AssessmentsMiscellaneous antifungal medications
Miscellaneous antifungal medications
USMLE® Step 1 style questions USMLE
USMLE® Step 2 style questions USMLE
A 7-year-old boy comes to the office for an annual wellness checkup. His mother expresses concern that her son might have asthma. The boy reports that his chest sounds "squeaky" whenever he rides his bike. During those episodes, he borrows one of his older brother’s asthma inhalers but does not notice much improvement with inhaler use. These episodes have occurred 5-6 days a week, sometimes several times in one day, for the past 6 months. Physical examination shows the following:
Which of the following is the most appropriate therapy for the boy's condition?
Contributors:Tanner Marshall, MS, Evan Debevec-McKenney, Maria Emfietzoglou, Ursula Florjanczyk, MScBMC
Antifungal agents are a class of medications used to treat mycoses, or fungal infections.
Mycoses can be superficial, meaning they are localized on the skin, or develop into systemic infections in immunodeficient patients.
Antifungals work either through fungistatic action, meaning that they inhibit fungal growth, or through fungicidal action, meaning they kill the fungi.
Now, antifungals include the azole family and a novel class of medications, echinocandins; but there are also many other antifungals with similar or different mechanisms that we’ll talk about in this video.
Okay, most fungal cells have a tough outer cell wall and an inner cell membrane.
The cell membrane is mostly made of phospholipids with some sterol or modified steroid molecules mixed in.
Humans have cholesterol, while fungi have ergosterol. Both sterol molecules help keep the cell membrane stable at a wide range of temperatures.
Now, the precursor to both molecules is lanosterol.
The precursor of lanosterol is squalene.
The conversion of squalene to lanosterol is catalyzed by an enzyme called squalene epoxidase.
Fungi have a cytochrome p450 enzyme called fourteen-alpha-demethylase in their mitochondria and endoplasmic reticulums, which converts lanosterol to ergosterol.
Without ergosterol, the structure of the cell membrane will be disrupted.
This will cause membrane-bound proteins, like ion channels, to stop working properly.
The membrane also becomes fragile, which eventually leads to inhibition of fungal growth.
Okay, let’s start with polyenes, which are naturally-derived antifungal antibiotics that alter cell membrane permeability.
Polyenes have both hydrophilic, meaning they love water, and lipophilic, meaning they love fats, characteristics.
They bind to ergosterol, and the hydrophilic core causes the formation of artificial pores in the cell membrane, thereby creating a leaky membrane.
This causes significant changes in ion balance including the loss of intracellular potassium.
Depending on their concentration, polyenes are either fungistatic or fungicidal.
Now, amphotericin B is one of the most important medications for the treatment of systemic mycoses. It’s used to fight systemic infections caused by Aspergillus, Blastomyces, Candida albicans, Cryptococcus, Histoplasma, and Mucor, either alone or in combination with other drugs.
However, nowadays several azoles and echinocandins are proving to be just as effective in specific systemic mycoses as amphotericin B is, with less risk of toxicity.
Amphotericin B is also used in the treatment of visceral Leishmaniasis, caused by protozoan parasites of the genus Leishmania, that presents with fever, weight loss, fatigue, anemia, and substantial swelling of the liver and spleen.
It’s usually given by slow intravenous infusion, as it is poorly absorbed by the gastrointestinal tract.
In fungal meningitis intrathecal administration, meaning injection into the spinal canal, or into the subarachnoid space, has been used, since the drug is widely distributed to all tissues except the central nervous system, or CNS, when administered intravenously.
It can also be administered locally in the treatment of mycotic corneal ulcers and keratitis.
Amphotericin is mainly eliminated via hepatic metabolism, while a small fraction is excreted through the kidneys.
Alright, now common side effects are infusion-related and include fever, chills, muscle spasms, vomiting, headache, and in more severely affected individuals, hypotension and anaphylactoid reactions.
The most serious side effect is renal toxicity which is dose dependent and can be decreased with hydration.
Anemia may also occur due to reduction of erythropoietin production from the kidneys.
The electrolyte imbalance can cause arrythmias.
Next, nystatin is an antifungal agent that is only effective in the treatment of Candida infections of the skin, mucous membranes and gastrointestinal tract.
It’s used either topically for superficial infections or orally to fight gastrointestinal fungi in patients with impaired defense mechanisms.
Side effects for the oral form include gastrointestinal disturbances like nausea, abdominal pain, vomiting, and diarrhea.
Both the oral and the topical form can cause hypersensitivity reactions such as Stevens-Johnson syndrome, which is a dangerous immune-mediated condition that affects the skin and mucous membranes such as the mouth and genitals, and also rashes, itching, and burning.
Moving on to terbinafine, which is a synthetic antifungal antibiotic that alters cell membrane permeability.
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