Azoles

Azoles are a widely used class of antifungal medications inhibiting the production of ergosterol, a critical component in the fungal cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane. The 2 primary subclasses of azoles are the imidazoles, older agents typically only used for topical applications, and the triazoles, newer agents with a wide spectrum of uses. Various members of the class are indicated in the treatment and prophylaxis of candidiasis Candidiasis Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis, aspergillosis Aspergillosis Aspergillosis is an opportunistic fungal infection caused by Aspergillus species, which are common spore-forming molds found in our environment. As Aspergillus species are opportunistic, they cause disease primarily in patients who are immunocompromised. The organs that are most commonly involved are the lungs and sinuses. Aspergillus/Aspergillosis, cryptococcus Cryptococcus Cryptococcosis is an opportunistic, fungal infection caused by the Cryptococcus species. The principal pathogens in humans are C. neoformans (primary) and C. gattii. Cryptococcus neoformans is typically found in pigeon droppings and acquired by inhaling dust from contaminated soil. The majority of affected patients are immunocompromised. Cryptococcus/Cryptococcosis meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis, dimorphic fungal infections (e.g., blastomycosis Blastomycosis Blastomycosis is an infection caused by inhalation of the spores of the fungus, Blastomyces. Blastomyces species thrive in moist soil and decaying material and are common in the Ohio and Mississippi River valleys and the Great Lakes regions of the United States and Canada. Although most patients are asymptomatic, some can develop pneumonia. Blastomyces/Blastomycosis), and mucormycosis Mucormycosis Mucormycosis is an angioinvasive fungal infection caused by multiple fungi within the order, Mucorales. The fungi are ubiquitous in the environment, but mucormycosis is very rare and almost always occurs in patients who are immunocompromised. Inhalation of fungal spores can cause rhinocerebral or pulmonary mucormycosis, direct inoculation can cause cutaneous mucormycosis, and ingestion can cause gastrointestinal mucormycosis. Mucorales/Mucormycosis. Significant adverse effects are possible and include hepatotoxicity, GI distress, cardiac issues, and neurotoxicity. Azoles interact with the CYP450 system causing significant drug-to-drug interactions with many other medications, potentially limiting the usefulness in medically complex individuals.

Last update:

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp

Classification

Azoles are a group of widely used antifungal medications, which can be classified into 2 subgroups:

  • Imidazoles:
    • Ketoconazole (rarely used systemically due to higher toxicity/lower efficacy than triazoles)
    • Miconazole (topical only)
    • Clotrimazole (topical only)
  • Triazoles:
    • Fluconazole
    • Itraconazole
    • Voriconazole
    • Posaconazole
    • Isavuconazole

Chemistry and Pharmacodynamics

Chemical structure

  • All azoles contain a 5-membered, nitrogen-containing azole ring.
  • Imidazoles have 2 nitrogen atoms in the azole ring.
  • Triazoles have 3 nitrogen atoms in the azole ring.

Mechanism of action

Azoles cause deterioration in the fungal cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane by inhibiting ergosterol production.

  • Ergosterol:
    • A critical component of fungal cell membranes (the equivalent to cholesterol in human cell membranes)
    • Synthesized by lanosterol 14-α-demethylase, a fungal CYP450 enzyme converting lanosterol to ergosterol:
      • Azoles have a higher affinity for fungal enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes than human enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes.
      • Triazoles have a better selective affinity for fungal enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes than imidazoles.
  • Azoles inhibit lanosterol 14-α-demethylase → inhibits ergosterol production
  • Without new ergosterol production: 
    • Fungi are unable to maintain the cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane or create new membranes.
    • ↑ Fungal cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane permeability → cell lysis
  • Azoles are generally considered to be fungistatic.
Antifungal agents and mechanisms of action

Antifungal agents and mechanisms of action

Image by Lecturio. License: CC BY-NC-SA 4.0

Pharmacokinetics

Different azoles have variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables (and sometimes complex) pharmacokinetics.

Absorption

  • Good oral absorption:
    • Fluconazole
    • Voriconazole
    • Posaconazole
  • Variable absorption:
    • Itraconazole
    • Ketoconazole

Distribution

  • High volumes of distribution → drugs accumulate in tissues throughout the body
  • All are widely distributed in tissue (with CSF and urine as notable exceptions).
  • Drugs collecting in urine and CSF:
    • Urine: fluconazole (due to significant excretion as an unchanged drug)
    • CSF: fluconazole, voriconazole
  • Azoles are teratogenic to the developing fetus and systemic azoles are generally contraindicated in pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care.
Table: Pharmacokinetics of azoles
Drugs Protein binding Metabolism and clearance Half-life Enzyme inhibition Enzyme inhibition Enzyme inhibitors bind to enzymes and decrease their activity. Enzyme activators bind to enzymes and increase their activity. Molecules that decrease the catalytic activity of enzymes can come in various forms, including reversible or irreversible inhibition. Enzyme Inhibition
Imidazoles
Ketoconazole 99% Partial hepatic metabolism by CYP3A4 Biphasic:
  • Initial: 2 hours
  • Terminal: 8 hours
Significantly more inhibition of mammalian CYP450 than the triazoles
Triazoles
Fluconazole Approximately 10%
  • Renal (as an unchanged drug): 80%
  • Hepatic: 10%
25 hours
  • CYP2C19 (strong)
  • CYP2C9 (moderate)
  • CYP3A4 (moderate, more at high doses)
Itraconazole 99%
  • Extensive hepatic metabolism by CYP3A4 to active metabolites
  • Dose-dependent elimination
24–48 hours
  • CYP3A4 (strong)
  • P-gp efflux
Voriconazole Approximately 60% Extensive hepatic metabolism by CYP2C19 (major), 2C9, and 3A4 (minor) 6 hours
  • CYP3A4 (strong)
  • CYP2C19 (moderate)
Posaconazole 98%
  • Minimal hepatic metabolism
  • Fecal excretion (primarily as an unchanged drug): approximately 70%
25–35 hours CYP3A4 (moderate)
Isavuconazole 99% Hepatic by CYP3A4 and glucuronidation 130 hours
  • CYP3A4 (moderate)
  • P-gp efflux (weak)
P-gp: P-glycoprotein

Indications

Azoles have a wide variety of uses and unique indications for each medication.

Imidazoles

  • Clotrimazole (Lotrimin®) (topical use only):
    • Candidiasis (including vaginal candidiasis Candidiasis Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis) due to Candida Candida Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis albicans
    • Tinea pedis (athletes foot)
    • Tinea cruris (jock itch): typically affecting the groin
    • Tinea corporis (ringworm): anywhere on the body
  • Miconazole (Monistat®) (topical use only): vaginal candidiasis Candidiasis Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis 
  • Ketoconazole: 
    • Only use when both:
      • Another effective antifungal therapy is not available/tolerated.
      • The benefits of use outweigh the risks.
    • Potential use in systemic fungal infections:
      • Blastomycosis
      • Histoplasmosis Histoplasmosis Histoplasmosis is an infection caused by Histoplasma capsulatum, a dimorphic fungus. Transmission is through inhalation, and exposure to soils containing bird or bat droppings increases the risk of infection. Most infections are asymptomatic; however, immunocompromised individuals generally develop acute pulmonary infection, chronic infection, or even disseminated disease. Histoplasma/Histoplasmosis
      • Coccidioidomycosis Coccidioidomycosis Coccidioidomycosis, commonly known as San Joaquin Valley fever, is a fungal disease caused by Coccidioides immitis or Coccidioides posadasii. When Coccidioides spores are inhaled, they transform into spherules that result in infection. Coccidioidomycosis is also a common cause of community-acquired pneumonia and can cause severe disease in the immunocompromised. Coccidioides/Coccidioidomycosis

Triazoles

In addition to the specific indications listed below, most of the triazoles can also be used as prophylaxis against fungal infections in immunosuppressed individuals.

  • Fluconazole: good activity against yeasts (e.g., Candida Candida Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis), no significant activity against molds (e.g., Aspergillus):
    • Candidiasis from susceptible organisms such as C. albicans (C. krusei and C. glabrata are typically resistant to fluconazole):
      • Mucocutaneous infections (1st-line agent): esophageal, oropharyngeal, and vaginal
      • Peritoneal
      • Urinary tract infections Urinary tract infections Urinary tract infections (UTIs) represent a wide spectrum of diseases, from self-limiting simple cystitis to severe pyelonephritis that can result in sepsis and death. Urinary tract infections are most commonly caused by Escherichia coli, but may also be caused by other bacteria and fungi. Urinary Tract Infections
      • Pneumonia
      • Systemic infections (e.g., candidemia) 
    • Cryptococcus infections:
      • Meningitis
      • Pneumonia
    • Coccidioidomycosis Coccidioidomycosis Coccidioidomycosis, commonly known as San Joaquin Valley fever, is a fungal disease caused by Coccidioides immitis or Coccidioides posadasii. When Coccidioides spores are inhaled, they transform into spherules that result in infection. Coccidioidomycosis is also a common cause of community-acquired pneumonia and can cause severe disease in the immunocompromised. Coccidioides/Coccidioidomycosis
  • Itraconazole: good activity against dimorphic fungi Fungi Fungi belong to the eukaryote domain and, like plants, have cell walls and vacuoles, exhibit cytoplasmic streaming, and are immobile. Almost all fungi, however, have cell walls composed of chitin and not cellulose. Fungi do not carry out photosynthesis but obtain their substrates for metabolism as saprophytes (obtain their food from dead matter). Mycosis is an infection caused by fungi. Mycology: Overview (fungus existing as both a mold and yeast):
    • Blastomycosis:
      • 1st-line agent for mild-moderate cases
      • Used in severe cases as step-down therapy after a course of amphotericin B
    • Histoplasmosis Histoplasmosis Histoplasmosis is an infection caused by Histoplasma capsulatum, a dimorphic fungus. Transmission is through inhalation, and exposure to soils containing bird or bat droppings increases the risk of infection. Most infections are asymptomatic; however, immunocompromised individuals generally develop acute pulmonary infection, chronic infection, or even disseminated disease. Histoplasma/Histoplasmosis (1st-line agent for mild-moderate cases)
    • Sporothrix infections
    • Onychomycosis
    • Candidiasis
  • Voriconazole: similar effectiveness as itraconazole against dimorphic fungi Fungi Fungi belong to the eukaryote domain and, like plants, have cell walls and vacuoles, exhibit cytoplasmic streaming, and are immobile. Almost all fungi, however, have cell walls composed of chitin and not cellulose. Fungi do not carry out photosynthesis but obtain their substrates for metabolism as saprophytes (obtain their food from dead matter). Mycosis is an infection caused by fungi. Mycology: Overview:
    • Aspergillosis (1st-line agent)
    • Candida Candida Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis infections (including infections due to fluconazole-resistant species):
      • Mucocutaneous candidiasis Candidiasis Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis
      • Candidemia
      • Disseminated infections in the heart, abdomen, kidney, bladder, and wounds
    • Serious infections caused by:
      • Scedosporium spp.
      • Fusarium spp.
  • Posaconazole and isavuconazole: broadest spectrum of azoles:
    • Candidiasis (including strains resistant to fluconazole)
    • Aspergillosis (2nd-line agent)
    • Mucormycosis

Adverse Effects and Contraindications

Adverse effects

  • GI distress: nausea, vomiting, and/or diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Dermatologic symptoms:
    • Photosensitivity
    • Rash
    • Alopecia Alopecia Alopecia is the loss of hair in areas anywhere on the body where hair normally grows. Alopecia may be defined as scarring or non-scarring, localized or diffuse, congenital or acquired, reversible or permanent, or confined to the scalp or universal; however, alopecia is usually classified using the 1st 3 factors. Alopecia
  • Hepatotoxicity:
    • Possible with all the azoles
    • Ranges from mild ↑ in transaminases (approximately 5–10% of individuals) to hepatitis/fulminant hepatic failure
  • Ketoconazole:
    • Adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease: hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia, and alkalosis
    • The worst GI symptoms and hepatotoxicity of all the azoles
  • Itraconazole:
    • Hypokalemia
    • Heart failure
  • Voriconazole:
    • Vision changes: 
      • May include abnormal vision, flashes of light, photophobia, and/or color changes
      • Typically starts within 30 minutes of administration and lasts 30–60 minutes
      • Seen in 20%–30% of patients
    • Neurotoxicity:
      • Visual hallucinations
      • Confusion and/or agitation
      • Myoclonic movements
      • Demyelinating neuropathy in the lower extremities (extremely rare, typically in patients also taking tacrolimus)
    • QT prolongation
    • Photosensitivity
    • Periostitis ( inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of the periosteum (the connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue around the bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones))
  • Posaconazole and isavuconazole: generally fewer side effects and better tolerated than voriconazole

Contraindications

  • Hypersensitivity to azole medications
  • Hepatic disease
  • Coadministration of medications affecting relevant CYP enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes:
    • Because numerous drug-to-drug interactions exist for the azoles, carefully evaluate medications to avoid toxicity or underdosing.
    • A common issue for immunosuppressed individuals (often on many medications and at higher risk for fungal infections)
  • Heart failure (itraconazole)
  • Arrhythmias (voriconazole and ketoconazole)
  • Adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease (voriconazole and ketoconazole)
  • Pregnancy

Monitoring

  • Serum azole concentrations are monitored often (recommended for itraconazole, voriconazole, and posaconazole)
  • Transaminases (especially voriconazole and ketoconazole)
  • Adrenal function

Mechanisms of Resistance

The common mechanisms contributing to antifungal resistance include:

  • Mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations of the drug’s target site → ↓ drug affinity for lanosterol 14-α-demethylase → ↓ inhibition
  • ↑ Efflux pumps → less drug within the fungal cell
  • Reduced uptake of the drug → less drug within the fungal cell
  • Target enzyme is overproduced.

Comparison of Antifungal Medications

Table: Comparison of antifungal medications
Drug class (examples) Mechanism of action Clinical relevance
Azoles (Fluconazole, Voriconazole) Inhibits the production of ergosterol (a critical component of the fungal cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane) by blocking the lanosterol 14-α-demethylase enzyme
  • Widely used antifungals with a relatively broad spectrum of activity
  • Many drug-to-drug interactions due to effects on the CYP450 system
  • Hepatotoxicity
  • Overall less toxic than amphotericin B
Polyenes Polyenes Polyenes are a class of fungicidal agents that consist of 2 primary drugs in current use, namely, nystatin and amphotericin B. Both these drugs exert their effects by binding to ergosterol (a critical component of fungal cell membranes) and creating pores in the membrane, leading to the leakage of intracellular components and ultimately cell lysis. Polyenes (Amphotericin B, Nystatin) Binds to ergosterol in the fungal cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane creating artificial pores in the membrane → results in leakage of cellular components and leads to cell lysis (death) Amphotericin B:
  • Reserved for life-threatening fungal infections
  • Broad spectrum of activity
  • Relatively ↑ toxicity (especially nephrotoxicity)
  • Overall less toxic than amphotericin B

Nystatin:
  • Topical use only: skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin, mucous membranes, GI lumen
Echinocandins Echinocandins Echinocandins are a group of fungicidal agents that target the fungal cell wall. Echinocandins inhibit β-glucan synthase, which in turn inhibits the production of β-glucan, a key structural component of fungal cell walls. The 3 primary drugs in this class include caspofungin, micafungin, and anidulafungin. Echinocandins (Caspofungin, Micafungin, Anidulafungin) Inhibits β-glucan synthase (the enzyme synthesizing β-glucan and an important structural component of the fungal cell wall) → weakened cell wall → cell lysis
  • Treats Candida Candida Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis and Aspergillus infections in critically ill and neutropenic patients
  • Minimal toxicity
  • Minimal drug-to-drug interactions
Griseofulvin Griseofulvin In addition to the 3 other major classes of antifungal agents (azoles, polyenes, and echinocandins), several other clinically important antifungal agents are used, including flucytosine, griseofulvin, and terbinafine. Griseofulvin acts within the stratum corneum of the skin and are used to treat dermatophyte infections of the skin, hair, and nails. Flucytosine, Griseofulvin, and Terbinafine
  • Binds to the keratin in newly forming skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin, making the human cells resistant to invasion → over time the new, uninfected hair/ skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin/nail structures replace the old, infected structures
  • Inhibits the assembly of microtubules in dermatophytes Dermatophytes Tinea infections are a group of diseases caused by fungi infecting keratinized tissue (hair, nails, and skin). These infections are termed dermatomycoses and are caused by the dermatophyte fungi. There are approximately 40 dermatophyte fungi that are part of 3 genera, including Trichophyton, Epidermophyton, and Microsporum. These infections can affect any part of the body but occur most often in warm, moist regions like the groin and the feet. Dermatophytes/Tinea Infections → inhibits fungal cell replication
  • Treats dermatophyte infections of the hair, skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin, and nails
  • Oral medication only (not topically active)
  • Affects the CYP450 system (more drug-to-drug interactions)
  • Largely replaced by newer agents (e.g., terbinafine Terbinafine In addition to the 3 other major classes of antifungal agents (azoles, polyenes, and echinocandins), several other clinically important antifungal agents are used, including flucytosine, griseofulvin, and terbinafine. Terbinafine acts within the stratum corneum of the skin and are used to treat dermatophyte infections of the skin, hair, and nails. Flucytosine, Griseofulvin, and Terbinafine)
Terbinafine Inhibits the squalene epoxidase enzyme → blocks the production of squalene epoxide, which is a precursor to ergosterol and a critical component of the cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane
  • Treats dermatophyte infections of the hair, skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin, and nails
  • Agent of choice for onychomycosis
  • Relatively low toxicity
Flucytosine A pyrimidine analog with metabolites:
  • Competing with uracil and disrupting RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure synthesis
  • Irreversibly inhibiting thymidylate synthase → fungus is unable to synthesize or correct DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure
  • Always used in combination with other agents due to:
    • Positive synergistic effects
    • ↑ Resistance with monotherapy
  • Major indications:
    • Cryptococcal meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis
    • Chromoblastomycosis
  • Toxicity: myelosuppression

References

  1. Sheppard, D., Lampiris, H.W. (2012). Antifungal Agents. In Katzung, B.G., Masters, S.B., and Trevor, A.J. (Eds.), Basic and Clinical Pharmacology (12th Ed., pp. 853‒855).
  2. Dodds Ashley, E., Perfect, J.R. (2020). Pharmacology of azoles. In Bogorodskaya, M. (Ed.), UpToDate. Retrieved July 21, 2021, from https://www.uptodate.com/contents/pharmacology-of-azoles 
  3. Kauffman, C.A. (2021). Management of candidemia and invasive candidiasis in adults. In Baron, E.L. (Ed.), UpToDate. Retrieved July 21, 2021, from https://www.uptodate.com/contents/management-of-candidemia-and-invasive-candidiasis-in-adults 
  4. Cox, G.M., Perfect, J.R. (2020). Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated infection in HIV seronegative patients. In Bogorodskaya, M. (Ed.), UpToDate. Retrieved July 21, 2021, from https://www.uptodate.com/contents/cryptococcus-neoformans-treatment-of-meningoencephalitis-and-disseminated-infection-in-hiv-seronegative-patients 
  5. Cox, G.M. (2021). Mucormycosis (zygomycosis). In Bond, S. (Ed.), UpToDate. Retrieved July 21, 2021, from https://www.uptodate.com/contents/mucormycosis-zygomycosis 
  6. Patterson, T.F. (2021). Treatment and prevention of invasive aspergillosis. In Bond, S. (Ed.), UpToDate. Retrieved July 21, 2021, from https://www.uptodate.com/contents/treatment-and-prevention-of-invasive-aspergillosis 
  7. Kauffman, C.A. (2020). Diagnosis and treatment of pulmonary histoplasmosis. In Bogorodskaya, M. (Ed.), UpToDate. Retrieved July 21, 2021, from https://www.uptodate.com/contents/diagnosis-and-treatment-of-pulmonary-histoplasmosis 
  8. Bradsher, R.W. (2020). Treatment of blastomycosis. In Bogorodskaya. M. (Ed.), UpToDate. Retrieved July 21, 2021, from https://www.uptodate.com/contents/treatment-of-blastomycosis 
  9. Hidalgo, J.A. (2020). Which medications in the drug class Azole antifungals are used in the treatment of candidiasis? In Medscape. Retrieved July 21, 2021, from https://www.medscape.com/answers/213853-30150/which-medications-in-the-drug-class-azole-antifungals-are-used-in-the-treatment-of-candidiasis 
  10. Nivoix, Y., Ledoux, M., and Herbrecht, R. (2020). Antifungal therapy: new and evolving therapies. Semin Respir Crit Care Med. 2020;41(1):158-174. Retrieved July 21, 2021, from https://www.medscape.com/viewarticle/924712_4 
  11. Lexicomp Drug Information Sheets. (2021). In UpToDate. Retrieved July 21, 2021, from:

USMLE™ is a joint program of the Federation of State Medical Boards (FSMB®) and National Board of Medical Examiners (NBME®). MCAT is a registered trademark of the Association of American Medical Colleges (AAMC). NCLEX®, NCLEX-RN®, and NCLEX-PN® are registered trademarks of the National Council of State Boards of Nursing, Inc (NCSBN®). None of the trademark holders are endorsed by nor affiliated with Lecturio.

Study on the Go

Lecturio Medical complements your studies with evidence-based learning strategies, video lectures, quiz questions, and more – all combined in one easy-to-use resource.

Learn even more with Lecturio:

Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

User Reviews

0.0

()

¡Hola!

Esta página está disponible en Español.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.

Details