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Echinocandins

Echinocandins are a group of fungicidal Fungicidal Polyenes agents that target the fungal 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. 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 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 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 Antifungal Azoles classes, they are clinically useful because of their relatively low toxicity Toxicity Dosage Calculation 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 Amphotericin B Macrolide antifungal antibiotic produced by streptomyces nodosus obtained from soil of the orinoco river region of venezuela. Polyenes. 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 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.

Last updated: Aug 12, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Classification

Echinocandins are a group of antifungal Antifungal Azoles agents that target the fungal 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 and are typically used to treat invasive candidiasis Invasive candidiasis An important nosocomial fungal infection with species of the genus candida, most frequently candida albicans. Invasive candidiasis occurs when candidiasis goes beyond a superficial infection and manifests as candidemia, deep tissue infection, or disseminated disease with deep organ involvement. 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 Antifungal Azoles 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 Amphotericin B Macrolide antifungal antibiotic produced by streptomyces nodosus obtained from soil of the orinoco river region of venezuela. Polyenes):

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 Penetration X-rays into the CSF and eye, and low dissolution in the urine

Mechanism of action

Echinocandins exert their effects by inhibiting fungal 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 production by interfering with the synthesis Synthesis Polymerase Chain Reaction (PCR) of β-glucan, an important structural enzyme.

  • Fungal 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 is composed of 3 primary layers (in order from outside to inside):
    • Proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis
    • β-Glucans:
      • Form essential crosslinks between the proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis above and chitin below
      • Constitute approximately 30%‒60% of the 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 mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast 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 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
    • Significant ↑ in the susceptibility of the fungal cell to osmotic forces → fungicidal Fungicidal Polyenes effect
    • Echinocandins have fungistatic Fungistatic Azoles activity against Aspergillus species
  • 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 Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure.
    • Mutations in these genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure can lead to 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 to echinocandins.
  • β-glucan and β-glucan synthase are not found in human cells → significantly less toxicity Toxicity Dosage Calculation than some other antifungal Antifungal Azoles agents (e.g., amphotericin B Amphotericin B Macrolide antifungal antibiotic produced by streptomyces nodosus obtained from soil of the orinoco river region of venezuela. Polyenes)
  • Echinocandin activity complements the antifungal Antifungal Azoles 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 Penetration X-rays into:
    • Eyes
    • CNS
  • Neither significantly metabolized by, nor are inducer/inhibitors of cytochrome P450 Cytochrome P450 A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism. Drug-Induced Liver Injury (CYP450)
  • Do not require dosing adjustments in renal
  • Caspofungin requires dose adjustment in hepatic impairment (the other two do not).
  • 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 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 and distribution:
    • Significant tissue distribution leads to an initial rapid decline in plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products 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)
    • Interacts with cyclosporine Cyclosporine A cyclic undecapeptide from an extract of soil fungi. It is a powerful immunosupressant with a specific action on T-lymphocytes. It is used for the prophylaxis of graft rejection in organ and tissue transplantation. Immunosuppressants (increases risk of hepatotoxicity Hepatotoxicity Acetaminophen)
  • Excretion:
    • 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:
      • 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 Loading Dose Dosage Calculation 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 Sirolimus A macrolide compound obtained from streptomyces hygroscopicus that acts by selectively blocking the transcriptional activation of cytokines thereby inhibiting cytokine production. It is bioactive only when bound to immunophilins. Sirolimus is a potent immunosuppressant and possesses both antifungal and antineoplastic properties. Immunosuppressants and cyclosporine Cyclosporine A cyclic undecapeptide from an extract of soil fungi. It is a powerful immunosupressant with a specific action on T-lymphocytes. It is used for the prophylaxis of graft rejection in organ and tissue transplantation. Immunosuppressants metabolism
  • Excretion:
    • 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: 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 Hydrolysis The process of cleaving a chemical compound by the addition of a molecule of water. Proteins and Peptides
  • Excretion:

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 Mycoses Diseases caused by fungi. Mycology (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 Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease.

  • 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:
    • 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 Biofilms Encrustations formed from microbes (bacteria, algae, fungi, plankton, or protozoa) embedded in an extracellular polymeric substance matrix that is secreted by the microbes. They occur on body surfaces such as teeth (dental deposits); inanimate objects, and bodies of water. Biofilms are prevented from forming by treating surfaces with dentifrices; disinfectants; anti-infective agents; and anti-fouling agents. Proteus
    • Candidemia and disseminated disease
    • Intraabdominal abscess Abscess Accumulation of purulent material in tissues, organs, or circumscribed spaces, usually associated with signs of infection. Chronic Granulomatous Disease, peritonitis Peritonitis Inflammation of the peritoneum lining the abdominal cavity as the result of infectious, autoimmune, or chemical processes. Primary peritonitis is due to infection of the peritoneal cavity via hematogenous or lymphatic spread and without intra-abdominal source. Secondary peritonitis arises from the abdominal cavity itself through rupture or abscess of intra-abdominal organs. Penetrating Abdominal Injury, and pleural-space 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
  • Fungal prophylaxis Prophylaxis Cephalosporins 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 Febrile neutropenia Fever accompanied by a significant reduction in the number of neutrophils. Neutropenic Fever ( empiric therapy Empiric Therapy Meningitis in Children, generally preferred over amphotericin B Amphotericin B Macrolide antifungal antibiotic produced by streptomyces nodosus obtained from soil of the orinoco river region of venezuela. Polyenes)
  • Salvage therapy in invasive aspergillosis Invasive aspergillosis Lung infections with the invasive forms of aspergillus, usually after surgery, transplantation, prolonged neutropenia or treatment with high-doses of corticosteroids. Invasive pulmonary aspergillosis can progress to chronic necrotizing pulmonary aspergillosis or hematogenous spread to other organs. Aspergillus/Aspergillosis

Adverse Events and Contraindications

Adverse effects

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

  • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
  • Minor GI side effects: 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
  • Reaction/ phlebitis Phlebitis Inflammation of a vein, often a vein in the leg. Phlebitis associated with a blood clot is called (thrombophlebitis). Glycopeptides at the infusion site
  • Infusion reactions (generally with rapid infusion):
    • Bronchospasm Bronchospasm Asthma Drugs 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 Pruritus An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. Atopic Dermatitis (Eczema), and/or rash Rash Rocky Mountain Spotted Fever
  • 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 and Types, leukopenia, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia
  • Hepatotoxicity Hepatotoxicity Acetaminophen (rare):
    • ↑ 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
    • Hepatic dysfunction (extremely rare): hepatitis and/or 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

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 echinocandins
  • Suspected hereditary fructose intolerance Hereditary fructose intolerance An autosomal recessive fructose metabolism disorder due to deficient fructose-1-phosphate aldolase activity, resulting in accumulation of fructose-1-phosphate. The accumulated fructose-1-phosphate inhibits glycogenolysis and gluconeogenesis, causing severe hypoglycemia following ingestion of fructose. Prolonged fructose ingestion in infants leads ultimately to hepatic failure and death. Patients develop a strong distaste for sweet food, and avoid a chronic course of the disease by remaining on a fructose- and sucrose-free diet. Disorders of Fructose Metabolism (as anidulafungin formulations contain fructose)

Resistance

  • 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 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 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 in some strains that are also resistant to fluconazole Fluconazole Triazole antifungal agent that is used to treat oropharyngeal candidiasis and cryptococcal meningitis in aids. Azoles and voriconazole Voriconazole A triazole antifungal agent that specifically inhibits sterol 14-alpha-demethylase and cytochrome p-450 cyp3a. Azoles
    • 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 may be as high as 12%.
  • Primary mechanism of 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 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 Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics → ↓ affinity of echinocandins to their target, β-glucan synthase

Comparison of Antifungal Medications

Table: Comparison of antifungal Antifungal Azoles medications
Drug class (examples) Mechanism of action Clinical relevance
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 ( Fluconazole Fluconazole Triazole antifungal agent that is used to treat oropharyngeal candidiasis and cryptococcal meningitis in aids. Azoles, Voriconazole Voriconazole A triazole antifungal agent that specifically inhibits sterol 14-alpha-demethylase and cytochrome p-450 cyp3a. Azoles) Inhibits the production of ergosterol Ergosterol A steroid occurring in fungi. Irradiation with ultraviolet rays results in formation of ergocalciferol (vitamin d2). Azoles (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 Ergosterol A steroid occurring in fungi. Irradiation with ultraviolet rays results in formation of ergocalciferol (vitamin d2). Azoles 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 (Caspofungin, Micafungin, Anidulafungin) Inhibits β-glucan synthase (the enzyme synthesizing β-glucan and an important structural component of the fungal 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) → 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 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 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 epoxidase Squalene Epoxidase Flucytosine, Griseofulvin, and Terbinafine enzyme → blocks the production of squalene epoxide Squalene Epoxide Flucytosine, Griseofulvin, and Terbinafine, which is a precursor to ergosterol Ergosterol A steroid occurring in fungi. Irradiation with ultraviolet rays results in formation of ergocalciferol (vitamin d2). Azoles 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 Cryptococcal meningitis Meningeal inflammation produced by cryptococcus neoformans, an encapsulated yeast that tends to infect individuals with acquired immunodeficiency syndrome and other immunocompromised states. The organism enters the body through the respiratory tract, but symptomatic infections are usually limited to the lungs and nervous system. The organism may also produce parenchymal brain lesions (torulomas). Clinically, the course is subacute and may feature headache; nausea; photophobia; focal neurologic deficits; seizures; cranial neuropathies; and hydrocephalus. Cryptococcus/Cryptococcosis
    • 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., 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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