topic 16 Flashcards
What are 4 categories of fungal infections? How are they treated?
Superficial Mycoses
Cutaneous
Topical or less toxic oral
Subcutaneous Mycoses
Systemic Mycoses
oral or IV, often more toxic
What are some examples and characteristics of superficial mycoses?
Fungus only in the most external epidermis
Signs/symptoms mostly due to by-products of fungus
Examples: Dandruff Tinea versicolor Malessezia globosa, malessezia furfur Normally found on skin, unclear reason for why it is symptomatic only in some people
What are some characteristics and examples of cutaneous mycoses?
Often associated with areas of the body that have poor aeration with excessive moisture/sweating, tight clothing, high humidity climates
Tinea refers to a fungal infection of the skin
Aka skin mycoses, ringworm. Often presents as a raised ring with central area of healing, dry flaking, loss of hair in involved area
Tinea corporis
Tinea pedis (“athlete’s foot”)
Tinea cruris (“jock itch”)
Tinea capitis (mycosis of the scalp)
Tinea barbae (mycosis of the beards and moustaches)
Tinea unguium (often called Onychomycosis, mycosis of the nails).
What are some characteristics and examples of subcutaneous mycoses?
Often caused by puncture wounds contaminated with soil fungi
Often appear as a small nodule that grows and may drain or ulcerate
May become systemic, especially in immunocompromised
Examples:
Chromoblastomycosis
Tropical or subtropical areas
Pseudallescherias boydii
Soil fungus
Sporotrichosis
Caused by Sprothrix schenckii
aka Rose-gardener’s disease
What are some characteristics and examples of systemic mycoses?
Fungal infection other than skin or subcutaneous nodules Soft Tissue Infection Urinary Tract Infection Lungs-Pneumonia CNS-Meningitis Septicemia
What are some examples of endemic mycoses and opportunistic mycoses?
Endemic: Soil fungi, usually inhaled, large inoculum to start disease, rare
Blastomycosis (Blastomyces dermatitides)*
Mississippi river, Ohio river, Great lakes
Coccidiomycosis (Coccidioides immitis)*
Southwest USA
Paracoccidiomycosis (Paracoccidiodes brasiliensis)*
Central and South America
Histoplasma (Histoplasma capsulatum)*
Eastern and central USA
Bat and bird droppings
“Cave disease”
Opportunistic
Aspergillus **
Cryptococcus**
Candida **
What are some characteristics of candida albicans?
Normally found in GI tract, vagina of many healthy humans, kept under control by normal bacterial flora
Overgrowth can cause disease, can be cutaneous (including mucosal), subcutaneous, or systemic
Risk factors for candida infections Antibiotics Immunosuppressed states Steroid use Pregnancy
Cutaneous involvement, usually in moist areas
Groin, axilla, gluteal fold, abdominal folds, inframammary crease
Mucosal
Mucosal candidal infection is sometimes referred to as “thrush” (more common for oral involvement)
Oral
Vulvovaginal
Systemic
Esophogeal (immunocompromised) In blood (candidemia/fungemia)
What are two examples of polyenes and what are their mech of action?
Amphotericin B, nystatin
Preferentially binds to ergosterol found in fungi (as opposed to cholesterol found in human cells)
With ergosterol, they form pores in membranes
Also form pores in human cells with cholesterol with significant side effects
Monovalent ions pass through the pores
What is the admin, adsorp of nystatin? What is it used for?
Highly insoluble and toxic if given IV
Oral-Minimal GI absorption
Available in oral and topical forms
Effective against Candida
Used for cutaneous mycoses, especially cutaneous candidal infections (not for systemic mycoses)
Oral or vulvovaginal candidiasis
Powder for tinea
What is the admin, adsorp, distrib of amphotericin B? What is it used for? What are its major side effects?
Drug of choice for most systemic, life-threatening infections
Broad spectrum of activity against most fungi
Fungicidal
Does not enter CNS – intrathecal injection for fungal meningitis
Administered IV – poorly absorbed by the gastrointestinal tract
Major side effects of IV form
nephrotoxicity – dose dependent, >50% of patients
Monitor creatinine
Common reactions associated with IV administrations: hypotension, fever, chills, headache, nausea
Anemia
Neurological effects with intrathecal
Given topically, it is poorly absorbed and doesn’t have all the side effects.
How can the nephrotoxicity involved with amphotericin B be reduced? What is the downfall?
Lipid formulations of Amphotericin B, as compared to the conventional formulation, are less nephrotoxic, and may have less toxicity associated with infusion (fever, chills, hypotension).
The lipid formulations, however, are much more expensive.
May be able to give higher doses of Ampho B, used for treatment failure with conventional Ampho B. Also used in patients with renal failure.
What is the mech of action of 5-fluorocysteine?
5-FC enters cell through a permease
5-FC is converted to 5-fluorouracil by cytosine deaminase, then converted to 5-FdUMP
Permease is not found in human cells
5-FdUMP inhibits DNA synthesis by inhibiting dTMP synthesis
What is the admin, absorp of 5-FC? What is it used for? What are the side effects?
Very high rates of resistant strains when used alone
Don’t use as monotherapy
Used in conjunction with Amphotericin B
Ampho B increases cell wall permeability, allowing 5-FC to enter fungal cell more easily
Inhibits fungal DNA synthesis
Administered orally
Effective against
Candida
Cryptococcus
Aspergillus
Major side effects Elevated hepatic enzymes Gastrointestinal disturbances Hematological Bone marrow suppression
What is the mech of action of azoles? What are the two different kinds? Examples of each? Difference between the two kinds?
They inhibit lanosterol 14-alpha demethylase.
There are imidazoles :
Ketoconazole,
Miconazole (only in topical form),
Clotrimazole (only in topical form))
Triazoles: (lower toxicity profile) Fluconazole Itraconazole Voriconazole Posaconazole
What are the admin and absorp of miconazole and clotrimazole?
Too toxic to give IV, are available only as topical preparations (which are poorly absorbed)
What is the admin, absorp, distrib, spectrum, and side effects of Ketoconazole?
Broad spectrum
Does not penetrate into CSF
Oral and topical (e.g. Nizoral for dandruff)
Major side effects Gynecomastia Inhibits testosterone and cortisol production by interfering with CYP450 metabolism GI distress Hepatic dysfunction
Oral preparation requires acidic gastric environment, decreased absorption with antacids, H2-receptor blockers, proton pump blockers
Has been replaced by the Triazoles which have more favorable side-effect profiles, better pharmacokinetics, and are generally more effective for systemic mycoses
What is the admin, absorp, distrib of triazoles? What is their spectrum? What are their side effects?
Triazoles available in the US Fluconazole Itraconazole Voriconazole Posaconazole
All are broad spectrum
Oral and IV
Improved adverse-effect profile
No steroid metabolism interference
Better GI tolerance
Still has CYP450 interactions, multiple drug interactions
All triazoles penetrate into CSF except itraconazole
Voriconazole is now drug of choice for Aspergillus, replacing Amphotericin B
The triazoles have largely replaced ketaconazole in the treatment of systemic mycoses
What are 4 general characteristics of azoles concerning side effects of drug interactions?
All azoles are metabolized by and affect cytochrome P450 activity. Numerous drug interactions are known.
All azoles can cause hepatic dysfunction.
Azoles should be avoided during pregnancy.
Theoretically, azoles should antagonize Amphotericin B, and probably should not be used together
What are 3 examples of echinocandins? How are they used? What is their mechanism? side effects? cost?
Caspofungin, micafungin, anidulafungin
Newer on the market
Usually used as second-line agents after Ampho B or azoles
Inhibits cell wall biosynthesis
Inhibit fungal beta(1,3)-glucan synthesis
Effective against Aspergillus and Candida
Relatively few side effects
Expensive
What is an example of a grisan? What is its mechanism? Where does it bind on the body? What is its admin? What are its side effects?
Inhibits microtubule function – prevents mitosis
Binds to keratin in skin and hair, makes the skin and hair resistant to fungal infections
Typically 6-12 week therapy
Effective against dermatophytes, used in a variety of tinea infections
Given orally
Major side affects - rare Headache Hepatoxicity GI irritation Bone marrow suppression
What are 3 examples of allylamines and how are they administered? What is their mechanism? What are they used to treat? What are their side effects?
Terbinafine (oral and topical), Butenafine (topical), Naftifine (topical)
Terbinafine is commercially sold as Lamisil (fungus demon commercials)
Inhibits squalene epoxide, needed in ergosterol synthesis
Used to treat tinea,Oral terbenafine often used for onychomycosis.
Adverse effects with terbenafine are uncommon, mostly GI upset and headaches
What are three drugs that fungi develop resistance against and what are examples of how they do it?
5-FC Resistance very common when used alone Mechanisms of resistance Mutation in cytosine permease Mutation in deaminase
Azole resistance
Change in expression of efflux pumps
Mutation in demethylase
Upregulation of demethylase
Amphotericin resistance – rarely occurs
Reduced amount of membrane ergosterol
Altered membrane lipids/sterol composition
