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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 Prophylaxis Cephalosporins 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 Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease (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 Hepatotoxicity Acetaminophen, GI distress, cardiac Cardiac Total Anomalous Pulmonary Venous Return (TAPVR) 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 updated: Aug 2, 2021

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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 Toxicity Dosage Calculation/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 Nitrogen An element with the atomic symbol n, atomic number 7, and atomic weight [14. 00643; 14. 00728]. Nitrogen exists as a diatomic gas and makes up about 78% of the earth’s atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. Urea Cycle atoms in the azole ring.
  • Triazoles have 3 nitrogen Nitrogen An element with the atomic symbol n, atomic number 7, and atomic weight [14. 00643; 14. 00728]. Nitrogen exists as a diatomic gas and makes up about 78% of the earth’s atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. Urea Cycle 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 Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism in human cell membranes)
    • Synthesized by lanosterol Lanosterol A triterpene that derives from the chair-boat-chair-boat folding of 2, 3-oxidosqualene. It is metabolized to cholesterol and cucurbitacins. Cholesterol Metabolism 14-α-demethylase, a fungal CYP450 enzyme converting lanosterol Lanosterol A triterpene that derives from the chair-boat-chair-boat folding of 2, 3-oxidosqualene. It is metabolized to cholesterol and cucurbitacins. Cholesterol Metabolism 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 Lanosterol A triterpene that derives from the chair-boat-chair-boat folding of 2, 3-oxidosqualene. It is metabolized to cholesterol and cucurbitacins. Cholesterol Metabolism 14-α-demethylase → inhibits ergosterol production
  • Without new ergosterol production: 
    • Fungi Fungi A kingdom of eukaryotic, heterotrophic organisms that live parasitically as saprobes, including mushrooms; yeasts; smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi, commonly known as molds, refer to those that grow as multicellular colonies. Mycology 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

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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 Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics.

Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption

  • Good oral absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption:
    • Fluconazole
    • Voriconazole
    • Posaconazole
  • 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 absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and 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 Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat as notable exceptions).
  • Drugs collecting in urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat and CSF:
    • Urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat: 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 The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care.
Table: Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics of azoles
Drugs Protein binding Metabolism and clearance Half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics 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 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) 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
Itraconazole 99% 24–48 hours
Voriconazole Approximately 60% Extensive hepatic metabolism by CYP2C19 (major), 2C9, and 3A4 (minor) 6 hours
Posaconazole 98%
  • Minimal hepatic metabolism
  • Fecal excretion (primarily as an unchanged drug): approximately 70%
25–35 hours CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) (moderate)
Isavuconazole 99% Hepatic by CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) and glucuronidation 130 hours
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 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 (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 Tinea pedis Dermatological pruritic lesion in the feet, caused by Trichophyton rubrum, T. mentagrophytes, or Epidermophyton floccosum. Dermatophytes/Tinea Infections (athletes foot Foot The foot is the terminal portion of the lower limb, whose primary function is to bear weight and facilitate locomotion. The foot comprises 26 bones, including the tarsal bones, metatarsal bones, and phalanges. The bones of the foot form longitudinal and transverse arches and are supported by various muscles, ligaments, and tendons. Foot: Anatomy)
    • Tinea cruris Tinea cruris Fungal infection of the groin. The main causative fungus is Trichophyton. Dermatophytes/Tinea Infections (jock itch): typically affecting the groin Groin The external junctural region between the lower part of the abdomen and the thigh. Male Genitourinary Examination
    • Tinea corporis Tinea corporis Dermatophytes/Tinea Infections ( ringworm Ringworm Dermatophytes/Tinea Infections): 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 Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease:
      • 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
      • 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 Prophylaxis Cephalosporins against fungal infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease 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 Aspergillus A genus of mitosporic fungi containing about 100 species and eleven different teleomorphs in the family trichocomaceae. Echinocandins):
    • 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 from susceptible organisms such as C. albicans (C. krusei and C. glabrata are typically resistant to fluconazole):
      • Mucocutaneous infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease (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 (UTIs)
      • Pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia
      • Systemic infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease (e.g., candidemia) 
    • 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 infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease:
      • 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
      • Pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. 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 Dimorphic fungi Mycology (fungus existing as both a mold Mold Mycology and yeast Yeast A general term for single-celled rounded fungi that reproduce by budding. Brewers’ and bakers’ yeasts are saccharomyces cerevisiae; therapeutic dried yeast is yeast, dried. Mycology):
    • 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:
      • 1st-line agent for mild-moderate cases
      • Used in severe cases as step-down therapy after a course of amphotericin B Amphotericin B Macrolide antifungal antibiotic produced by streptomyces nodosus obtained from soil of the orinoco river region of venezuela. Polyenes
    • 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 Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
    • Onychomycosis
    • 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
  • Voriconazole: similar effectiveness as itraconazole against dimorphic fungi Dimorphic fungi Mycology:
    • 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 (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 Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease (including infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease 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 Disseminated infections IL-12 Receptor Deficiency in the heart, abdomen, kidney, bladder Bladder A musculomembranous sac along the urinary tract. Urine flows from the kidneys into the bladder via the ureters, and is held there until urination. Pyelonephritis and Perinephric Abscess, and wounds
    • Serious infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease caused by:
      • Scedosporium spp.
      • Fusarium spp.
  • Posaconazole and isavuconazole: broadest spectrum of azoles:
    • 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 (including strains resistant to fluconazole)
    • 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 (2nd-line agent)
    • 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

Adverse Effects and Contraindications

Adverse effects

  • GI distress: nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, 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 Photosensitivity Tetracyclines
    • Rash Rash Rocky Mountain Spotted Fever
    • 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 Hepatotoxicity Acetaminophen:
    • Possible with all the azoles
    • Ranges from mild ↑ in transaminases Transaminases A subclass of enzymes of the transferase class that catalyze the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally a 2-keto acid). Most of these enzymes are pyridoxyl phosphate proteins. Autoimmune Hepatitis (approximately 5–10% of individuals) to hepatitis/fulminant hepatic failure Hepatic failure Severe inability of the liver to perform its normal metabolic functions, as evidenced by severe jaundice and abnormal serum levels of ammonia; bilirubin; alkaline phosphatase; aspartate aminotransferase; lactate dehydrogenases; and albumin/globulin ratio. Autoimmune Hepatitis
  • Ketoconazole:
    • Adrenal insufficiency Adrenal Insufficiency Conditions in which the production of adrenal corticosteroids falls below the requirement of the body. Adrenal insufficiency can be caused by defects in the adrenal glands, the pituitary gland, or the hypothalamus. 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 Alkalosis A pathological condition that removes acid or adds base to the body fluids. Respiratory Alkalosis
    • The worst GI symptoms and hepatotoxicity Hepatotoxicity Acetaminophen of all the azoles
  • Itraconazole:
    • 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
    • Heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR)
  • Voriconazole:
    • Vision Vision Ophthalmic Exam changes: 
      • May include abnormal vision Vision Ophthalmic Exam, flashes of light, photophobia Photophobia Abnormal sensitivity to light. This may occur as a manifestation of eye diseases; migraine; subarachnoid hemorrhage; meningitis; and other disorders. Photophobia may also occur in association with depression and other mental disorders. Migraine Headache, and/or color changes
      • Typically starts within 30 minutes of administration and lasts 30–60 minutes
      • Seen in 20%–30% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
    • Neurotoxicity:
      • Visual hallucinations Hallucinations Subjectively experienced sensations in the absence of an appropriate stimulus, but which are regarded by the individual as real. They may be of organic origin or associated with mental disorders. Schizophrenia
      • Confusion and/or agitation Agitation A feeling of restlessness associated with increased motor activity. This may occur as a manifestation of nervous system drug toxicity or other conditions. St. Louis Encephalitis Virus
      • Myoclonic movements
      • Demyelinating neuropathy Neuropathy Leprosy in the lower extremities (extremely rare, typically in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship also taking tacrolimus Tacrolimus A macrolide isolated from the culture broth of a strain of streptomyces tsukubaensis that has strong immunosuppressive activity in vivo and prevents the activation of T-lymphocytes in response to antigenic or mitogenic stimulation in vitro. Immunosuppressants)
    • QT prolongation
    • Photosensitivity Photosensitivity Tetracyclines
    • Periostitis Periostitis Inflammation of the periosteum. The condition is generally chronic, and is marked by tenderness and swelling of the bone and an aching pain. Acute periostitis is due to infection, is characterized by diffuse suppuration, severe pain, and constitutional symptoms, and usually results in necrosis. Reactive Arthritis ( 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 Periosteum Thin outer membrane that surrounds a bone. It contains connective tissue, capillaries, nerves, and a number of cell types. Bones: Structure and Types (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: Histology 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. Bones: Structure and Types))
  • Posaconazole and isavuconazole: generally fewer side effects and better tolerated than voriconazole

Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation

  • 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 Toxicity Dosage Calculation or underdosing.
    • A common issue for immunosuppressed individuals (often on many medications and at higher risk for fungal infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease)
  • Heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR) (itraconazole)
  • Arrhythmias (voriconazole and ketoconazole)
  • Adrenal insufficiency Adrenal Insufficiency Conditions in which the production of adrenal corticosteroids falls below the requirement of the body. Adrenal insufficiency can be caused by defects in the adrenal glands, the pituitary gland, or the hypothalamus. Adrenal Insufficiency and Addison’s Disease (voriconazole and ketoconazole)
  • Pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care

Monitoring

  • Serum azole concentrations are monitored often (recommended for itraconazole, voriconazole, and posaconazole)
  • Transaminases Transaminases A subclass of enzymes of the transferase class that catalyze the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally a 2-keto acid). Most of these enzymes are pyridoxyl phosphate proteins. Autoimmune Hepatitis (especially voriconazole and ketoconazole)
  • Adrenal function

Mechanisms of Resistance

The common mechanisms contributing to antifungal resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing 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 Lanosterol A triterpene that derives from the chair-boat-chair-boat folding of 2, 3-oxidosqualene. It is metabolized to cholesterol and cucurbitacins. Cholesterol Metabolism 14-α-demethylase → ↓ inhibition
  • Efflux pumps Efflux Pumps Lincosamides → 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 Lanosterol A triterpene that derives from the chair-boat-chair-boat folding of 2, 3-oxidosqualene. It is metabolized to cholesterol and cucurbitacins. Cholesterol Metabolism 14-α-demethylase enzyme
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 Amphotericin B Macrolide antifungal antibiotic produced by streptomyces nodosus obtained from soil of the orinoco river region of venezuela. Polyenes, Nystatin Nystatin Macrolide antifungal antibiotic complex produced by streptomyces noursei, s. Aureus, and other streptomyces species. The biologically active components of the complex are nystatin a1, a2, and a3. Polyenes) 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 Amphotericin B Macrolide antifungal antibiotic produced by streptomyces nodosus obtained from soil of the orinoco river region of venezuela. Polyenes:
Nystatin Nystatin Macrolide antifungal antibiotic complex produced by streptomyces noursei, s. Aureus, and other streptomyces species. The biologically active components of the complex are nystatin a1, a2, and a3. Polyenes:
  • 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. Skin: Structure and Functions, 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 Caspofungin A cyclic lipopeptide echinocandin and beta-(1, 3)-d-glucan synthase inhibitor that is used to treat internal or systemic mycoses. Echinocandins, Micafungin Micafungin A cyclic lipo-hexapeptide echinocandin antifungal agent that is used for the treatment and prevention of candidiasis. Echinocandins, Anidulafungin Anidulafungin Echinocandin antifungal agent that is used in the treatment of candidemia and candidiasis. Echinocandins) Inhibits β-glucan synthase (the enzyme synthesizing β-glucan and an important structural component of the fungal cell wall Fungal Cell Wall Echinocandins) → weakened cell wall Cell wall The outermost layer of a cell in most plants; bacteria; fungi; and algae. The cell wall is usually a rigid structure that lies external to the cell membrane, and provides a protective barrier against physical or chemical agents. Cell Types: Eukaryotic versus Prokaryotic → 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 Aspergillus A genus of mitosporic fungi containing about 100 species and eleven different teleomorphs in the family trichocomaceae. Echinocandins infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease in critically ill and neutropenic patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
  • Minimal toxicity Toxicity Dosage Calculation
  • 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 Keratin A class of fibrous proteins or scleroproteins that represents the principal constituent of epidermis; hair; nails; horny tissues, and the organic matrix of tooth enamel. Two major conformational groups have been characterized, alpha-keratin, whose peptide backbone forms a coiled-coil alpha helical structure consisting of type I keratin and a type II keratin, and beta-keratin, whose backbone forms a zigzag or pleated sheet structure. Alpha-keratins have been classified into at least 20 subtypes. In addition multiple isoforms of subtypes have been found which may be due to gene duplication. Seborrheic Keratosis 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. Skin: Structure and Functions, 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. Skin: Structure and Functions/nail structures replace the old, infected structures
  • Inhibits the assembly Assembly The assembly of viral structural proteins and nucleic acid (viral DNA or viral RNA) to form a virus particle. Virology of microtubules Microtubules Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin and are influenced by tubulin modulators. The Cell: Cytosol and Cytoskeleton 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 Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease 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. Skin: Structure and Functions, 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 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 Inhibits the squalene Squalene A natural 30-carbon triterpene. Cholesterol Metabolism epoxidase enzyme → blocks the production of squalene Squalene A natural 30-carbon triterpene. Cholesterol Metabolism 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 Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease 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. Skin: Structure and Functions, and nails
  • Agent of choice for onychomycosis
  • Relatively low toxicity Toxicity Dosage Calculation
Flucytosine Flucytosine Flucytosine is a pyrimidine analog that disrupts fungal DNA and RNA synthesis. Flucytosine is always used in combination with other antifungal agents and is primarily used to treat cryptococcal meningitis. Flucytosine, Griseofulvin, and Terbinafine A pyrimidine analog Pyrimidine Analog Flucytosine, Griseofulvin, and Terbinafine with metabolites:
  • Competing with uracil Uracil One of four nucleotide bases in the nucleic acid RNA. Nucleic Acids and disrupting RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure synthesis Synthesis Polymerase Chain Reaction (PCR)
  • Irreversibly inhibiting thymidylate synthase Thymidylate synthase An enzyme of the transferase class that catalyzes the reaction 5, 10-methylenetetrahydrofolate and dump to dihydrofolate and dtmp in the synthesis of thymidine triphosphate. Purine and Pyrimidine Metabolism → fungus is unable to synthesize or correct DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure
  • Always used in combination with other agents due to:
    • Positive synergistic effects
    • Resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing 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 Toxicity Dosage Calculation: myelosuppression Myelosuppression Oxazolidinones

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:

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