Antifungals Flashcards
1
Q
Nearly __% of deaths due to nosocomial infections are due to fungi
_______ is responsile for 70%
A
40%; Candida
2
Q
Predisposition to Serious Fungal Infections
A
Immunocompromised
- Chemotherapy
- Immunomodulation
- Organ transplantation
- AIDS
Broad spectrum antibacterials use
Indwelling catheters
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
4
Q
Classification of Mycoses
A
- Systemic
- Debilitated or immunosuppressed patients
- Geographically localized
- Occupational
- Superficial
- Mucous membranes
- Dermatophytic
5
Q
Potential Antifungal Targets
A
- Membranes (ergosterol)
- Nucleic acids (limited)
- Cell wall (1 drug class)
6
Q
Drugs used for systemic fungal infections
A
- Amphotericin B
- Flucytosine
- Imidazoles
- Fluconazole
- Itraconazole
- Voriconazole
- Caspofungin
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
8
Q
Amphotericin B is _______ at serum levels in humans
A
Fungistatic
9
Q
Mechanism of Action: Amphotericin
A
Forms a pore in the fungal membrane - causes leaky membranes
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)
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
12
Q
Flucystosine (5-FC)
Uses:
A
- Serious infections
- Candida, Cryptococcus
- Used in conjunction with amphotericin B
- Fungistatic
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
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
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
16
Q
Imadazole and Triazole antifungals for serious fungal infections
A
- Fluconazole
- Voriconazole
- Itraconazole
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
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
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
20
Q
Voriconazole
Fungi and clinical use:
A
- Aspergillus
- Fusarium
- Scedosporium
- Cadida
- Covers many species including glabrata and krusei
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
Itraconazole - contraindications
* Do not give itraconazole with other drugs that are metabolized by CYP3A4
* Potential for serious cardiovascular events including death
26
\_\_\_\_\_\_\_ has the lowest incidence of hepatotoxicity among the -azole antifungals
Fluconazole
27
Voriconazole Side Effects
Visual disturbances (30%)
Photosensitive component to rash
Contraindicated with St. John's wort
28
Anti-fungal that targets cell wall
Caspofungin
29
Caspofungin
## Footnote
Uses:
Other species treated:
Mechanism:
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
Capsofungin
## Footnote
Administration:
Metabolism:
Side Effects:
Administration: IV infusion
Metabolism: slow metabolism, fecal and renal elimination
Side Effects:
* Fever, nausea/vomiting, flushing
* Phlebitis at injection site
* Pulmonary edema
31
Superficial Mycoses: infection of...
Mucous membranes
* Oropharyngeal
* Bladder
* Vagina (13 million/yr)
32
Drugs for treatment of superficial mycoses
* Nystatin
* Fluconazole
* Miconazole
* Ketoconazole
* Clotrimazole
* Itraconazole
* Natamycin (Opthalmic infections)
33
Candida Species - Major Etiologic Agents
* Candida albicans*
* Candida tropicalis*
* Candida krusei*
* Candida parapsilosis*
* Candida lusitaniae*
* Candida glabrata*
34
Fluconazole indications for superficial *Candida* infections:
* Vaginal (single oral dose)
* Urinary tract
* Oropharynx
35
Miconazole indications for *Candida*
* Same mechanism as fluconazole
* Creams/suppositories for vaginal *Candida*
* Side effects with topical use:
* Burning, itching, irritation
36
Clotrimazole indications with *Candida *and side effects
* 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
Itraconazole and *Candida*
* Oropharyngeal and esophageal
38
Nystatin use for *Candida *and Side Effects
* 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
Treatment of opthalmic fungal linfections
* Natamycin
* Keratitits, conjunctivitis, blepharitis
* Especially useful for Fuarium, Cephalosporium, Aspergillus (less for *Candida*)
* Mechanism similar to amphotericin B
* Toxicity: conjunctival chemosis and hyperemia
40
Dermatophytic Infections
## Footnote
Causative Agents:
* Trichophyton
* Epidermophyton
* Microsporum
41
Topical treaments for Dermatophytes
* Miconazole, Clotrimazole
* Tolnaftate
* Terbinafine
* Ciclopirox
42
Ciclopirox
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
Dermatophyte Therapy - Oral Preparations generally reserved for:
* Severe dermatophyte infections
* Those that are refractory to topical therapy
44
Terbinafine (therapy)
* 12 week therapy for nail infections
* Likely superior to griseofulvin for nail infections
45
Terbinafine Mechanism of Action
Blocks squalene epoxidase
While this prevents ergosterol synthesis, squalene also accumulates, forming lipid droplets that disrupt fungal cell membrane: **FUNGICIDAL**
46
Terbinafine - Side Effects
* Diarrhea
* Dyspepsia
* Abdominal pain
* Inhibits CYP2D6
47
Griseofulvin (use and treatment)
* For recalicitrant dermatophytic infections of skin, hair nails
* Long term treatment (6-12 months)
* Therapy for children, especially for tinea capitis
48
Griseofulvin
## Footnote
Mechanism:
Adminsistration:
Metabolism:
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
Griseofulvin Side Effects
* Contraindicated inthose with porphyria and advanced liver disease
* Increased metabolism of several drugs (CYP inducer)
* Use with caution in those with penicillin allergies
50
Itroconazole (dermatophytic infection)
* Oral 3 month therapy for fungal toenail infections
