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Microbiology Part 2 > Lec41 Antifungals > Flashcards

Lec41 Antifungals Flashcards

1
Q

What are the 3 main targets for antifungal therapy?

A

cell membrane: fungi use argosterol instead of cholesterol
DNA synthesis: restricted to serious infections because more side effects
cell wall: fungi have cell wall, we do not

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2
Q

What are two types of cell wall inhibitors?

A

inhibitors of glucan synthesis = echinocandins

inhibitors of chitin synthesis = nikkomycin

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3
Q

what is mech of action of cell membrane inhibitors? example?

A

they inhibit ergosterol synthesis

- azoles

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4
Q

What type of antifungal causes direct cell membrane damage?

A

polyenes

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5
Q

What are the two types of polyene antibiotics?

A
  • amphotericin B

- nystatin [topical]

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6
Q

What are the classifications of systemic azole antibiotices?

A

imidazoles: ketoconazole
triazoles: itraconazole, fluconazole,
2nd gen triazoles: voriconazole, posaconazole

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7
Q

What are benefits of azoles for systemic use?

A
  • broad therapeutic window, wide spectrum of activity, low toxicity
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8
Q

What is mech of action of azoles?

A
  • bind lanosterol 14a-demethylase a P450 enzyme responsible for production of ergosterol
  • thus blocks ergosterol production
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9
Q

What are potential side effects of azoles?

A
  • azoles act by blocking a fungus cyt p450 enzyme, may see cross reactivity with human cyt p450
  • – drug interactions
  • – impairment of steroidneogenesis [keto, itra]
  • nausea, vomiting, rash –> more likely with high doses and AIDS
  • may cause hepatotoxicity
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10
Q

What are advantages and disadvantages of fluconazole?

A

advantages: low side effects, both IV/PO formations, high bioavailability
- favorable pharmacokinetics

disadvantages: fungistatic, resistance is increasing, narrow spectrum, possible p450 drug interactions

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11
Q

What is fluconazole good for treating?

A
  • primarily used for Candida albicans, cryptococcus neoformans
  • also active against dermatophytes [trichophyton], dimorphic fungi
  • see primary resistance in many non-albicans candida
  • -> C. krusei always resistant
  • -> C glabrata often resistant
  • -> tropicalis rarely resistant
  • no activity against aspergillus or most mould fungi
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12
Q

What are fluconazoles drug interactions

A
  • iincreases phenytoin, cyclosporin, rifabutin, warfarin, zidovudine conc
  • rifampin reduces fluconazole level to half
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13
Q

Can fluconazole penetrate CSF?

A

yes very well

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14
Q

What is bioavailability to fluconazole?

A

very high >90% means little difference between oral and IV forms

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15
Q

What can itraconazole treat?

A
  • similar candida coverage as fluconazole [C albicans, C tropicalis, sometimes C. globrata, never C. krusei]
  • also can treat aspergillus
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16
Q

How is fluconazole cleared?

A

mostly renal

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17
Q

How is itraconazole excreted?

A
  • hepatic metabolism and via bile
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18
Q

Can itraconazole pentetrate the CSF?

A

nope! so not good for meningeal fungal infection

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19
Q

Is there an oral form of itraconazole?

A

yep but not very good absorption

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20
Q

what can voriconazole treat?

A
  • very broad
  • includes most candida, aspergillus, fusarium
  • can’t treat zygomycoses
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21
Q

Is there an oral form of voriconazole?

A

Yep with >90% bioavailability

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22
Q

How is voriconazole cleared?

A

mostly hepatic

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23
Q

Can voriconazole penetrate CSF?

A

Yep! good for meningitis

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24
Q

What are adverse side effects of itraconazole?

A
  • nausea and vomitting
  • osmotic diarrhea
  • taste disturbances
  • maybe hepatic
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25
Q

What are adverse side effects of voriconazole?

A
  • nausea and vomitting
  • visual disturbances [reversible, decreased vision, altered color perception, worse with IV than oral]
  • hallucination in 2-5%
  • hepatic
  • rash
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26
Q

Of fluconazole, itraconazole, and voriconazole whihc have most drug interactions?

A
  • itraconazole has strong interactions
  • voriconazole moderate - strong
  • fluconazole weak

inhibit cyp 34A

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27
Q

What is fluconazole usually used to treat?

A
  • invasive or mucocutaneous candidiasis
  • maintenance therapy for cryptococcal meningitis
  • coccidiodomycosis
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28
Q

What is itraconazole usually used to treat?

A
  • azole of choice for invasive histoplasma, blastomycosis, sporothrix
  • dermatophyte infections and onychomycosis
29
Q

What is voriconazole usually used to treat?

A
  • drug of choice for invasive aspergillosis

- cancer/neutropenia prophylaxis

30
Q

What is posaconazole usually used to treat?

A
  • prevent mold infections in patients with neutropenia/cancer [only have oral form
31
Q

How is psaconazole administered? what is it used to treat?

A
  • broad activity including against zygomycetes
  • only oral form
  • requires fatty meal for absorption
  • use for prophylaxis prevention of invasive mold infections in pts at risk
32
Q

What is terbinafine used to treat?

A
  • its a systemic antifungal agent but used to treat superficial fungal infections
  • mainly used for onychomycosis
33
Q

What is mech of terbinafine? side effects?

A
  • interferes with ergosterol synthesis
  • no drug interactions
  • can cause liver inflammation
34
Q

How is terbinafine administered?

A

orally

35
Q

What is nystatin? what do you treat? side effects?

A
  • a topical polyene
  • treat mucocutaneous candidiasis [oral thrush]
  • little toxicity
36
Q

What is clotrimazole? what do you treat? side effects?

A
  • a topical azole antifungal
  • treat mucocutaneous candidiasis, dermatophyte infections
  • little toxicity
37
Q

What is amphotericin B? mech of action?

A
  • amphoteric polyene macrolide
  • binds sterols in fungal cell membrane
  • creates transmbembrane channel and electrolyte leakage [creates pores]
38
Q

What is amphotericin B active against?

A

active against most fungi except aspergillus terreus, scedosporium

39
Q

What are side effects of original amphotericin? what are the new preparation?

A
  • classic formulation –> serious toxic side effects, renal damage
  • lipid associated formulations make it less toxic [liposomal amphotericin B {L-AMB}, amphotericin B colloidal dispersion {ABCD}, amphotericin B lipid complex {ABLC}]
40
Q

What are the drug names for the 3 different lipid formulatiosn of amphotericin B?

A 
ambisome = L-AMB
albecet = ABLC
amphotec = ABCD
41
Q

What are side effects of amphotericin B as administered?

A
  • renal toxicity
  • — increase renal vascular resistance –> low GFR, azotemia = accumulation of urea in blood stream
  • — increase tubular permeability –> distal tube ischemia, wasting of K, Na, Mg
  • get bigger renal effects in pts volume depleted or on concomitant nephrotoxic agents –> MAKE SURE PT HAS FLUIDS
42
Q

What is amphotericin B used to treat?

A
  • standard antifungal therapy –> drug of choice for:
  • – cryptococcal meningitis
  • – mucormycosis in combo with surgery
  • – induction therapy for histoplasmosis
  • – invasive fungal infections that don’t respond to other therapy
  • cannot tret: aspergillus terreus, scedosporium, some candida lusitanae, maduralla, some paecilomyes
43
Q

What is flucytosine [5FC]? administration?

A
  • anti-metabolite against DNA/RNA symthesis
  • marketed as Ancotil
  • IV or oral administration
44
Q

What are side effects of fluytosine [5FC]? When do you particularly need to monitor?

A
  • vomitting, diarrhea
  • altered liver function tests
  • bone marrow toxicity
  • need to monitor blood conc of drug when used in conjunction with amphotericin B
45
Q

What do you treat with flucytosine?

A
  • fungistatic and fungicidal acativity against yeasts, only fungistatic against aspergillus fumigatus
46
Q

What is mech of action of echinocandins?

A
  • inhibit fungal cell wall synthesis of glucan

- loss of cell wall glucan –> osmotic fragility

47
Q

What can echinocandins be used to treat?

A
  • fungicidal against: most candida species including non-albicans, pnseumocystis carinii
  • acive but usually not fungicidal against: aspergillus
  • no activity against cryptococcus neoformans
  • no activity against other molds: fusarium, zygomycosis, trichosporon
48
Q

What are 2 drugs of choice for aspergillus?

A
  • floriconazole

- amphotericin

49
Q

What are the 3 echinocandins?

A
  • capsofungin
  • micafungin
  • anidulafungin
50
Q

What are adverse effects of capsofungin?

A
  • mostly mild and do not require treatment discontinuation
  • usually infusion related: intravenous site irritation, mild to moderate infusion related fever/headache/flushing/erythema/rash
  • asymptomatic increase serum transaminases
51
Q

What are common causes of fungal endopthalmitis?

A
  • candida albicans most common [slow progression, better prognosis]
  • aspergillus [rapid progression, vision threatening]
52
Q

What are predisposing factors to fungal endopthalmitis?

A
  • invasive disease
  • immunosuppression
  • malignancy
  • long term broad spectrum antibiotics
  • neutropenia
  • organ transplant
  • dialysis
  • AIDS
  • liver disease
  • indwelling cathers
  • IV drug use
53
Q

What are signs of fungal endopthalmitis?

A
  • decreased vision
  • photoboia
  • pain
  • red eye
  • viritis [esp. in aspergillus]
  • pseudo-hypopynon [layering exudate]
  • retinal findings
54
Q

What is treatment for fungal endopthalmitis?

A
  • usually systemic amphotericin + intravitreal administration
  • or: systemic fluconazole, systemic flucytosine, systemic and intravitreal voriconazole
55
Q

Which fungi are dimorphic?

A
  • histoplasma
  • coccidioides
  • blastomyces
  • paracoccidioides
  • penicillium
56
Q

What are major treatments for candida?

A
  • fluconazole
  • amphotericin
  • echinocandins
57
Q

What are major treatments for cryptococcus neoformans?

A
  • amphotericin [maybe with combined 5FC]

- fluconazole for prophylaxis

58
Q

What are major treatments for histoplasma?

A
  • amphotericin
  • itraconazole
  • voriconazole
59
Q

What are major treatments for blastomyces dermatidis?

A
  • amphotericin
  • itraconazole
  • fluconazole
60
Q

What are major treatments for coccidioides?

A
  • amphotericin

- then fluconazole in immunosuppressed

61
Q

What are major treatments for paracoccidioides brasiliensis?

A
  • itraconazole, amphotericin B, or TMP-SMX
62
Q

What are major treatments for penicillium marneffei?

A
  • amphotericin and 5FC
63
Q

What is treatment for zygomytes?

A
  • surgical debridement with amphotericin

- posaconazole for prophylaxis

64
Q

What is treatment for aspergillus?

A
  • voriconazole or amphotericin for invasive disease
65
Q

What is treatment for pnseumocystis jiroveci?

A
  • TMP-SMX
66
Q

What is major treatment for topical dermatophytes

A

topical meds –>

67
Q

What is major treatment for eumycetoma?

A
  • surgical

- posaconazole on compassionate bases

68
Q

What is major treatment for sporotrichiosis?

A
  • itraconazole [sporonox]

Microbiology Part 2 (30 decks)

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