fungi are mostly eukaryotic organisms that live as ___ or ___
saprobes or parasites
fungi have a ___ cell wall composed of ___
the fungal cell membrane is composed of ___, which acts like cholesterol in the human cell membranes
ergosterolunlike eukaryotes, bacterial membranes generally do not contain sterols
are antibacterial agents effective against fungal infections?
___ fungal infections involve the skin and other soft tissues
___ fungal infections involve the whole body and are thus a major cause of death in immunocompromised patients
antifungal agents target what 4 things?
- fungal cell membrane
- cell wall synthesis
- nucleic acid synthesis (DNA and RNA)
- microtubule function
what 3 drugs are the primary drugs used for treating systemic fungal infections?
amphotericin B, azoles, and echinocandins
how are amphotericin B, azoles, and echinocandins selectively toxic to fungi?
they interact with or inhibit ergosterol synthesis, a sterol unique to fungal cell membranes
which drugs work by disrupting fungal cell membrane function and permeability?
amphotericin B, nystatin, itraconazole, fluconazole, naftifine, and terbinafine
which drugs are the polyenes that bind to ergosterol in fungal cell membranes to disrupt membrane function and permeability?
amphotericin B and nystatin
which two imidazoles and triazoles inhibit 14-alpha-sterol demethylase, prevent ergosterol synthesis, and lead to accumulation of 14-alpha-methylsterols?
itraconazole and fluconazole
which allylamines inhibit squalene epoxidase and prevent ergosterol synthesis?
naftifine and terbinafine
which drug inhibits fungal cell wall synthesis?
describe polyene antibiotics
- amphotericin B and nystatin
- fungistatic bind to plasma membrane ergosterol and damages the membrane by forming pores which cause leakage of potassium ions
what is the spectrum of amphotericin B?
broad spectrum: effective against most serious systemic fungal infections
how is amphotericin B administered?
parenteral only; usually given IV in hospital setting
what are the common side effects of amphotericin B?
- highly toxic chronic reactions (nephrotoxic and neurotoxic) at higher doses
- immediate reactions - infusion related toxicity
- slower reactions - renal toxicity and neurotoxicity
___ is the first line therapy for invasive, life-threatening systemic and localized candidemia, and is also effective for aspergillus infections
___ is often reserved for severe infections in critically ill or immunocompromised patients due to its extensive side effects
how is nystatin administered?
topical onlynot absorbed well but still too toxic if ingested orally
what are the clinical uses of nystatin?
- availabe as a mouthwash or cream
- topical treatment for oral and esophageal candidiasis albicans (thrush) as mouthwash
- topical cream for vaginal candidiasis (yeast infections)
what are the adverse effects of nystatin?
- higher systemic toxicity, so should never be administered systemically
- disulfuram-like reactions
describe the classifications of azole antifungals
- based on the number of nitrogen atoms attached to the ring
- imidazoles - 2 nitrogen atoms
- triazoles - 3 nitrogen atoms
what is the mechanism of azole antifungals?
inhibit ergosterol synthesis by blocking lanosine 14-alpha-demethylase
how are azole antifungals administered?
topically or systemically depending on drug and use
what are the contraindications of azole antifungals?
pregnancy, during lactation, or in patients with hepatic dysfunction
what drugs lack selectivity and inhibit human gonadal and steroid synthesis, cause loss of libido/impotency, gynecomastia in males, menstrual irregularity in females, and hypercortilism, and are hepatotoxic?
which azole antifungal drug is the most commonly prescribed systemic antifungal, is the drug of choice for most candidiasis albicans, does not treat aspergillis, and is used to treat fungal cryptococcal meningitis in AIDs patients?
which azole antifungal drug is highly teratogenic and should be avoided during pregnancy?
which azole antifungal drug was the first azole used for systemic and topical therapy?
which azole antifungal drug is more toxic than fluconazole, but is effective against aspergillis?
which two azole antifungals are available over the counter, topical only, and are used to treat vulvo-vaginal candidiasis (yeast infection), oral candidiasis (as lozenge), or as ointment for athlete’s foot and jock rash (dermatophytosis)?
clotrimazole and miconazole
which azole antifungal is the 1st line treatment for aspergillis infections?
ketoconazole should never be given with ___
what is the mechanism of flucytosine?
inhibits thymidylate synthetase which inhibits both DNA and RNA synthesis in fungi
describe the spectrum of flucytosine
narrow spectrum, for systemic fungal infections
how is flucytosine administered?
- well absorbed after oral administration concentration in CSF is 50-90% that in plasma, making it good for fungal meningitis
___ is synergistic when given in combination with amphotericin B for cryptococcol meningitis
___ is the main adverse effect of flucytosine
bone marrow suppression
what is the mechanism of echinocandins (caspofungin)?
block cell wall synthesis and maintenance via inhibition of 1,3-beta glucan synthase
which class of drugs are fungicidal against some candida species, fungistatic against some molds (aspergillis), and are used in azole-resistant candida or as a 2nd line agent for refractory aspergillosis?
echinocandins (ex. caspofungin)
echinocandins (caspofungin) is adminstered ___
___ is embryotoxic (category C) and thus should be avoided if possible in pregnancy
echinocandins (ex. caspofungin)
___ binds to and disrupts microtubule function, inhibiting fungal mitosis
griseofulvin inhibits the growth of ___
is griseofulvin used commonly?
rarely used anymore - largely replaced by terbinafine
griseofulvin is not effective topically, and has entirely ___ effects
___ induces human CYP that metabolized drugs like warfarin (increase metabolism)
what are the adverse effects of griseofulvin?
teratogenic, carcinogenic, and severe headaches
what is the mechanism of terbinafine?
inhibits the fungal enzyme squalene epoxidase to inhibit ergosterol synthesis, which disrupts cell membrane permeability
___ is used for treating dermatophytes, and has largely replaced griseofulvin for treatment of onychomycosis
what is the adverse effect of terbinafine?
___ antifungals are used for localized candidiasis in pateints with normal immune function
___ antifungals are used for disseminated disease and in immunocompromised patients