Id: Fungal Infections

Front 1

4 Common subtypes of fungi

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1. Yeasts
2. Moulds
3. Dimorphic Fungi
4. Dermatophytes

Front 2

Name the subtypes of the 4 common subtypes of fungi

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1. Yeasts:
a. Candida
b. Cryptococcus

2. Moulds
a. Aspergillus
b. Fusarium (exception: in blood, not tissues)
c. Zygomycetes

3. Dimorphic Fungi
a. Histoplasma
b. Blastomyces
c. Coccidoides

4. Dermatophytes
a. Trichophyton
b. Microsporon

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Trichophyton

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Dermatophyte

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Microsporon

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Dermatophyte

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Coccidoides

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Dimorphic fungi

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Histoplasma

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Dimorphic fungi

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Blastomyces

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Dimorphic fungi

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Aspergillus

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Moulds

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Fusarium

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Moulds

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Zygomycetes

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Moulds

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Candida

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Yeasts

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Cryptococcus

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Yeasts

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Antifungal Agents

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Griseofulvin
Polyenes (Nystatin & Amphotericin B)
Amphotericin B
5FC
Terbinafine
Azoles
Echinocandins (caspofungin, micafungin, anidulafungin)

Front 14

Griseofulvin

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Common dosing for adults with normal renal function
• Microsize (Grifulvin V®) – 500-1000 mg/day in single or divided doses
• Ultramicrosize (Gris-PEG®) – 330-375 mg/day in single or divided doses

MOA – Inhibits fungal cell mitosis and nucleic acid synthesis; binds to human keratin making it
resistant to fungal invasion (fungistatic)

SOA – Dermatophytes

PK
• Eliminated hepatically
• Take with a fatty meal to increase absorption

ADRs – Photosensitivity, headaches, dizziness, drowsiness, rash, urticaria

DIs – Weak inducer of CYP 1A2, 2C8/9, 3A4
• May decrease the effect of warfarin and oral contraceptives
• Barbiturates may decrease griseofulvin concentrations
• Disulfiram like reaction with alcohol

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Nystatin

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Common dosing
• Oral suspension – 400,000-600,000 units swish and swallow QID
• Lozenge – 200,000-400,000 units QID
• Vaginal tablet – 100,000 unit tablet every 24 hrs
• Topical – apply topically BID-TID
• No IV b/c too much toxicity

MOA – Binds to ergosterol in fungal cell membrane → increased cell membrane permeability →
loss of intracellular contents → cell death (fungicidal)

Spectrum of Activity (SOA) – Candida spp. only

PK – Poor oral absorption

ADRs – Contact dermatitis with topical application on skin
Give Nystatin lozenge or the swish and swallow kind to someone who has thrush

Front 16

Which antifungal is eliminated hepatically?

Back 16

Griseofulvin,
terbinafine,
ketoconazole, itraconazole, voriconazole, posaconazole, caspofungin, and micafungin are eliminated hepatically

Front 17

Which antifungal causes disulfiram-ilke reaction with alcohol?

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Griseofulvin

Front 18

Which drug class decreases griseofulvin's concentrations

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Barbiturates

Front 19

Which CYP450 enzymes does griseofulvin induce?

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CYP1A2
CYP2C8/9
CYP3A4
T/f decreases effectiveness of warfarin and oral contraceptives

Front 20

Nystatin is available in 4 formulations:

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Oral suspension, lozenge, vaginal tablet, topical

Front 21

What is the MOA of griseofulvin?

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Inhibits fungal cell mitosis and nucleic acid synthesis. Binds to human keratin making it resistant to fungal invasion (fungistatic).

Front 22

What is the SOA of griseofulvin?

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Dermatophytes

Front 23

What is the MOA of nystatin?

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Binds to ergosterol in fungal cell membrane -> increased cell permeability -> loss of intracellular contents -> cell death (fungicidal)

Front 24

What is the SOA of nystatin?

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Candida

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Amphotericin B

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• Amphotericin B deoxycholate (conventional, Fungizone®)
o Common dosing – 0.25-1 mg/kg IV every 24 hrs
• Amphotericin B lipid complex (ABLC, Abelcet®)
o Common dosing – 5 mg/kg IV every 24 hrs
• Amphotericin B cholesteryl sulfate (colloidal dispersion, ABCD, Amphotec®)
o Common dosing – 3-6 mg/kg IV every 24 hrs
• Liposomal amphotericin B (AmBisome®)
o Common dosing – 3-5 mg/kg IV every 24 hrs
Don’t need to remember doses but know that the doses change according to the formulation!
MOA – Binds to ergosterol in fungal cell membrane → increased cell membrane permeability →
loss of intracellular contents → cell death (fungicidal)

SOA – Very broad spectrum! Yeasts (not C. lusitaniae), Aspergillus spp. (except A. terreus, variable for A. flavus), Zygomycetes, dimorphic fungi

PK
• Eliminated by the reticuloendothelial system
• Deoxycholate has good CNS activity despite poor CNS penetration (clinically useful)

ADRs “Ampho-terrible”
• Infusion related toxicities (lower incidence with liposomal, similar incidence with ABCD)
o Fever, chills, rigors, myalgias, nausea, headaches
o Tolerance does develops after 1-2 doses

o Prevention/Management of infusion related toxicities
 Slow down the rate of infusion (usually infused over 2-6 hrs)
 Give as a continuous infusion (but this is tricky b/c then needs separate IV line, check compatibility with other medications)
 Premedications 30-60 minutes prior to administration
• APAP, aspirin, NSAID – prevent fevers, myalgias
• Diphenydramine – causes drowsiness, blocks histamine release
• Hydrocortisone – interferes with cytokine pathway
• Typically give APAP plus diphenhydramine
 Symptomatic treatment
• Meperidine – to treat rigors
• Chlorpromazine, other antiemetics – to reduce nausea

• Nephrotoxicity (lower incidence with lipid formulations but will occur with any formulation)
o Glomerular: increased BUN and serum creatinine
o Tubular: K+ and/or Mg2+ wasting
o Prevention/Management
 0.5-1 L normal saline 30-60 min prior to every dose
 Replacement of electrolytes
• Others: phlebitis, anemia, lipid formulations may cause a pulmonary reaction, liposomal may cause hyperbilirubinemia

DIs
• Other nephrotoxins (e.g. aminoglycosides, vancomycin, cyclosporine)
• Incompatible with many IV solutions – risk of precipitation

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There are four formulations of Amphotericin B:

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1. Amphotericin B deoxycholate (conventional, Fungizone®)
o IV
2. Amphotericin B lipid complex (ABLC, Abelcet®)
o IV
3. Amphotericin B cholesteryl sulfate (colloidal dispersion, ABCD, Amphotec®)
o IV
4. Liposomal amphotericin B (AmBisome®)
o IV

Front 27

What is the MOA of amphotericin B?

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Binds to ergosterol in fungal cell membrane → increased cell membrane permeability → loss of intracellular contents → cell death (fungicidal)

Front 28

What is the SOA of amphotericin B?

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very broad spectrum!
Yeasts (not C. lusitaniae), Aspergillus spp. (except A. terreus, variable for A. flavus), Zygomycetes, dimorphic fungi

Front 29

Which drug is eliminated by the reticuloendothelial system?

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Amphotericin B

Front 30

Why is Amphotericin B called "Ampho-terrible"?

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• Infusion related toxicities (lower incidence with liposomal, similar incidence with ABCD)
o Fever, chills, rigors, myalgias, nausea, headaches
o Tolerance does develop after 1-2 doses

• Nephrotoxicity (lower incidence with lipid formulations but will occur with any formulation)
o Glomerular: increased BUN and serum creatinine
o Tubular: K+ and/or Mg2+ wasting

• Others: phlebitis, anemia, lipid formulations may cause a pulmonary reaction, liposomal may cause hyperbilirubinemia

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Meperidine

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treats rigors.
Rigors is one of the infusion-related toxicities associated with Amphotericin B infusion.

Front 32

What drugs interact with amphotericin B?

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Other nephrotoxins (aminoglycosides, vancomycin, cyclosporine)
Incompatible with many IV solutions b/c of risk of precipitation (give it in its own separate IV line)

Front 33

Antimetabolite- Flucytosine

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Common dosing – 25-37.5 mg/kg PO Q 6 hrs
• Increase dosing interval for renal dysfunction based on Clcr

MOA – Inhibits fungal RNA, DNA, and protein synthesis

SOA – Yeasts (used with other agents only, resistance develops rapidly when used alone)
Never give Fluocytosine alone! Usually given in combination with Amphotericin B for pneumococcal meningitis b/c it has excellent CNS penetration
PK
• Excellent CNS penetration
• Eliminated renally
• Therapeutic range is 25-100 mcg/mL (to decrease risk of bone marrow suppression)

ADRs – Dose-related bone marrow suppression, GI upset, rash, photosensitivity, increased
BUN/serum creatinine

DIs
• Other bone marrow suppressive agents (zidovudine, chemotherapeutic drugs, TMP/SMX)
• Caution with nephrotoxins due to risk of accumulating flucytosine

Front 34

What is the SOA of Flucytosine?

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Yeasts (but must use 5FC with other agents! Cannot be used for monotherapy.)

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How is 5FC eliminated?

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renally

Front 36

What drugs interact with 5-FC?

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• Other bone marrow suppressive agents (zidovudine, chemotherapeutic drugs, TMP/SMX)
• Caution with nephrotoxins due to risk of accumulating flucytosine

Front 37

Allylamine- Terbinafine (Lamisil)

Back 37

Common dosing
• Oral
o Not recommended if Clcr < 50 mL/min
o Not recommended in chronic or active liver disease
• Topical – apply topically BID

MOA – Inhibition of squalene epoxidase → decreased ergosterol → increased cell membrane
permeability → loss of intracellular contents → cell death (fungicidal)

SOA – Dermatophytes, Candida spp.

PK
• Eliminated hepatically
• Distributed mostly to the skin and skin structures

ADRs – Headache, dizziness, rash, pruritus, GI upset, taste disturbance, visual disturbance, LFT
elevations, hepatitis

DIs
• CYP 2D6 inhibitor – may increase concentrations of tricyclic antidepressants, cyclosporine, theophylline, warfarin
• Rifampin may induce terbinafine metabolism
• Cimetidine may inhibit terbinafine metabolism

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Terbinafine can be administered ____ and ____.

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orally and topically.

Front 39

What is the MOA of terbinafine?

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Inhibition of squalene epoxidase → decreased ergosterol → increased cell membrane permeability → loss of intracellular contents → cell death (fungicidal)

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How is terbinafine eliminated?

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Hepatically

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What drugs do terbinafine interact with?

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it is a CYP2D6 inhibitor so it may increase concentrations of TCAs, cyclosporine, theophylline, warfarin.
Rifampin might induce terbinafine metabolism while cimetidine may inhibit terbinafine metabolism.

Front 42

Azoles-name some of the topical azoles.

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Clotrimazole, econazole, miconazole, butoconazole, ticonazole, terconazole

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What dosage forms do topical azoles come in?

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Topical azole dosage forms:
Vaginal tabs, creams, or suppositories
Topical creams, solutions, and sprays for the skin,
Oral troches

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Azoles- name some of the Systemic Azoles

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Ketoconazole
Fluconazole (Diflucan)
Itraconazole
Voriconazole
Posaconazole

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Ketoconazole comes in 3 forms:

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Oral, topical, shampoo

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Fluconazole comes in 2 forms:

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IV & PO

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Itraconazole comes in:

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PO only

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Voriconazole comes in 2 forms:

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IV & PO

Front 49

Posaconazole comes in:
(See hint)

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PO. (take with a fatty meal)

Hint 49

Remember that POsaconazole is PO only

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SOA of topical azoles

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Candida (yeasts), dermatophytes

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SOA of systemic azoles

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See notes p.10

Front 52

Which is the broadest spectrum azole?

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Posaconazole

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Which two azoles have excellent oral BA as well as CNS penetration?

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Fluconazole and voriconazole

Front 54

How are the systemic azoles eliminated?

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Ketoconazole, Itraconazole, Voriconazole, and posaconazole are all eliminated hepatically.

Exception is fluconazole, renally.

Front 55

The order of CYP3A4 inhibition in decreasing order

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keto > itra ≥ vori ≥ posa > flu
(But later she wrote that Keto is not included in this?? Which one is correct?)

Front 56

Echinocandins include:

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Caspofungin, micafungin, Anidulafungin

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MOA of Echinocandins

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Inhibit the synthesis of Beta (1,3) D glucan, an essential part of the fungal cell wall (fungicidal)

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SOA of echinocandins

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Candida (variable for parapsilosis), Aspergillus

Front 59

How are the echinocandins eliminated?

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Caspofungin and micafungin-hepatic
Anidulafungin - nonenzymatic degradation

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DIs of Echinocandins

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• Rifampin, phenytoin, carbamazepine, dexamethasone, efavirenz, and nevirapine may induce caspofungin metabolism
o May need to increase dose of caspofungin to 70 mg IV every 24 hrs
• Cyclosporine may increase caspofungin concentrationsª
• Caspofungin may decrease tacrolimus concentrationsª
• Micafungin may increase sirolimus and nifedpine concentrationsª
ª but these are not very clinically significant as compared to azole drug interactions

Front 61

Which antifungal(s) is/are effective against Dermatophytes?

Back 61

Griseofulvin & Terbinafine (Lamisil)