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PDA Block 3 > Antifungals > Flashcards

Antifungals Flashcards

1
Q

Nearly __% of deaths due to nosocomial infections are due to fungi

_______ is responsile for 70%

A

40%; Candida

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2
Q

Predisposition to Serious Fungal Infections

A

Immunocompromised

  • Chemotherapy
  • Immunomodulation
  • Organ transplantation
  • AIDS

Broad spectrum antibacterials use

Indwelling catheters

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3
Q

Difficulties in Treating Fungal Infections

A
  • Fungi are Eukaryotes
  • Number of agents available for clinical use is small
  • Many fungal infections occur in poorly vascularized areas
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4
Q

Classification of Mycoses

A
  • Systemic
    • Debilitated or immunosuppressed patients
    • Geographically localized
    • Occupational
  • Superficial
    • Mucous membranes
    • Dermatophytic
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5
Q

Potential Antifungal Targets

A
  • Membranes (ergosterol)
  • Nucleic acids (limited)
  • Cell wall (1 drug class)
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6
Q

Drugs used for systemic fungal infections

A
  • Amphotericin B
  • Flucytosine
  • Imidazoles
    • Fluconazole
    • Itraconazole
    • Voriconazole
  • Caspofungin
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7
Q

Amphotericin B

  • Effective for:
A
  • Effective (broad spectrum agent) for most serious systemic mycoses
    • Especially those that are immediately life threatening
  • Gold standard for anti fungal effectiveness by which other drugs are judged
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8
Q

Amphotericin B is _______ at serum levels in humans

A

Fungistatic

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9
Q

Mechanism of Action: Amphotericin

A

Forms a pore in the fungal membrane - causes leaky membranes

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10
Q

Amphotericin B

Administration and Dosing:

A
  • Prolonged therapy usually necessary (6-12 weeks)
  • Administration
    • IV
    • Intrathecally or intraperitoneally
    • Not absorbed from GI tract
  • Total cumulative dose is also important for reasonse of permanent renal toxicity
  • Difficult to administer - highly lipophilic; amphotericin deoxycholate suspension (3 lipid forms now available)
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11
Q

Amphotericin - Side Effects

A

Ampho-Terrible

  • Fever, nausea, vomiting, headache, chills
  • Hypotension, hypokalemia, tachypnea
  • 90% will show nonpermanent nephrotoxicity
    • Permanent renal damage can occur
  • Reversible hypochromic, normocytic anemia
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12
Q

Flucystosine (5-FC)

Uses:

A
  • Serious infections
    • Candida, Cryptococcus
  • Used in conjunction with amphotericin B
  • Fungistatic
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13
Q

5-FC Mechanism of Action

A
  • Crosses fungal wall with cytosine permease
  • Fungal cytosine deaminase (5-FC →5-FU)
  • Inside the fungus
    • Inhibits thymidylate synthtease and thus DNA synthesis
    • Incorporated in RNA in place of Uracil
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14
Q

Flucytosine - Side Effects

A
  • Nausea, vomiting, diarrhea, enterocolitis
  • Leukopenia, thrombocytopenia
  • Reversible elevated hepatic enzymes
  • Use extreme caution in those with renal insufficiency or bone marrow depression
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15
Q

Other drugs for serious fungal infections (relative to amphotericin)

A
  • Narrower spectrum of action
  • Some not for immediately life-threatening infections
  • Have fewer/less serious side effects
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16
Q

Imadazole and Triazole antifungals for serious fungal infections

A
  • Fluconazole
  • Voriconazole
  • Itraconazole
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17
Q

Mechanism of action of imidazoles and triazoles

A
  • Inhibits 14-α-sterol demethylase, a fungal cytochrome P450 that converts lanosterol to ergosterol
  • Net effect is to inhibit ergosterol synthesis, which eventually leads to membrane instability
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18
Q

Fluonazole

Fungi and clinical use:

A
  • Cryptococcus: meningitis
  • Candida: many sites including CNS and urinary
  • Candida spectrum
    • Some albicans and glabrata
    • Not C. crusei
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19
Q

Itraconazole

Fungi and clinical use:

A
  • Blastomyces, Histoplasma
  • Candida: Esophagus and oropharynx (not CNS and urinary)
  • Candida spectrum
    • More albicans and glabrata
    • Some C. krusei in vitro
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20
Q

Voriconazole

Fungi and clinical use:

A
  • Aspergillus
  • Fusarium
  • Scedosporium
  • Cadida
    • Covers many species including glabrata and krusei
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21
Q

________ is superior to Amphotericin for invasive Aspergillus

A

Voriconazole

22
Q

Adminstration and Exretion of -azoles

Administration:

Elimination:

A

Administration: All Oral or IV

Elimination:

  • Fluconazole - 90% renal, unchanged
  • Itraconazole - Hepatic
  • Voriconazole - Hepatic, inactive metabolites in urine
23
Q

Exserohilum rostratum

A

Fungal meningitis due to contaminated steroid injections

Treat with Voriconazole + amphotericin B

24
Q

Side Effects common to -azoles

A
  • Nausea, vomiting, rash, diarrhea, headache
  • Mild hepatotoxicity
    • Discontinue with onset of liver dysfunction
  • Inhibit metabolism of several other drugs
    • Potent inhibitor of cytochrome P450s (CYP3A and 2C families)
25
Q

Itraconazole - contraindications

A
  • Do not give itraconazole with other drugs that are metabolized by CYP3A4
  • Potential for serious cardiovascular events including death
26
Q

_______ has the lowest incidence of hepatotoxicity among the -azole antifungals

A

Fluconazole

27
Q

Voriconazole Side Effects

A

Visual disturbances (30%)

Photosensitive component to rash

Contraindicated with St. John’s wort

28
Q

Anti-fungal that targets cell wall

A

Caspofungin

29
Q

Caspofungin

Uses:

Other species treated:

Mechanism:

A

Uses: Treatment of invasive Aspergillus

Other species treated: Candida, esophageal and systemic

Mechanism: Inhibits fungal cell wall synthesis by noncompetitively blocking synthesis of ß(1-3)-D-glucan in filamentous fungi

  • No cross-resistance with imidazoles and triazoles
30
Q

Capsofungin

Administration:

Metabolism:

Side Effects:

A

Administration: IV infusion

Metabolism: slow metabolism, fecal and renal elimination

Side Effects:

  • Fever, nausea/vomiting, flushing
  • Phlebitis at injection site
  • Pulmonary edema
31
Q

Superficial Mycoses: infection of…

A

Mucous membranes

  • Oropharyngeal
  • Bladder
  • Vagina (13 million/yr)
32
Q

Drugs for treatment of superficial mycoses

A
  • Nystatin
  • Fluconazole
  • Miconazole
  • Ketoconazole
  • Clotrimazole
  • Itraconazole
  • Natamycin (Opthalmic infections)
33
Q

Candida Species - Major Etiologic Agents

A
  • Candida albicans*
  • Candida tropicalis*
  • Candida krusei*
  • Candida parapsilosis*
  • Candida lusitaniae*
  • Candida glabrata*
34
Q

Fluconazole indications for superficial Candida infections:

A
  • Vaginal (single oral dose)
  • Urinary tract
  • Oropharynx
35
Q

Miconazole indications for Candida

A
  • Same mechanism as fluconazole
  • Creams/suppositories for vaginal Candida
  • Side effects with topical use:
    • Burning, itching, irritation
36
Q

Clotrimazole indications with *Candida *and side effects

A
  • Topical use (oral troches or vaginal creams/solutions)
  • Not for opthalmic use
  • Mechanism similar to fluconazole
  • Side effects: allergic/irritation reactions
  • SIde effects of oral troches: Abnormal liver function tests
37
Q

Itraconazole and Candida

A
  • Oropharyngeal and esophageal
38
Q

Nystatin use for *Candida *and Side Effects

A
  • Topical use for Candida
    • Skin, mucous membranes, vaginal infections, GI tract
    • Not for opthalmic use
  • Oral use for GI Candida infections
  • Side effects:
    • Topical: well tolerated
    • Oral: GI distress, bad taste
39
Q

Treatment of opthalmic fungal linfections

A
  • Natamycin
    • Keratitits, conjunctivitis, blepharitis
    • Especially useful for Fuarium, Cephalosporium, Aspergillus (less for Candida)
    • Mechanism similar to amphotericin B
    • Toxicity: conjunctival chemosis and hyperemia
40
Q

Dermatophytic Infections

Causative Agents:

A
  • Trichophyton
  • Epidermophyton
  • Microsporum
41
Q

Topical treaments for Dermatophytes

A
  • Miconazole, Clotrimazole
  • Tolnaftate
  • Terbinafine
  • Ciclopirox
42
Q

Ciclopirox

A

Only FDA approved topical Rx for mild-to-moderate fungal nail infections

  • Daily application for up to 48 weeks (1 year)
  • Periodic nail trimming
43
Q

Dermatophyte Therapy - Oral Preparations generally reserved for:

A
  • Severe dermatophyte infections
  • Those that are refractory to topical therapy
44
Q

Terbinafine (therapy)

A
  • 12 week therapy for nail infections
    • Likely superior to griseofulvin for nail infections
45
Q

Terbinafine Mechanism of Action

A

Blocks squalene epoxidase

While this prevents ergosterol synthesis, squalene also accumulates, forming lipid droplets that disrupt fungal cell membrane: FUNGICIDAL

46
Q

Terbinafine - Side Effects

A
  • Diarrhea
  • Dyspepsia
  • Abdominal pain
  • Inhibits CYP2D6
47
Q

Griseofulvin (use and treatment)

A
  • For recalicitrant dermatophytic infections of skin, hair nails
    • Long term treatment (6-12 months)
  • Therapy for children, especially for tinea capitis
48
Q

Griseofulvin

Mechanism:

Adminsistration:

Metabolism:

A

Mechanism: Slowly depositied into skin, hair, nails

  • Interferes with microtubule function/mitotic spindle/mitosis
  • Incorporated into keratin precursor cells, prevents infection in new cells

Adminsistration: Oral administration - absorption aided by high-fat foods

Metabolism: Hepatic metabolism - demethylation/glucuronidation

49
Q

Griseofulvin Side Effects

A
  • Contraindicated inthose with porphyria and advanced liver disease
  • Increased metabolism of several drugs (CYP inducer)
  • Use with caution in those with penicillin allergies
50
Q

Itroconazole (dermatophytic infection)

A
  • Oral 3 month therapy for fungal toenail infections

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