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ATU > Antifungals > Flashcards

Antifungals Flashcards

1
Q

What are the two forms of oropharyngeal candidosis in HIV ?

A

Pseudomembranous and erythematous

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2
Q

Which form of oropharyngeal seen in HIV is more common in younger patients ?
- what is the presentation

A

Pseudomembranous oropharyngeal candidosis

  • cottage cheese appearance in mouth and throat
  • very low CD40 (
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3
Q

What is the presentation of erythematous oropharyngeal candidosis?

A

Inflamed sore mouth, most commonly in older people

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4
Q

What is the main complication of oropharyngeal candidosis?

A

Oesophagitis, occurs in 10-20%

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5
Q

Name the main AIDS defining illnesses

A
  • pneumocystis jiroveci pneumonia
  • Kaposi’s sarcoma
  • cryptococcal meningitis
  • oropharyngeal candidosis
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6
Q

Which cells does HIV infect ?

A

CD4+ - t helper cells

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7
Q

What is the causative organism of oropharyngeal candidosis, which species is most common?

A

Candida spp - c. Albicans in 50-60%

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8
Q

Which species of candida is intrinsically resistant to fluconazole and ketoconazole ?

A

C. Krusei

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9
Q

Which species of candida are more common causes of IV catheter infections and endocarditis than C. Albicans ?

A

C. Parapsilosis and c. Tropicalis

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10
Q

Which candida species is often found colonising patients receiving fluconazole prophylaxis ?

A

C. Krusei

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11
Q

Which species of candida are associated with low survival rates in ICU patients?

A

C. Glabrata

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12
Q

Which WBC is most important in fighting fungal infections ?. And therefore which patients are of particular risk ?

A

Neutrophils

- neutropenic patients

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13
Q

What is the quick, inexpensive test to differentiate dermatophytes and C. Albicans from other skin conditions (e.g. Psoriasis)

A 
KOH test (potassium hydroxide preparation)
- shows either fungi or no fungi, doesn't identify specific organisms
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14
Q

As C. Krusei is intrinsically resistant to some azoles (flu and keto-conazole), and less susceptible to other azoles and AmpB, which class of antifungal does it remain susceptible to ?

A

Echocandins

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15
Q

C. Lusitaniae is frequently resistant to which antifungal?

A

AmpB

*susceptible to azoles

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16
Q

Aspergillus terreus is resistant to which antifungal?

A

AmpB

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17
Q

Why is AmpB reserved for severe infections and those in immunocompromised patients ?

A

Extensive side effects

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18
Q

The discovery of azoles coincided with the emergence of which disease ?.

A

HIV/AIDS

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19
Q

Which antifungal agent has gynaecomastia as a side effect and why?

A

Ketoconazole, inhibits testosterone synthesis ?

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20
Q

Name the 5 newer azoles

A
  • fluconazole (1991)
  • itraconazole (1992)
  • voriconazole (2003)
  • posaconazole (2007)
  • isavuconazole (2015)

*ALL triazoles

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21
Q

Name the clinically relevant imidazoles

A
  • clotrimazole
  • miconazole
  • ketoconazole

*others available but rarely used

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22
Q

What is the mode of action of the imidazoles?

A
  • inhibit ergosterol synthesis (main sterol in fungal cell membrane)
  • bind to CYP450
  • interfere with demethylation of 14-a-methyl sterol intermediates
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23
Q

Are azoles fungistatic or fungicidal?

A

Mostly fungistatic, may be cidal at v high concentrations

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24
Q

Side effects of fluconazole ?

A

Generally well tolerated, may have abnormal LFTs

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25
Q

Which organisms is fluconazole mostly used to treat?

A

Candida spp. And Cryptococcus spp.

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26
Q

What is the mechanism of resistance in C. krusei to fluconazole ?

A

Diminished sensitivity of target enzyme CytP450 sterol 14-a-demethylase (CYP51) to inhibition by azole agents

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27
Q

Which study showed that the use of fluconazole to treat recurrent OPC in HIV/AIDS patients correlates with development of resistance?

A

Redding et al 1994

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28
Q

Which antifungal is the worst for drug interactions ?

A

Itraconazole

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29
Q

What is itraconazole mainly used to treat?

A
  • fluconazole resistant Candida spp.

- Aspergillus spp.

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30
Q

Which organisms does itraconazole have limited activity against ?.

A
  • fusarium spp.

- Zygomycetes

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31
Q

In the study by Cartledge 1997, what percentage of C. albicans isolates from OPC in HIV patients were resistant to at least 2 azoles?

A

20% - suggests some cross resistance

  • 13% to fluconazole and ketoconazole
  • 7% to f and k + itraconazole
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32
Q

In the study by cartledge 1997, what percentage of the fluconazole resistant isolates (C. Albicans from OPC in HIV patients) were sensitive to Itraconazole ?

A

59% - suggests a good second line option in fluconazole resistant cases

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33
Q

In a study by Muller (2000), on azole sensitivity in C. albicans in recurrent OPC in children with AIDS, describe the findings about cross resistance

A
  • 59% fluconazole resistance
  • of those 60% also showed itraconazole resistance
  • of those 67% also had high MICs for voriconazole
  • success high levels of cross resistance, propensity of C. Albicans to develop MDR in patients with AIDS
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34
Q

What did White, 1997, conclude about the genetic basis of the development azole resistance and cross resistance?

A

Resistance develops gradually as the sum of several different changes, all contributing to the final resistance phenotype

  • phenotype can remain stable for 600 generations
  • levels of fluconazole resistant increased 200 fold over 2 years- due to selective pressure of recurrent OPC treatments
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35
Q

What is MDR1 and what is its significance in candida spp.?

A
  • membrane transport protein of major facilitator family, ATP dependent efflux pump which broad substrate specificity
  • in candida was found to correlate with fluconazole resistance (white 1997)
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36
Q

Which ABC transporter Confers resistance to azoles in candida spp.?

A
  • CDR

- associated with cross resistance with itraconazole and ketoconazole as well as fluconazole (white 1997)

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37
Q

What does the ERG16 gene encode?

- what type of mutation causes azole resistance

A
  • 14-a- lanosterol demethylase

- point mutation can confer resistance to azoles in candida spp

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38
Q

Genetic knockouts of the transport proteins CDR and MDR1causes what effect in Candida spp.? (White 1997)

A

Hypersensitivity to antifungals

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39
Q

Name two ways the advent of HAART therapy for HIV/AIDS affected the incidence and virulence of candida infections

A
  • less susceptible patients

- protease inhibitors inhibit the aspartic acid (virulence factor of candida which acts as cytolysin in macrophage)

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40
Q

Risk factors for severe oral candiasis

A
  • immunosupression e.g. Diabetes, HIV
  • dentures
  • inhaled corticosteroids
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41
Q

First line treatment for oral candidosis

A
  • mild = oral miconazole gel or nystatin

- mod - severe = fluconazole (oral)

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42
Q

A study (thompson 2010) found that 81% of HIV patients were colonised with oral Yeast, what percentage of these were fluconazole resistant ?

A

25%!

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43
Q

Is Aspergillus a mould or yeast ?

A

Mould

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44
Q

Which species of Aspergillus most commonly cause human disease?

A
  • A. fumigatus (90%)
  • A. flavus
  • A. niger
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45
Q

Outline the factors influence disease form and severity in Aspergillus infection

A
  • growth rate (fumigatus= fastest)
  • spore size (fumigatus=smallest, deep into lung)
  • protection against host defences (hydrophobic coat of conidia)
  • adherence I.e. To epithelium (fumigatus most effective)
  • enzyme/toxin e.g. Aflatoxin from A. flavus
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46
Q

What are the host defences against Aspergillus ?

A
  • lung macrophages
  • T cells (allergic and chronic)
  • complement
  • neutrophils (damage hyphae)
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47
Q

What is the treatment of choice for Aspergillus infections ?

A 
Liposomal AmpB (expensive)
Voriconazole or caspofungin
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48
Q

What is the gold standard diagnostic method for invasive Aspergillus infection and why is it not often used?

A

Histology

- invasive and most patients are too ill

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49
Q

What are the benefits of amBisome over conventional AmpB?

A
  • fewer infusion related side effects
  • less nephrotoxicity

*equivalent efficacy but much more expensive

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50
Q

A mutation in which gene is associated with azole resistance in A fumigatus ?

A

CYP51A

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51
Q

How does azole resistance occur in patients who have had no exposure to azoles ?

A
  • azole use in agriculture e.g. Azole fungicides
  • azole use in animal farming e.g. Avian farms
  • azole use in other humans
  • selective pressure favours de novo mutations which occur during treatment, or in plant pathogens etc
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52
Q

What is the mortality rate in voriconazole resistant aspergillosis compared with azole susceptible aspergillosis ?

A
  • resistant = 88%

- susceptible = 39-53%

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53
Q

Why are aspergillomas difficult to treat and often associated with increased resistance ?.

A
  • hyphae packed tightly, antifungals not diffusing through, only reaching outer layers
  • not successful in killing fungi, so antifungal presence drives selection pressure favouring resistant strains
54
Q

Are fungi eukaryotic or prokaryotic ?

A

Eukaryotic

55
Q

Which carbohydrates are characteristic of a fungal cell wall?

A
  • chitin

- B-1-3-glucan

56
Q

Most fungi are saprotrophs, what does this mean?

A

They obtain their nutrients from dead or decomposing matter by absorbing solvable organic compounds

57
Q

Define facultative parasite

A

Primarily a saprotroph but when opportunity presents can become a parasite

*generally more aggressive and likely to kill host than obligate parasite which weakens host but does not kill it (as this would probably kill itself too)

58
Q

Define parasite

A

Heterotroph deriving nutrition from the living cells of another organism

59
Q

Define hetertroph

A

Cannot make own food, gains nutrition by absorption

60
Q

Hyphae and mycelium are characteristic of Yeasts or moulds?

A

Moulds

61
Q

Name the antifungals in the polyene class

A
  • AmpB

- nystatin

62
Q

What is the mode of action of griseofulvin ?.

A

Mitosis inhibition - prevents chromosomes separating

63
Q

Clotrimazole, miconazole and ketoconazole are in which class of azoles ?

A

Imidazoles

64
Q

What class of antifungal is terbinafine? MOA?

A

Allylamine - targets ergosterol synthesis

65
Q

What is the mode of action of echinocandins?

A

Fungal cell wall - inhibits glucan synthase, which prevents the formation of B-1-3-glucan

66
Q

What is the MOA of flucytosine?

A

Inhibits DNA synthesis

-

67
Q

Name the 3 classes of antifungal which target the cell membrane

A
  • polyenes - bind ergosterol
  • azoles - inhibit lanosterol 14a-demethylase
  • allylamines - inhibit squalene epoxidase
68
Q

which antifungal targets mitosis?

A

Griseofulvin

69
Q

What does squalene epoxidase do?

A

Catalyses squalene to lanosterol in ergosterol synthesis pathway

70
Q

AmpB treats most yeasts and moulds, what are the Important exceptions that AmpB cannot treat?

A
  • Aspergillus terreus

- Scedosporium

71
Q

What type of fungal infections is nystatin used to treat?

A

Most yeasts, NOT used for moulds - only used topically

72
Q

Why can flucytosine not be used as a monotherapy, which agents is it used in combo with

A

Resistance develops rapidly

- used with AmpB or fluconazole

73
Q

Treatment for cryptococcal meningitis

A

AmpB and flucytosine

74
Q

Why must serum levels be monitored in flucytosine therapy ?

A

Can cause Hepatotoxicity and bone marrow suppression

75
Q

Which is the only antifungal to target the cell wall?

A

Echinocandins

76
Q

Which subunit do echinocandins bind to in order to inhibit B1,3-D-glucan synthesis

A

Fks1p

77
Q

Which gene mutation is implicated Cross resistance to 5FC and fluconazole in C. lusitaniae ?

A

Point mutation in fcy2 gene

  • codes for cytosine permease
  • causes truncated proteins due to premature stop codon
78
Q

The sensitivity of Aspergillus to which antifungal is pH dependent ?

A

Flucytosine

- at 7= resistant at 5= sensitive

79
Q

Describe the mechanism of resistance to AmpB

A
  • reduced ergosterol in membrane
  • mutations in ERG3 coding for sterol desaturase resulting in resistance in in C. Albicans
  • increased catalase activity may reduce oxidative damage caused by AmpB
80
Q

Mechanism of resistance to terbinafine

A
  • v. Rare
  • substitution mutations in squalene epoxidase gene
  • seen in Trichophyton rubrum
81
Q

Name the 6 different mechanisms by which resistance to azoles can develop

A
  1. Transporter upregulation (efflux)
  2. Target modification
  3. Target upregulation
  4. Absence of target
  5. Decease in toxic metabolite (ERG3 none sense mutation)
  6. Formation of multicellular complex (biofilm)
82
Q

Which two families if efflux pump are involved in azole resistance and which genes encode them ?

A
  • ATP binding cassette (ABC) family - CDR gene

- major facilitator (MFS) family - MDR gene

83
Q

Upregulation in the gene encoding MFS efflux pump causes resistance to which antifungals in Candida spp.

A

Fluconazole and voriconazole

84
Q

In Candida albicans what genes regulate CDR1/2 and MDR1

A

TAC1 and MRR1 respectively

85
Q

What is the mechanism of resistance to fluconazole in C. Krusei ?

A
  • innate resistance

- non-susceptible demethylase enzyme I.e. Absence of target

86
Q

What is the mechanism of resistance to fluconazole in Aspergillus fumigatus?

A

Target modification - structural changes in 14a- lanosterol demethylase

87
Q

Which study identified the point mutation in the fcy2 gene which conferred cross resistance to 5FC and fluconazole in C. Lusitaniae ?

A

Florent, 2009

88
Q

Which study proved that fluconazole resistance in A fumigatus was due to structural differences in lanosterol demethylase?

A

Martel 2010

- expressed CYP51A gene from A fumigatus in S cerevisiae which then became fluconazole resistant

89
Q

Accumulation of 14a-methyl fecosterol in fungal membrane has what effect ?

A

Tolerated and can replace ergosterol, therefore can resist azoles and AmpB
*due to loss of function mutations in ERG3 gene

90
Q

Gain of function mutation in which gene resulting in antifungal resistance also results in reduced virulence ?

A

UPC2 - regulates CYP51A In C albicans

91
Q

Which antifungal is quadriphasic ? How ?

A

Echinocandins

* high levels up regulate chitin biosynthesis and cell wall integrity pathway e.g. Protein kinase C

92
Q

Which antifungals are used in prophylaxis?

A

Fluconazole, itraconazole, posaconazole

93
Q

Which antifungals are used for empirical therapy ?

A

AmpB and caspofungin

94
Q

Define pharmacokinetics

A

Study of the movement of drugs into, within and out of the body
I.e. What the body does to the drug

95
Q

Define pharmacodynamics

A

The relationship between drug concentration and effect

I.e. What the drug does to the body

96
Q

Absorption of AmpB ?

A

IV

*some studies show that significant intestinal absorption into systemic circulation following oral admin (diglyceride-phospholipid formulation) with pharmacokinetics and bio distribution similar to IV prep in rat models (Gershkovich et al 2009)

97
Q

What % of AmpB is protein bound ?

A

95%

98
Q

Outline the areas of high, medium and low distribution of AmpB in the body

A

High: liver and spleen
Med: lung and kidney
Low: heart and brain

99
Q

Half-life of AmpB ?

A

Initially 24-26hrs then 15d (owing to high % protein bound)

100
Q

Dosing interval of AmpB

A

Once daily

101
Q

Elimination route of AmpB

A

Bile (34%)
Urine (21%)
Renal (3%)

102
Q

Wishy does the dose of AmpB not need adjusting for kidney function?

A

As it is mainly excreted via metabolism, only 3% renal

103
Q

Why must AmpB be injected but flucytosine is not ?

A

Flucytosine has v good absorption from digestive tract, whereas AmpB has minimal

104
Q

Compare the distribution of AmpB and flucytosine

A 
Flucytosine = high in tissues and fluids
AmpB = poor distribution
105
Q

Excretion of flucytosine

A

> 90% in urine/kidneys, unchanged

106
Q

Half life of flucytosine

A

3-6h - because it is minimally bound to proteins

107
Q

Dosing interval of flucytosine

A

3-4x daily

108
Q

% protein binding of fluconazole, and what is the consequence of this?

A

11-20% - low

  • better penetration into aqueous sites e.g. Eye, CSF, synovial fluid
  • volumes of distribution that approximate total body water
109
Q

Which classes of antifungals have variable tissue penetration but tend to have prolonged residence times?

A

Echinocandins and polyenes

110
Q

Which of the azoles are more lipophilic and what does this result in?

A

Itraconazole and posaconazole

  • larger vol of distribution
  • penetrate preferentially into tissues with high lipid content
111
Q

Which azoles have high oral availability ?

A
  • fluconazole (95%) no food effect
  • voriconazole (96%) fasting
  • isavuconazole (98%)
  • posaconazole tablet (82%)
112
Q

Azoles are metabolised by which cytochrome P450 enzyme?

A

CYP3A4

113
Q

Which azoles is gastric pH clinically relevant to ?

A

Itraconazole and posaconazole

114
Q

Variation in which cytochrome enzyme can cause a 5 fold difference in voriconazole levels between individuals ?

A

CYP2C19

115
Q

Name the factors that are genetically variable and can result in inter individual variation in antifungal efficacy

A
  • absorption - gastric pH, p-GP/MDR1
  • distribution - variation in plasma proteins
  • metabolism - polymorphisms in CYP
  • elimination - transporters
116
Q

What are the factors affecting antifungal susceptibility testing? (4)

A
  • Inoculum size and form
  • pH, lower pH = higher MIC
  • medium
  • incubation temp and duration
117
Q

Disc diffusion susceptibility testing is suitable for which antifungals ?

A

Water sol e.g. Flucytosine, fluconazole, voriconazole

Echinocandins

118
Q

Problems with disc diffusion method?

A
  • over estimates resistance

- poor inter lab reproducibility

119
Q

How do you read off MIC in E tests?

A

MIC read at point at which zone intersects the strip

120
Q

Problems with E test method of susceptibility ?

A
  • trailing end points
  • finishing lines unclear
  • subjective
  • not good with fastidious organisms e.g. Cryptococcus neoformans
121
Q

What is Yeats one sensititre method used for ?

A

Susceptibility testing of candida spp to echinocandins (anidulafungin, caspofungin and micafungin)
- MIC determination

122
Q

What is the gold standard method of antifungal susceptibility testing ? What its main disadvantage ?

A

CLSI: M27-A3 yeast broth dilution

- contamination

123
Q

How do you measure the end point in CLSI: M27-A3 yeast broth dilution test?

A

Look for significant reduction in growth, NOT where growth stops

124
Q

What are the main differences between the CLSI and EUCAST methods of yeast broth dilution susceptibility testing ?

A
  • Inoculum - less used in EUCAST

- endpoint - generally lower in EUCAST

125
Q

What are the fluconazole clinical break points for EUCAST and CLSI yeast broth dilution methods ?

A

Susceptible: 64 (CLSI) >4 (EUCAST)

126
Q

What is the 90-60 rule ?

A

Infections due to susceptible isolates respond to therapy 90% of the time, resistant isolates respond 60% of the time

127
Q

Key parameter in azoles?

A

AUC/MIC

128
Q

Key parameter in polyenes ?

A

Cmax/MIC

129
Q

Key parameter in echinocandins ?

A

Cmax/MIC or AUC/MIC

130
Q

4 reasons to monitor drug levels in antifungal therapy ?

A
  • variation in absorption
  • interactions with other drugs affects levels
  • toxicity with higher levels
  • correlation between concentration levels and efficacy

ATU (3 decks)

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