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 are mainly used to treat 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 individuals who are critically ill or have neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia. Although echinocandins have a narrower spectrum of activity than some other antifungal classes, they are clinically useful because of their relatively low toxicity profiles and significantly fewer drug interactions than the azoles Azoles Azoles are a widely used class of antifungal medications inhibiting the production of ergosterol, a critical component in the fungal 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. Azoles and amphotericin B. Resistance to echinocandins is generally uncommon, but is emerging in some strains of C. glabrata, usually through mutations that reduce the affinity of this drug to β-glucan synthase.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

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Classification

Echinocandins are a group of antifungal agents that target the fungal cell wall and are typically used to treat invasive 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 in individuals with neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia or those who are critically ill.

  • 3 drugs from this class are currently used clinically:
    • Caspofungin
    • Micafungin
    • Anidulafungin
  • Key benefits of echinocandins over other antifungal drug classes (e.g., azoles Azoles Azoles are a widely used class of antifungal medications inhibiting the production of ergosterol, a critical component in the fungal 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. Azoles and amphotericin B):
    • Low potential for renal or hepatic toxicity
    • Few serious drug-drug interactions

Chemistry and Pharmacodynamics

Chemical structure

  • Large cyclic peptides
  • The large ring is linked to a long fatty-acid chain that acts as an anchor, holding the drug in place 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.
  • Large molecules → poor penetration into the CSF and eye, and low dissolution in the urine

Mechanism of action

Echinocandins exert their effects by inhibiting fungal cell wall production by interfering with the synthesis of β-glucan, an important structural enzyme.

  • Fungal cell wall is composed of 3 primary layers (in order from outside to inside):
    • Proteins
    • β-Glucans:
      • Form essential crosslinks between the proteins above and chitin below
      • Constitute approximately 30%‒60% of the cell wall mass in 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 spp.
    • Chitin
  • Echinocandins inhibit β-glucan synthase, which is the enzyme that synthesizes β-glucan. Inhibition of this enzyme results in:
    • Impairing the ability of the fungus to create and/or maintain its cell wall
    • Significant ↑ in the susceptibility of the fungal cell to osmotic forces → fungicidal effect
  • Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics:
    • Key subunits of β-glucan synthase are encoded in the FKS1 and FKS2 genes.
    • Mutations in these genes can lead to resistance to echinocandins.
  • β-glucan and β-glucan synthase are not found in human cells → significantly less toxicity than some other antifungal agents (e.g., amphotericin B)
  • Echinocandin activity complements the antifungal effects of other drug classes → suitability in combination therapy
Antifungal agents and mechanisms of action

Antifungal agents and mechanisms of action

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Pharmacokinetics

Common characteristics

Characteristics common to all 3 drugs in this class:

  • Poor 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 → IV formulations only
  • High levels of protein binding
  • Poor penetration into:
    • Eyes
    • CNS
  • Neither significantly metabolized by, nor are inducer/inhibitors of cytochrome P450 (CYP450)
  • Do not require dosing adjustments in renal or hepatic impairment
  • Nondialyzable

Caspofungin

Caspofungin exhibits complicated, triphasic, nonlinear 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 and distribution:
    • Significant tissue distribution leads to an initial rapid decline in plasma levels.
    • Next, there is a re-release of the drug from the extravascular tissue.
    • Highly protein bound
  • Metabolism:
    • Slow but extensive hepatic metabolism (somewhat faster in younger individuals)
    • Interferes with cyclosporine metabolism
  • Excretion:
    • Half-life:
      • Distribution: approximately 10 hours
      • Terminal: 40‒50 hours
    • Urine (40%), primarily as metabolites
    • Feces (35%), primarily as metabolites
  • Clinical relevance of caspofungin 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: requires a loading dose followed by lower once-daily dosing

Micafungin

Micafungin exhibits more predictable, linear 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.

  • Metabolism:
    • Slow but extensive hepatic metabolism (somewhat faster in younger individuals)
    • Undergoes minor hydroxylation by CYP3A
    • Interferes with sirolimus metabolism
  • Excretion:
    • Half-life: 11‒21 hours
    • Primarily fecal (71%)

Anidulafungin

Anidulafungin exhibits more predictable, linear 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.

  • Metabolism:
    • No hepatic metabolism
    • Undergoes slow chemical hydrolysis
  • Excretion:
    • Half-life: 40‒50 hours
    • Fecal (30%)

Indications

Echinocandins are generally interchangeable with regard to their activity and indications.

Spectrum of activity

  • Active against:
    • 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 spp., including some fluconazole-resistant strains of C. glabrata and C. krusei
    • Aspergillus spp.
  • Some activity against endemic mycoses (though generally not adequate to be effective treatment agents):
    • 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
  • No significant activity against:
    • 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 spp.
    • Zygomycosis
    • 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

Clinical uses

Echinocandins are most commonly used in individuals with neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia or 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.

  • Candidiasis:
    • Esophageal
    • Refractory oropharyngeal disease
    • 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 biofilms
    • Candidemia and disseminated disease
    • Intraabdominal abscess, peritonitis, and pleural-space infections
  • Fungal prophylaxis in individuals with neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia and cancer
  • Febrile neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia (empiric therapy, generally preferred over amphotericin B)
  • Salvage therapy in invasive 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

Adverse Events and Contraindications

Adverse effects

Echinocandins are generally very well tolerated and have low toxicity compared with other antifungal agents. Adverse effects, if seen, may include:

  • Fever
  • Minor GI side effects: 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
  • Reaction/phlebitis at the infusion site
  • Infusion reactions (generally with rapid infusion):
    • Bronchospasm and dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea
    • Flushing
    • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
    • Urticaria Urticaria Urticaria is raised, well-circumscribed areas (wheals) of edema (swelling) and erythema (redness) involving the dermis and epidermis with associated pruritus (itch). Urticaria is not a single disease but rather is a reaction pattern representing cutaneous mast cell degranulation. Urticaria (Hives), pruritus, and/or rash
  • 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
  • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview
  • Hepatotoxicity (rare):
    • ↑ In transaminases
    • Hepatic dysfunction (extremely rare): hepatitis and/or hepatic failure

Contraindications

  • Hypersensitivity to echinocandins
  • Suspected hereditary fructose intolerance (as anidulafungin formulations contain fructose)

Resistance

  • Resistance in most 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 spp. is rare, but possible.
  • Exception is with C. glabrata:
    • ↑ Resistance in some strains that are also resistant to fluconazole and voriconazole
    • Resistance may be as high as 12%.
  • Primary mechanism of resistance is a 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 in the FKS gene → ↓ affinity of echinocandins to their target, β-glucan synthase

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 (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., Trevor, A.J. (Eds.), Basic and Clinical Pharmacology (12th Ed., pp. 855).
  2. Lewis, R.E. (2020). Pharmacology of echinocandins. In Bogorodskaya, M (Ed.), UpToDate. Retrieved July 22, 2021, from https://www.uptodate.com/contents/pharmacology-of-echinocandins 
  3. Nivoix, Y., Ledoux, M., Herbrecht, R. (2020). Antifungal therapy: New and evolving therapies. Semin Respir Crit Care Med. 2020; 41, 158-174. Retrieved July 22, 2021, from https://www.medscape.com/viewarticle/924712_5 
  4. Fotsing, L.D. (2021). Caspofungin. StatPearls. Retrieved July 22, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/45651/ 
  5. Lexicomp Drug Information Sheets (2021). In UpToDate. Retrieved July 22, 2021, from:
    1. Caspofungin, https://www.uptodate.com/contents/caspofungin-drug-information 
    2. Micafungin, https://www.uptodate.com/contents/micafungin-drug-information 
    3. Anidulafungin, https://www.uptodate.com/contents/anidulafungin-drug-information

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