Table of Contents
Overview
Antifungal drugs are medications used to treat infections caused by fungi, including yeasts such as Candida and molds such as Aspergillus. For USMLE Step 1, you do not need clinical prescribing details, but you must recognize major classes, their mechanisms, key uses, and classic toxicities. Antifungals often target components unique to fungi, especially the cell membrane and cell wall, which helps achieve selective toxicity.
This chapter focuses only on what is specific to antifungals. General pharmacology principles, such as pharmacokinetics, receptor binding, or general adverse effect mechanisms, are addressed elsewhere.
Fungal Cell Targets
Fungi have a cell membrane that contains ergosterol instead of cholesterol, and many antifungals exploit this difference. Others target synthesis of the cell wall, nucleic acids, or microtubules.
The most important fungal targets are:
| Target structure or pathway | Antifungal examples |
|---|---|
| Ergosterol in cell membrane | Amphotericin B, nystatin, azoles |
| Ergosterol synthesis | Azoles, terbinafine |
| Cell wall (β glucan) | Echinocandins |
| Nucleic acid synthesis | Flucytosine |
| Microtubules | Griseofulvin |
Keep these targets in mind as you learn each drug class, since USMLE questions often test the link between target, mechanism, and toxicity.
Polyenes
Mechanism of Action
The polyenes, mainly amphotericin B and nystatin, bind directly to ergosterol in the fungal cell membrane. This binding forms pores in the membrane, which increases permeability and causes leakage of fungal cell contents. The fungal cell then dies.
Polyenes bind ergosterol and form membrane pores that cause fungal cell death.
These drugs have poor selectivity, because mammalian cell membranes contain cholesterol, which is structurally related to ergosterol. This partial cross reactivity explains many toxicities.
Amphotericin B
Amphotericin B is a broad spectrum systemic antifungal that is often used for severe, life threatening fungal infections, including many invasive systemic mycoses such as cryptococcosis, mucormycosis, and disseminated histoplasmosis.
Amphotericin B is usually given intravenously. It does not cross the blood brain barrier well, although intrathecal administration is sometimes used for fungal meningitis in specific settings.
The most testable adverse effects are infusion related and dose related.
Infusion related reactions often include fever, chills, hypotension, and muscle spasms during or shortly after administration. These are sometimes called “shake and bake” reactions. Premedication with antipyretics or antihistamines can blunt these symptoms.
Dose related toxicities reflect damage to human cell membranes and kidneys.
The classic toxicity is nephrotoxicity. This may manifest as increased serum creatinine, electrolyte abnormalities such as hypokalemia and hypomagnesemia, and renal tubular acidosis. Hydration with normal saline and using lipid formulations can reduce renal damage.
Other adverse effects include anemia from decreased erythropoietin production, and thrombophlebitis at the injection site.
Lipid formulations of amphotericin B are less nephrotoxic because they preferentially deliver drug to fungal cells and reduce exposure of renal tissues.
Amphotericin B is highly nephrotoxic and can cause electrolyte wasting, especially hypokalemia and hypomagnesemia.
Nystatin
Nystatin has the same basic mechanism as amphotericin B. It binds ergosterol and forms membrane pores, but it is too toxic for systemic use and is therefore used topically or locally.
Nystatin is used mainly for Candida infections involving mucosal or cutaneous surfaces, such as oral thrush, diaper rash, or vaginal candidiasis. It is commonly given as a “swish and swallow” or “swish and spit” suspension for oral candidiasis.
Systemic adverse effects are minimal because the drug is not significantly absorbed from the gastrointestinal tract or skin.
Azoles
Mechanism of Action
Azoles inhibit the fungal cytochrome P450 enzyme 14 alpha demethylase. This enzyme is required for conversion of lanosterol to ergosterol, a key component of the fungal cell membrane.
Inhibition of this enzyme reduces ergosterol synthesis and disrupts membrane structure and function, which impairs fungal growth. Most azoles are considered fungistatic rather than fungicidal, although this can vary with the organism and concentration.
Azoles inhibit fungal ergosterol synthesis by blocking 14α demethylase, a cytochrome P450 enzyme.
Because azoles interact with cytochrome P450, they often cause clinically important drug interactions and can also interfere with human steroid synthesis.
Azoles are often subdivided into imidazoles and triazoles. For USMLE, you focus on individual drugs rather than on those subcategories.
Ketoconazole
Ketoconazole is an older azole that is less used systemically because of its toxicity and strong CYP450 inhibition, but it remains clinically relevant for conceptual questions.
It inhibits fungal ergosterol synthesis, but also strongly inhibits human steroid synthesis, including cortisol and testosterone. This leads to endocrine side effects such as gynecomastia, decreased libido, impotence in men, and menstrual irregularities in women. It can also cause adrenal insufficiency.
Hepatotoxicity is another important adverse effect. Because ketoconazole strongly inhibits CYP450 enzymes, it can raise levels of many coadministered drugs.
Fluconazole
Fluconazole has good oral bioavailability and excellent penetration into cerebrospinal fluid. It is a first line agent for many mucocutaneous and systemic Candida infections and an important drug for cryptococcal meningitis, especially for maintenance therapy after induction with amphotericin B and flucytosine.
Fluconazole is relatively well tolerated, but it can still cause hepatotoxicity and inhibit CYP450 enzymes, although usually to a lesser degree than ketoconazole.
For USMLE, you should associate fluconazole with oral and esophageal candidiasis, candidemia in non neutropenic patients, and suppression of cryptococcal meningitis in AIDS.
Itraconazole
Itraconazole is important for the treatment of several endemic mycoses such as histoplasmosis, blastomycosis, and sporotrichosis. It is also used for some onychomycoses.
It does not penetrate the cerebrospinal fluid well, so it is not used for fungal meningitis. Like other azoles, itraconazole can cause hepatotoxicity and has significant CYP450 interactions.
USMLE questions often highlight itraconazole as an oral option for mild to moderate infections with endemic fungi in stable patients, especially as a step down from amphotericin B.
Voriconazole
Voriconazole is especially important for invasive Aspergillus infections. It is a drug of choice for invasive aspergillosis and also has activity against Candida species.
Its most distinctive toxicity is visual disturbances. Patients may experience transient changes in color vision, photophobia, or blurred vision, often shortly after dosing. Other adverse effects include hepatotoxicity and skin reactions, especially photosensitivity with chronic use.
Posaconazole and Isavuconazole
Posaconazole and isavuconazole have broad antifungal spectra, including activity against some strains of Aspergillus and Mucorales. They are often used in high risk patients for prophylaxis or treatment of invasive mold infections.
On USMLE, you primarily need to recognize that newer azoles like posaconazole and isavuconazole are options for serious mold infections, including mucormycosis, and that they share the general azole profile of CYP450 interactions and possible hepatotoxicity.
Echinocandins
Mechanism of Action
Echinocandins inhibit the synthesis of β 1,3 glucan, an essential component of the fungal cell wall. Without this component, the cell wall is weakened and the fungal cell becomes susceptible to osmotic damage and lysis.
Echinocandins block β 1,3 glucan synthesis in the fungal cell wall.
Because humans do not have cell walls, echinocandins are relatively selective and have a favorable toxicity profile.
The main echinocandins you should know are caspofungin, micafungin, and anidulafungin.
Clinical Uses
Echinocandins are used intravenously for systemic Candida infections and as salvage or combination therapy for invasive aspergillosis when other agents fail or are not tolerated.
They are especially important for candidemia and invasive candidiasis, including infections in critically ill or neutropenic patients.
Adverse Effects
Adverse effects are usually mild, including gastrointestinal discomfort, flushing, or mild transaminase elevations. Histamine related reactions can occur during infusion. Serious hepatotoxicity and hypersensitivity reactions are less common but possible.
USMLE questions may contrast echinocandins with amphotericin B by emphasizing reduced nephrotoxicity and distinct cell wall targeting.
Flucytosine
Mechanism of Action
Flucytosine is a pyrimidine analog. It enters fungal cells through cytosine permease and is converted by fungal cytosine deaminase into 5 fluorouracil (5 FU). 5 FU is then converted to metabolites that inhibit thymidylate synthase and disrupt DNA and RNA synthesis.
Because mammalian cells lack cytosine deaminase, activation of flucytosine occurs mainly within fungal cells, which provides some selectivity.
Flucytosine is converted in fungi to 5 fluorouracil, which inhibits DNA and RNA synthesis.
Clinical Uses
Flucytosine is used primarily in combination with amphotericin B for the treatment of serious infections such as cryptococcal meningitis. Combination therapy enhances antifungal activity and helps prevent resistance.
Monotherapy is rarely used because resistance develops rapidly when flucytosine is given alone.
Adverse Effects
Because 5 FU can also affect rapidly dividing human cells, flucytosine can cause bone marrow suppression with leukopenia, thrombocytopenia, and anemia. It may also cause gastrointestinal disturbances and hepatic toxicity.
Bone marrow suppression is the key adverse effect to remember for USMLE purposes.
Allylamines
Terbinafine
Terbinafine is an allylamine that inhibits the enzyme squalene epoxidase, which is involved in the early steps of ergosterol synthesis. Inhibition of this enzyme leads to accumulation of squalene and depletion of ergosterol, which is toxic to fungal cells.
Terbinafine inhibits squalene epoxidase and disrupts ergosterol synthesis.
Terbinafine is highly lipophilic and accumulates in skin, nails, and adipose tissue. It is widely used for dermatophyte infections, especially onychomycosis of the fingernails and toenails, and tinea infections of the skin.
Adverse effects include gastrointestinal upset, headaches, and taste disturbances. Hepatotoxicity is an important concern in systemic therapy, so liver function monitoring is recommended.
USMLE questions often pair terbinafine with onychomycosis and highlight that it targets squalene epoxidase, in contrast to azoles which target 14 alpha demethylase.
Griseofulvin
Mechanism of Action
Griseofulvin disrupts fungal cell mitosis by binding to fungal microtubules and interfering with the mitotic spindle. This prevents proper separation of chromosomes during cell division.
It is fungistatic and is most effective against dermatophytes.
Griseofulvin interferes with fungal microtubules and inhibits mitosis.
Clinical Uses
Griseofulvin is given orally and deposits in keratin containing tissues such as skin, hair, and nails. It is used to treat dermatophyte infections involving these tissues, including tinea capitis and tinea corporis, especially when topical therapy is inadequate.
Because it concentrates in keratin, treatment often must continue until normal tissue grows out fully, which can take weeks to months.
Adverse Effects and Interactions
Adverse effects include headaches, gastrointestinal upset, photosensitivity, and possible hepatotoxicity. Griseofulvin is a cytochrome P450 inducer, which can increase the metabolism of warfarin and other drugs and reduce their effectiveness.
Alcohol intolerance reactions similar to a disulfiram reaction may occur in some patients.
Topical Antifungals
Several antifungal agents are used primarily topically for cutaneous or mucosal infections. These often share mechanisms with systemic agents but have limited systemic absorption.
Common topical agents include clotrimazole and miconazole, both azoles used for candidal infections and dermatophytes on the skin and mucosa, and topical terbinafine for tinea infections of the skin.
For USMLE, you mainly need to recognize that many superficial fungal infections can be treated with topical azoles or terbinafine, and that systemic therapy is reserved for more extensive or nail and hair involvement.
Patterns for USMLE Questions
USMLE questions about antifungals often combine fungal organism, clinical setting, and toxicity profile. You should be able to match a drug to a scenario, identify a mechanism from a description, or predict an adverse effect.
Some high yield pairings are:
| Scenario or clue | Likely antifungal concept |
|---|---|
| Severe systemic mycosis followed by nephrotoxicity | Amphotericin B, ergosterol binding, membrane pores |
| Oral thrush treated with “swish and swallow” | Nystatin |
| Invasive aspergillosis with visual disturbances | Voriconazole |
| Cryptococcal meningitis induction then maintenance therapy | Amphotericin B plus flucytosine, followed by fluconazole |
| Endemic mycoses in stable patient, oral step down therapy | Itraconazole |
| Candidemia and cell wall β glucan inhibition | Echinocandins such as caspofungin |
| Onychomycosis with squalene epoxidase inhibition | Terbinafine |
| Dermatophyte infection, microtubule disruption | Griseofulvin |
| Gynecomastia and steroid synthesis inhibition | Ketoconazole |
Maintaining these links between mechanism, organism, and toxicity will help you quickly answer antifungal questions on the exam.