketoconazole is metabolized in the liver

16

Ketoconazole absorption is enhanced when given with _____. 

 

Ketoconazole absorption is enhanced when given with fats

17

Why would you not want to co-administer ketoconazole with an antacid?

Acidic stomach environment favors absorption! 

18

What are the main side effects of ketoconazole? How often does this happen? Dogs vs. cats. 

  • Occur in 10-14% dogs and 25% cats
    • More common with doses >10mg/kg/day
  • SIDE EFFECTS:
    • GI = most common 
    • Hepatotoxicity - cholangiohepatitis, increased LE, icterus
    • Fever
    • Neurological abnormalities
    • Pruritus
    • Cataracts
    • Alopecia
    • Reversible lightening of the hair (loss of guard hairs)
    • Endocrine effects
      • Steroid synthesis inhibited by blocking p450
        • Reduction in testosterone +/or cortisol synthesis can occur with doses as low as 10mg/kg
        • Effects on mineralocorticoids negligible

19

TRUE/FALSE

Ketoconazole is widely distributed when given

TRUE

Ketoconazole is widely distributed. 

Bile, cerumen, saliva, urine, synovial fluid, milk, CSF.
High levels in liver, kidneys, adrenals, pituitary
Moderate levels in lungs, bladder, bone marrow, myocardium
Major routes of delivery to the stratum corneum via sweat, sebum, incorporated into basal keratinocytes

20

What is the excretion of ketoconazole?

Primarily into feces via bile

Approximately 13% of dose excreted in the urine

2-4% of the drug is excreted unchanged in urine

21

What are the major contraindiciations for ketoconazole?

Hepatic disease

Thrombocytopenia

Stress – due to effects of cortisol synthesis

Pregnancy

Teratogen

Crosses placenta in rats

Cats? Hepatotoxic effects possible

Drug hypersensitivity

22

Should you give ketoconazole with mitotane?

No. 

Adrenolytic effects of mitotane may be inhibited by ketoconazole inhibition of cytochrome p450 enzymes

23

You just prescribed rifampin and ketoconazole. What should you remember about this drug interaction?

Rifampin can decrease ketocoazole 

Ketoconazome can increase rifampin

24

Why does ketoconazole increase cyclosporine levels?

Ketoconazole inhibits CYP 3A4 enzyme system 

Inhibit this - increase cyclosporine

25

Are anticoagulants affected by ketoconazole?

Yes! If you inhibit the CYP 2C9 enzyme system, you can enhance the effect of anticoagulants. 

26

Ivermectin and Ketoconazole. Friends or foes?

Giving these at the same time can increase risk of neurotoxicity

27

What are the indications for use of fluconazole?

  • Malassezia, Blastomycosis, Histoplasmosis, Coccidioidomycosis, cryptococcosis, sporotrichosis
  • May be useful for treatment of candidiasis, dermatophytosis
    • Not as effective as other azoles)
  • CNS and ocular fungal infections
  • +/- Aspergillus
  • Fungal urinary tract infections
  • Deep and intermediate mycoses

28

What are two main benefits of using fluconazole over ketoconazole?

  1. Increased potency and wider spectrum of activity than ketoconazole
  2. No effect on hormone synthesis

29

Is fluconazole fungistatic or fungicidal?

Fungistatic

30

What is the mechanism of action of fluconazole?

Inhibition of cytochrome P450 14a-demethylase 

31

Which drug has the best bioavailability of the azole antifungals?

Fluconazole

(90% in dogs, 100% in cats)

32

Is fluconazole affected by food/gastric pH?

Nope!

33

Does fluconazole achieve good penetration to the CSF? What about other parts of the body?

Yes - fluconazole has a wide distribution of activity

34

How long does it take for fluconzole to achieve steady state plasma levels?

6-14 days 

35

How much of fluconazole is excreted in urine?

70%

36

Contraindications for use of fluconazole...

Hepatotoxicity

Renal failure/impairment 

Hypersensitivity 

Pregnancy 

37

Here is a little Budgie. What medication should you not use in this bird?

Q image thumb

FLUCONAZOLE

38

Does fluconazole have endocrine effects?

No

39

You notice that a patient has elevated ALT while on fluconazole. Is this common?

15-20% dogs treated long term may have an elevated ALT

40

Fluconazole increases the serum level of various drugs.

Can you name 3 of them?

Aminophylline, buspirone, cisapride, cyclophosphamide, cyclosporine, fentanyl, glipizide, midazolam, NSAIDs, rifabutin, theophylline 

41

What is the main indication for use of itraconazole?

Blastomycocis 

Feline dermatophytosis

 

Considered 1st line treatment for non-life threatening systemic mycoses not involving the CNS. Aspergillosis, cryptococcal meningitis, blastomycosis, coccidioidomycosis, sporotrichosis and histoplasmosis. Can also be a useful adjunctive treatment for pythiosis, lagendosis, zygomycosis, phaoehyphomycosis and hyalohyphomycosis. 

42

Itraconazole is fungicidal. Right?

Nope. It is fungistatic. 

43

How does itraconazole work?

Blocks fungal ergosterol synthesis via inhibition of cytochrome P450 enzyme lanosterol 14-demeythlase. 

Inhibitor of CYP3A4

44

TRUE/FALSE
 

Like fluconazole, itraconazole is not dependent on a low gastric pH for absorption. 

FALSE

Unlike fluconazole, itraconazole is dependent on a low gastric pH for absorption. 

When given on an empty stomach - 50% absorption

When given on a full stomach - 100% absorption

45

The skin has ______ x higher concentration of itraconazole than plasma.

The skin has 3-10 x higher concentration of itraconazole than plasma.

46

TRUE/FALSE

You can detect itraconaozle in the skin 2-4 weeks after therapy is discontinued. 

TRUE

You can detect itraconaozle in the skin 2-4 weeks after therapy is discontinued. 

47

Sporanox is formulated with cyclodextrin. What is that?

 

 

Cyclodextrin is a ring of glucose molecules that can accept a lipophilic guest molecule within the ring. Enables the ITZ molecule to be delivered already adequately dissolved to the lipid interface of the gut lumen and absorbed without the cyclodextrin ring.

Enhances ITZ absorption

48

Itraconazole is metabolized in the ________. 

The active metabolite is _______. 

Itraconazole is metabolized in the liver

The active metabolite is hydroxyitraconazole

49

You have a patient with heart disease. Any special precautions that you should take with itraconazole?

Use caution. It could have a negative inotropic effect.

50

TRUE/FALSE
There is a dose related maternotoxicity, fetotoxicity and teratotoxicity for itraconazole. 

TRUE

There is a dose related maternotoxicity, fetotoxicity and teratotoxicity for itraconazole. Usually at doses of > 10 mg/kg/day.

51

This bird comes to you with a fungal infection. After trying to convince them to see another dermatologist, you then remember that you cannot use which drug in this species? 

Itraconazole. 

Leads to depression and anorexia.

52

Anorexia is the most common side effect of itraconazole. When is this s/e usually noticed? 

In the 2nd month of treatment! 

53

TRUE/FALSE

Increased ALT secondary to hepatotoxicity is the most significant s/e of itraconazole

TRUE

Increased ALT secondary to hepatotoxicity is the most significant s/e of itraconazole

54

A patient has itraconazole toxicosis. Can you recommend dialysis? 

Nope. Dialysis can only remove fluconazole. 

55

What is unique about Posaconazole?

  • Inhibition of cytochrome p450 14a-demethylase
  • More potent inhibitor of sterol C14 demethylation 
  • Not extensively metabolised by CYP450 enzymes 
  • Primarily metabolised by uridine diphosphate glucuronosyltransferase (UGT) enzymes rather than cytochrome p450 (CYP450) enzymes

56

Rifampin and Posaconazole. Discuss. 

Rifampin induces CYP450, P-glycoprotein and UGT enzymes. Therefore, coadministration of rifampin and posoconazole results in reduced posoconazole concentrations.

57

TRUE/FALSE
Triazoles have higher specificity for cytochrome P450 than imidizoles

TRUE

 

Triazoles have higher specificity for cytochrome P450 than imidizoles. 

This makes them more potent

58

Is terbinafine fungicidal or fungistatic?

Terbinafine is a synthetic allylamine antifungal that is fungicidal and fungistatic. 

Fungicidal = dermatophytes
Fungistatic = Malassezia, Candida

59

Wow! Is it true that terbinafine can persist in adipose tissue, skin and nails for 2-3 months?!

Kind of. 

Adiopse tissue, skin = 2-3 weeks

Nails = 2-3 months 

60

How does terbinafine work?

Terbinafine is a squalene epoxidase inhibitor

This does this by blocking the enzyme squalene monooxygenase (squalene 2,3-epoxidase). This inhibits the conversion of squalene to sterols. 

61

TRUE/FALSE

Terbinafine is not mediated by cytochrome P-450 enzymes.

TRUE

Terbinafine is not mediated by cytochrome P-450 enzymes.

62

TRUE/FALSE

Terbinafine and itraconazole are both fungicidal against dermatophytes. 

 

FALSE

Terbinafine is fungicidal against dermatophytes. 

Itraconazole is fungistatic against dermatophytes.

63

You want to make a new kick ass topical containing terbinafine. Does the evidence suggest that this will be well absorbed?

Pump the brakes. Topical preparations of terbinafine are minimally absorbed (<5%). 

64

TRUE/FALSE

When compared to azole antifungals, terbinafine has less drug reactions. 

TRUE

When compared to azole antifungals, terbinafine has less drug reactions. 

65

Cimetidine has what effect on terbinafine...

Cimetidine increases blood concentration of terbinafine.

66

A cat seems lethargic on terbinafine. Has this been reported?

Yes. 

Lethargy, facial pruritus, urticaria, macular/papular skin eruption have been reported in cats. 

67

Should you give itraconazole and terbinafine together?

No. This could increase the potential for cardiotoxicity.

68

You prescribe Griseofulvin for Malassezia...

....and then you remember.....

You prescribe Griseofulvin for Malassezia...

....and then you remember.....

that this drug is not effective against yeast

69

What is the main indication for use of Griseofulvin?

Dermatophytosis! 

This drug has good penetration of nails and claws. 

70

Griseofulvin is fungicidal, right?

Nope. Fungistatic. 

71

How is Griseofulvin made?

Fermantation of Penicillium griseofulvum

72

How does Griseofulvin work? 

  1. Disrupts mitotic spindle formation 
  2. Arrests division at metaphase
  3. Inhibits cell wall formation 
  4. Inhibits nucleic acid synthesis 
  5. Possibly antagonizes chitin synthesis in fungal cell wall 

73

Why would you briefly consider the use of griseofulvin for the treatment of juvenile cellulitis?

Suppresses delayed-type hypersensitivity reactions.

But, your side effect potential probably outweighs the benefit. 

74

Why does griseofulvin work best with dividing (vs. dormant) cells?

Griseofulvin enters the cell through an energy dependent transport system. 

75

Can you prevent fungal reinfection with griseofulvin?

Yes. This is because it is deposited and concentrated in keratin precursor cells. When these cells differentiate, the drug will remain bound and persistent in the keratin. The new growth of hair, nails or horn will be free from fungal infection.

76

Which phase of cell division does griseofulvin arrest?

Metaphase

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77

Griseofulvin is metabolized by the __________ via __________ to an inactive metabolite called ___________. 

Griseofulvin is metabolized by the liver via oxidative demethylation/glucuronidation to an inactive metabolite called 6-desmethylgriseofulvin

78

Cats (and especially kittens) are more susceptible to idiosyncratic __________ when given griseofulvin. 

Cats (and especially kittens) are more susceptible to idiosyncratic bone marrow suppression when given griseofulvin. 

79

Would you recommend giving griseofulvin to a cat who is FeLV/FIV positive?

No way, Jose. 

The reason for this is that there is a risk of bone marrow suppression which could worsen their viral disease(s). 

80

Please list some side effects of griseofulvin

  • GI signs - anorexia, vomiting, diarrhea
  • Anaemia, neutropenia, leukopenia, thrombocytopenia
    • Bone marrow suppression
  • Depression
  • Ataxia
  • Hepatotoxicity
  • Dermatitis
  • Photosensitivity
  • Toxic epidermal necrolysis

81

TRUE/FALSE
Griseofulvin increases cyclosporine levels. 

FALSE

Griseofulvin decreases cyclosporine levels. 

82

When would you consider using flucytosine?

This drug is usually used in combination with other antifungal medications (azole antifungals, amphotericin B). 

The reason for this is because - when used alone - resistance can develop rapidly. 

83

Flucytosine is a ________ _________. 

Flucytosine is a fluorinated pyrimidine. 

84

Flucytosine is fungistatic, right?

Yes

Flucytosine = fungistatic 

85

What is a requirement for a fungal cell to be susceptible to flycytosine?

  • Fungal cells are susceptible if they contain the enzyme cytosine permease
    • Flucytosine can be taken into cell
    • Flucytosine deaminated by cytosine deaminase to fluorouracil
    • Fluorouracil acts an antimetabolite by competing with uracil
    • Interferes with pyrimidine metabolism and eventually RNA and protein synthesis

86

Flucytosine is an anti-metabolite because it competes with _______. 

Flucytosine is an anti-metabolite because it competes with uracil

87

You have a dog who has renal disease. You decide that he needs a plan for his fungal disease. What drug should you leave out of that plan?

Flucytosine

 

88

TRUE/FALSE

Flucytosine can cause dose-dependent bone marrow suppression. 

TRUE

Flucytosine can cause dose-dependent bone marrow suppression. 

(remember Griseofulvin causes IDIOSYNCRATIC BM suppression)

89

You're using flucytosine in a patient. What type of monitoring should you do?

Make sure you monitor renal function, CBC/platelets and LEs monthly

 

Renal function – at least twice weekly if concurrent amphotericin B

90

Drug eruption of flucytosine has been reported in dogs. Where were these reactions seen?

Scrotum and nasal planum

91

Amphotericin B. What are your main indications for using this drug?

Progressive, potentially fatal fungal infections

Treatment of severe, systemic mycotic infections

 

Blastomycosis, Candidiasis, Coccidiomycosis, Paracoccidiodes, Cryptococcosis, Histoplasmosis, Sporothrix

 

92

TRUE/FALSE

 

Amphotericin B is a great choice for treatment of Aspergillosis. 

FALSE

 

Amphotericin B is an ineffective choice for treatment of Aspergillosis. 

93

Amphotericin B...

Blasto/Histo/Coccidiodes: combine with _________.

Crypto/Candiasis: combine with __________.  

Amphotericin B...

Blasto/Histo/Coccidiodes: combine with ketoconazole.

Crypto/Candiasis: combine with flucytosine.  

94

TRUE/FALSE 

Amphotericin B is polyene macrolide that is produced by Streptomyces nodosus. 

TRUE

Amphotericin B is polyene macrolide that is produced by Streptomyces nodosus. 

95

What is the MoA of Amphotericin B?

Irreversibly binds to sterols (primarily ergosterol) in the cell membrane (bacterial and fungal). 

Alters the permeability of the membrane allowing intracellular potassium and other cellular constituents to leak out which results in cell death

96

Why might amphotericin B be toxic to mammals?

Well, because it also binds cholesterol. 

Ergosterol > cholesterol. But, still. 

97

What are the immunomodulatory effects of Amphotericin B?

  • Enhanced cell-mediated immunity
  • Stimulates lymphocyte, macrophage, and neutrophil function
  • Induces production of TNF

98

Does Amphotericin B have a unique mechanism of elimination?

Yes! It is biphasic

Initial serum half-life of 24-48 hours

Longer terminal half-life of ~ 15 days

Amphotericin B can still be detected in the urine seven weeks after therapy has stopped 

99

What are the side effects of Amphotericin B?

  • Hypokalemia
  • Anorexia, vomiting
  • Distal renal tubular acidosis
  • HypoMg
  • Phlebitis
  • Cardiac arrhythmias
  • Non-regenerative anaemia
  • Fever
  • Calcinosis cutis
  • Anaphylaxis
  • Muscle tremors
  • Cats are more sensitive
  • Horses: tachycardia, tachypnoea, lethargy, fever, restlessness, anorexia, phlebitis, PU, collapse 

100

The most common adverse effect of Amphotericin B is _________. 

The most common adverse effect of Amphotericin B is nephrotoxicity

Direct toxic effects on the distal tubules leads to loss of Na+, K+, and Mg++

Impaired urinary acidification and concentration → renal tubular acidosis

Hypokalaemia is typically the first sign of distal tubular toxicity. Hypokalaemia and hypomagnesiumaemia frequently precede increases in serum creatinine, especially in patients who are well hydrated or receiving lipid formulations of amphotericin B

101

What are your indications for use of iodides? 

Cattle – Actinomycosis, Actinobacillosis

Horses – Mycetomas, Zygomycosis, Sporotrichum schenckii

Dogs, cats - Sporotrichosis, SC phycomycocis, SC rhinosporidiosis 

102

What are the symptoms of iodisim?

  • Cats more prone
  • Excessive tearing (lacrimation), nasal discharge, vomiting, diarrhea
  • Muscle twitching, cardiomyopathy, hyperthermia
  • Scaly hair coats, anorexia, weight gain, coughing 
  • Leakin' and freakin'

103

What is lufenuron?

Benzoylphenylurea derivative that is an insect development inhibitor 

104

What is the theory behind use of lufenuron for fungal infections?

  • Non specific effect on chitin synthesis likely to be related to serine protease inhibition 
  • Proposed to interfere with fungal cell wall

105

When might you consider Caspofungin? 

Would this be rogue?

This is used in people for treatment of invasive aspergillosis or disseminated Candida infections. However, there is very little information on use in dogs and cats and, therefore, this can't be recommended. 

106

TRUE/FALSE

Interferon-g has been shown to enhance activity of phagocytes against fungi.

TRUE

Interferon-g has been shown to enhance activity of phagocytes against fungi.

107

TRUE/FALSE

 

Vaccines produced using Pythium insidiosum have been used to treat pythiosis in dogs and horses; efficacy seems higher in dogs.

FALSE

 

Vaccines produced using Pythium insidiosum have been used to treat pythiosis in dogs and horses; efficacy seems higher in horses.

108

How can ketoconazole affect the hair coat?

Lighten coat color

109

What is the first sign of nephrotoxicity associated with amphotericin B?

Hypokalemia

110

What parasite in rabbits can be treated or prevented with lufenuron?

Encephalitozoon cuniculi

111

What is the MOA of caspofungin?

Inhibition of B-glucan synthase

112

What fungal disease cannot be treated with caspofungin? Why?

Cryptococcus

Contains very little B-glucan synthase

113

What is the MOA of miconazole?

Inhibits ergosterol synthesis via inhibiting 14-a-demethylation

114

What anti-fungal is often used for nasal aspergillosis in dogs and poultry barn aspergillosis?

Enilconazole

115

What is the MOA of clotrimazole?

Inhibits lanosterol 14-a-demethylase

116

What topical can be used to treat yeast infections in nestling and adult birds?

Nystatin

117

What enzyme system metabolizes posaconazole?

Uridine diphosphate glucuronyosyltransferase (UGT)

118

TRUE/FALSE

Topical lime sulfur is effective against endo and ectothrix infections.

FALSE

Topical lime sulfur is effective against ONLY ectothrix infections.

Topicals have little effect on endothrix/hyphae within hair infections.

119

This antifungal has known antibacterial effects...

Miconazole

120

Can you please explain to me the mechanism of action of lime sulfur...

Lime sulfur has calcium polysulfides which convert to pentathionic acid and hydrogen sulfide after application. These are fungicidal and bactericidal. 

121

Name the enzyme that terbinafine inhibits

Squalene epoxidase

Blocks conversion of squalene to lanosterol

122

What antifungal decreases cyclosporine levels?

Griseofulvin

123

What is the current treatment of choice for histoplasmosis?

Itraconazole

124

What new antifungal shows promise for treating fungal CNS infections?

Voriconazole

125

What azole is particularly effective against Aspergillus?

Posaconazole

126

You have an animal with thrombocytopenia. Which azole antifungal should you avoid?

Ketoconazole.

127

High doses of this azole antifungal have been associated with vasculitis in dogs.

High doses of this azole antifungal have been associated with vasculitis in dogs

 

Itraconazole

128

TRUE/FALSE

The potency of each azole is related to its affinity for binding the cytochrome P450 moiety. 

TRUE

The potency of each azole is related to its affinity for binding the cytochrome P450 moiety. 

129

TRUE/FALSE

Compared with ketoconazole, fluconazole has increased potency, decreased toxicity, and wider spectrum of action.

TRUE

Compared with ketoconazole, fluconazole​ has increased potency, decreased toxicity, and wider spectrum of action.

130

Which (antifungal) drug does this apply to?

 

Do not give with cisapride or terfenadine – fatal cardiac arrhythmia can occur. 

ITRACONAZOLE

Do not give with cisapride or terfenadine – fatal cardiac arrhythmia can occur. 

131

Which drugs does fluconazole potentiate the activity of?

List 4

FCZ potentiates activity of anticoagulants, thiazide diuretics, rifampin, cyclosporine, glipizide, antihistamines, diphenyldantoin, and theophylline

132

Name that drug 

 

Inhibits ergosterol biosynthesis and squalene epoxidase, resulting in fungal cell wall ergosterol deficiency and intracellular accumulation of squalene. 

TERBINAFINE

Inhibits ergosterol biosynthesis and squalene epoxidase, resulting in fungal cell wall ergosterol deficiency and intracellular accumulation of squalene. 

133

This dog comes in for a recheck exam. He has been on itraconazole at 10 mg/kg for about 3 weeks. You notice these newer lesions on the neck. What are your thoughts?

Q image thumb

Ulcerative dermatitis secondary to itraconazole. This is a potential side effect of higher doses of this drug. 

 

Ulcerative dermatitis developed in 7.5% of dogs receiving 10 mg/ kg/day of ITZ, but it did not develop in any dog receiving 5 mg/kg/ day. Ulcers were usually focal, 1 to 2.5 cm in diameter, and circular, with ischemic dermis from an underlying vasculitis. The lesions healed quickly after ITZ was stopped. Lesions did not recur when ITZ was restarted at a decreased dose. This reaction must not be interpreted as a recurrence of blastomycosis.