Antifungai Flashcards
what is Amphotericin B
Amphotericin B is a naturally occurring polyene antifungal produced by
Streptomyces nodosus. In spite of its toxic potential, amphotericin B remains
the drug of choice for the treatment of several life-threatening mycoses.
what is the MOA for Amphotericin B
✓ Amphotericin B binds to ergosterol in the plasma membranes of sensitive
fungal cells. There, it forms pores (channels) that require hydrophobic
interactions between the lipophilic segment of the polyene antifungal and the
sterol (Figure 42.4).
✓ The pores disrupt membrane function, allowing electrolytes (particularly
potassium) and small molecules to leak from the cell, resulting in cell death.
what is the spectrum for amphotericin B
✓ Amphotericin B is either fungicidal or fungistatic, depending on the organism
and the concentration of the drug.
✓ It is effective against a wide range of fungi, including Candida albicans,
Histoplasma capsulatum, Cryptococcus neoformans, Coccidioides immitis,
Blastomyces dermatitidis, and many strains of Aspergillus.
✓ It is also used in the treatment of the protozoal infection leishmaniasis.
how is resistance formed against Amphotericin B
✓ Fungal resistance, although infrequent, is associated with decreased ergosterol
content of the fungal membrane.
what are the PK for Amphotericin B
✓ Amphotericin B is administered by slow, IV infusion
✓ Amphotericin B is insoluble in water and must be coformulated with either
sodium deoxycholate (conventional) or a variety of artificial lipids to form
liposomes.
✓ The liposomal preparations have the primary advantage of reduced renal and
infusion toxicity. However, due to high cost, liposomal preparations are reserved
mainly as salvage therapy for patients who cannot tolerate conventional
amphotericin B.
✓ Amphotericin B is extensively bound to plasma proteins and is distributed
throughout the body. Inflammation favours penetration into various body fluids,
but little of the drug is found in the CSF, vitreous humor, or amniotic fluid.
✓ However, amphotericin B does cross the placenta.
✓ Low levels of the drug and its metabolites appear in the urine over a long period
of time, and some are also eliminated via the bile.
✓ Dosage adjustment is not required in patients with hepatic dysfunction, but
when conventional amphotericin B causes renal dysfunction, the total daily
dose is decreased by 50%
what are the side effects for Amphotericin B
✓ Amphotericin B has a low TI. The total adult daily dose of the conventional
formulation should not exceed 1.5 mg/kg/d, whereas lipid formulations have
been given safely in doses up to 10 mg/kg/d.
a. Fever and chills: These occur most commonly 1 to 3 hours after starting the IV
admin. Premedication with a corticosteroid or an antipyretic helps to prevent this
problem.
b. Renal impairment: Patients may exhibit a ↓ in GF rate and renal tubular
function. ↑ Serum creatinine, ↓Cr.Cl., and K+ and Mg+2 are lost.
Azotemia is exacerbated by other nephrotoxic drugs, such as aminoglycosides,
cyclosporine, pentamidine, and vancomycin, although adequate hydration can
decrease its severity.
✓ To minimize nephrotoxicity, sodium loading with infusions of normal saline
and the lipid-based amphotericin B products can be used.
c. Hypotension:
A shock-like fall in blood pressure accompanied by hypokalemia may occur,
requiring potassium supplementation.
Care must be exercised in patients taking digoxin and other drugs that can
cause potassium fluctuations.
d. Thrombophlebitis: Adding heparin to the infusion can alleviate this
problem.
what is the difference between imidazoles and triazole
✓ imidazoles are given topically for cutaneous infections,
✓ whereas triazoles are given systemically for the treatment or prophylaxis
of cutaneous and systemic fungal infections.
✓ [Note: Imidazole antifungals are discussed in the section on agents for
cutaneous mycotic infections.]
✓ The triazole antifungals include fluconazole, itraconazole, posaconazole,
and voriconazole.
what is the MOA for Azoles
Azoles are predominantly
fungistatic.
They inhibit 14-α demethylase (a
cytochrome P450 [CYP450]
enzyme),
Blocking the demethylation of
lanosterol to ergosterol .
The inhibition of ergosterol
biosynthesis disrupts fungal
membrane structure and function,
which, in turn, inhibits fungal cell
growth
what is Fluconazole
✓ Fluconazole was the first member of the triazole class of antifungal
agents.
✓ It is the least active of all triazoles, with most of its spectrum limited to
yeasts and some dimorphic fungi.
✓ It has no role in the treatment of aspergillosis or zygomycosis.
✓ It is highly active against Cryptococcus neoformans and certain species
of Candida, including C. albicans and C. parapsilosis.
✓ Resistance is a concern, however, with other species, including C. krusei
and C. glabrata.
✓ Fluconazole is used for prophylaxis against invasive fungal infections in
recipients of bone marrow transplants.
✓ It also is the drug of choice for Cryptococcus neoformans after
induction therapy with amphotericin B and flucytosine and is used for
the treatment of candidemia and coccidioidomycosis.
✓ Fluconazole is effective against most forms of mucocutaneous
candidiasis. It is commonly used as a single-dose oral treatment for
vulvovaginal candidiasis
✓ Fluconazole is available in oral or IV dosage formulations.
✓ It is well absorbed after oral administration and distributes widely to
body fluids and tissues.
✓ The majority of the drug is excreted unchanged via the urine, and doses
must be reduced in patients with renal dysfunction.
✓ The most common adverse effects with fluconazole are:
✓ nausea, vomiting, headache, and skin rashes. Hepatotoxicity can also
occur, and the drug should be used with caution in patients with liver
dysfunction.
what is itraconazole
✓ Itraconazole is a synthetic triazole that has a broad antifungal spectrum
compared to fluconazole.
✓ Itraconazole is the drug of choice for the treatment of blastomycosis,
sporotrichosis, paracoccidioidomycosis, and histoplasmosis.
✓ is rarely used for treatment of infections due to Candida and
Aspergillus species because of the availability of newer and more
effective agents
✓ Itraconazole is available in two oral dosage forms, a capsule and an oral
solution.
✓ The oral capsule should be taken with food, and ideally an acidic
beverage, to increase absorption.
✓ In contrast, the solution should be taken on an empty stomach, as food
decreases the absorption.
✓ The drug distributes well in most tissues, including bone and adipose
tissues.
✓ Itraconazole is extensively metabolized by the liver, and the drug and
inactive metabolites are excreted in the feces and urine.
✓ Adverse effects include nausea, vomiting, rash (especially in
immunocompromised patients), hypokalemia, hypertension, edema,
and headache. Hepatotoxicity can also occur, especially when given
with other drugs that affect the liver.
✓ Itraconazole has a negative inotropic effect and should be avoided in
patients with evidence of ventricular dysfunction, such as heart failure.
what is voriconazole
✓ Voriconazole, a synthetic triazole related to fluconazole,has the
advantage of being a broad-spectrum antifungal agent that is available
in both IV and oral dosage forms.
✓ Voriconazole has replaced amphotericin B as the drug of choice for
invasive aspergillosis.
✓ It is also approved for treatment of invasive candidiasis, as well as
serious infections caused by Scedosporium and Fusarium species.
✓ Voriconazole has high oral bioavailability and penetrates into tissues
well.
✓ Elimination is primarily by metabolism through the CYP450 enzymes.
✓ Voriconazole displays nonlinear kinetics, which can be affected by drug
interactions and pharmacogenetic variability, particularly CYP450 2C19
polymorphisms.
✓ AEs are similar to those of the other azoles; however, high trough
concentrations are associated with visual and auditory hallucinations
and an increased incidence of hepatotoxicity.
✓ Voriconazole is not only a substrate but also an inhibitor of CYP2C19,
2C9, and 3A4 isoenzymes.
✓ Inhibitors and inducers of these enzymes may impact levels of
voriconazole, leading to toxicity or clinical failure, respectively.
✓ In addition, drugs that are substrates of these enzymes are impacted by
voriconazole (next Figure).
✓ Due to significant interactions, use of voriconazole is contraindicated
with many drugs (for example, rifampin, rifabutin, carbamazepine, and
the herb St. John’s wort).
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what are echinocandis
✓ Echinocandins interfere with the synthesis of the fungal cell wall by inhibiting
the synthesis of β(1,3)-d-glucan, leading to lysis and cell death.
✓ Caspofungin, micafungin, and anidulafungin are available for IV administration
once daily.
✓ The echinocandins have potent activity against Aspergillus and most Candida
species, including those species resistant to azoles.
✓ However, they have minimal activity against other fungi.
✓ All three agents are well tolerated, with the most common adverse effects
being:
✓ fever, rash, nausea, and phlebitis at the infusion site.
✓ They can also cause a histamine-like reaction (flushing) when infused too
rapidly.
what is Caspofungin (echinocandis)
✓ Caspofungin was the first member of the echinocandin class of
antifungal drugs.
✓ Caspofungin is a first-line option for patients with invasive candidiasis,
including candidemia, and a second-line option for invasive
aspergillosis in patients who have failed or cannot tolerate
amphotericin B or an azole.
✓ The dose of caspofungin does not need to be adjusted in renal
impairment, but adjustment is warranted with moderate hepatic
dysfunction.
✓ Concomitant administration of caspofungin with certain CYP450
enzyme inducers (for example, rifampin) may require an increase in the
daily dose.
✓ Caspofungin should not be coadministered with cyclosporine due to a
high incidence of elevated hepatic transaminases with concurrent use.
what are micafungin and anidulafungin (echinocandins)
✓ Micafungin and anidulafungin are newer members of the echinocandin
class of antifungal drugs.
✓ Micafungin and anidulafungin are first-line options for the treatment of
invasive candidiasis, including candidemia.
✓ Micafungin is also indicated for the prophylaxis of invasive Candida
infections in patients who are undergoing hematopoietic stem cell
transplantation.
✓ Micafungin and anidulafungin do not need to be adjusted in renal
impairment or mild to moderate hepatic dysfunction.
✓ Anidulafungin can be administered in severe hepatic dysfunction, but
micafungin has not been studied in this condition.
✓ These agents are not substrates for CYP450 enzymes and do not have
any associated drug interactions.
