Antifungals Flashcards
Nearly __% of deaths due to nosocomial infections are due to fungi
_______ is responsile for 70%
40%; Candida
Predisposition to Serious Fungal Infections
Immunocompromised
- Chemotherapy
- Immunomodulation
- Organ transplantation
- AIDS
Broad spectrum antibacterials use
Indwelling catheters
Difficulties in Treating Fungal Infections
- Fungi are Eukaryotes
- Number of agents available for clinical use is small
- Many fungal infections occur in poorly vascularized areas
Classification of Mycoses
- Systemic
- Debilitated or immunosuppressed patients
- Geographically localized
- Occupational
- Superficial
- Mucous membranes
- Dermatophytic
Potential Antifungal Targets
- Membranes (ergosterol)
- Nucleic acids (limited)
- Cell wall (1 drug class)
Drugs used for systemic fungal infections
- Amphotericin B
- Flucytosine
- Imidazoles
- Fluconazole
- Itraconazole
- Voriconazole
- Caspofungin
Amphotericin B
- Effective for:
- 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
Amphotericin B is _______ at serum levels in humans
Fungistatic
Mechanism of Action: Amphotericin
Forms a pore in the fungal membrane - causes leaky membranes
Amphotericin B
Administration and Dosing:
- 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)
Amphotericin - Side Effects
Ampho-Terrible
- Fever, nausea, vomiting, headache, chills
- Hypotension, hypokalemia, tachypnea
- 90% will show nonpermanent nephrotoxicity
- Permanent renal damage can occur
- Reversible hypochromic, normocytic anemia
Flucystosine (5-FC)
Uses:
- Serious infections
- Candida, Cryptococcus
- Used in conjunction with amphotericin B
- Fungistatic
5-FC Mechanism of Action
- 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
Flucytosine - Side Effects
- Nausea, vomiting, diarrhea, enterocolitis
- Leukopenia, thrombocytopenia
- Reversible elevated hepatic enzymes
- Use extreme caution in those with renal insufficiency or bone marrow depression
Other drugs for serious fungal infections (relative to amphotericin)
- Narrower spectrum of action
- Some not for immediately life-threatening infections
- Have fewer/less serious side effects
Imadazole and Triazole antifungals for serious fungal infections
- Fluconazole
- Voriconazole
- Itraconazole
Mechanism of action of imidazoles and triazoles
- 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
Fluonazole
Fungi and clinical use:
- Cryptococcus: meningitis
- Candida: many sites including CNS and urinary
- Candida spectrum
- Some albicans and glabrata
- Not C. crusei
Itraconazole
Fungi and clinical use:
- Blastomyces, Histoplasma
- Candida: Esophagus and oropharynx (not CNS and urinary)
- Candida spectrum
- More albicans and glabrata
- Some C. krusei in vitro
Voriconazole
Fungi and clinical use:
- Aspergillus
- Fusarium
- Scedosporium
- Cadida
- Covers many species including glabrata and krusei
________ is superior to Amphotericin for invasive Aspergillus
Voriconazole
Adminstration and Exretion of -azoles
Administration:
Elimination:
Administration: All Oral or IV
Elimination:
- Fluconazole - 90% renal, unchanged
- Itraconazole - Hepatic
- Voriconazole - Hepatic, inactive metabolites in urine
Exserohilum rostratum
Fungal meningitis due to contaminated steroid injections
Treat with Voriconazole + amphotericin B
Side Effects common to -azoles
- 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)
Itraconazole - contraindications
- Do not give itraconazole with other drugs that are metabolized by CYP3A4
- Potential for serious cardiovascular events including death
_______ has the lowest incidence of hepatotoxicity among the -azole antifungals
Fluconazole
Voriconazole Side Effects
Visual disturbances (30%)
Photosensitive component to rash
Contraindicated with St. John’s wort
Anti-fungal that targets cell wall
Caspofungin
Caspofungin
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
Capsofungin
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
Superficial Mycoses: infection of…
Mucous membranes
- Oropharyngeal
- Bladder
- Vagina (13 million/yr)
Drugs for treatment of superficial mycoses
- Nystatin
- Fluconazole
- Miconazole
- Ketoconazole
- Clotrimazole
- Itraconazole
- Natamycin (Opthalmic infections)
Candida Species - Major Etiologic Agents
- Candida albicans*
- Candida tropicalis*
- Candida krusei*
- Candida parapsilosis*
- Candida lusitaniae*
- Candida glabrata*
Fluconazole indications for superficial Candida infections:
- Vaginal (single oral dose)
- Urinary tract
- Oropharynx
Miconazole indications for Candida
- Same mechanism as fluconazole
- Creams/suppositories for vaginal Candida
- Side effects with topical use:
- Burning, itching, irritation
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
Itraconazole and Candida
- Oropharyngeal and esophageal
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
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
Dermatophytic Infections
Causative Agents:
- Trichophyton
- Epidermophyton
- Microsporum
Topical treaments for Dermatophytes
- Miconazole, Clotrimazole
- Tolnaftate
- Terbinafine
- Ciclopirox
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
Dermatophyte Therapy - Oral Preparations generally reserved for:
- Severe dermatophyte infections
- Those that are refractory to topical therapy
Terbinafine (therapy)
- 12 week therapy for nail infections
- Likely superior to griseofulvin for nail infections
Terbinafine Mechanism of Action
Blocks squalene epoxidase
While this prevents ergosterol synthesis, squalene also accumulates, forming lipid droplets that disrupt fungal cell membrane: FUNGICIDAL
Terbinafine - Side Effects
- Diarrhea
- Dyspepsia
- Abdominal pain
- Inhibits CYP2D6
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
Griseofulvin
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
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
Itroconazole (dermatophytic infection)
- Oral 3 month therapy for fungal toenail infections
