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. Both nystatin and amphotericin B have a broad spectrum of antifungal activity, little to no oral absorption, and significant toxicity (especially nephrotoxicity) when used parenterally. Nystatin is too toxic to be administered intravenously; thus, it is only used to treat fungal infections of the 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, and GI lumen. Amphotericin B is administered via IV, intrathecal, or intraperitoneal routes, or using aerosols to treat serious, life-threatening fungal infections. Secondary resistance to nystatin and amphotericin B is rare but emerging.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

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Classification

Polyenes are one of the original classes of antifungal medications. There are 2 primary polyenes that are currently used:

  • 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, and GI lumen)
    • Too toxic for parenteral use
  • Amphotericin B:
    • Several nonoral routes of administration, including the IV route
    • Highly effective, but significant toxicity compared with other antifungal agents
    • Available as 2 primary formulations:
      • Liposomal amphotericin B (more commonly used due to better tolerability)
      • Amphotericin B deoxycholate

Chemistry and Pharmacodynamics

Chemical structure

Nystatin and amphotericin B have very similar chemical structures, including:

  • A large lactone ring
  • Multiple hydroxyl (-OH) groups on 1 side of the ring
  • Polyene structure on the other side of the ring:
    • Polyunsaturated organic compounds containing at least 3 alternating double and single carbon-carbon bonds (known as conjugated double bonds)
    • Contains a mycosamine group:
      • Binding site for ergosterol
      • Removal of mycosamine group results in the loss of antifungal properties.

Mechanism of action

Polyenes exert their effects by creating pores 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 through binding to ergosterol; however, the exact mechanism of action is unclear.

  • Ergosterol: a critical component of fungal cell membranes (the equivalent of cholesterol in human cell membranes)
  • Polyenes bind to ergosterol and create artificial pores in the cell, resulting in:
    • Leakage of intracellular components (including H+, K+, Cl, and Na+) → destabilizes the cell → cell lysis and death
    • ↑ Production of free radicals and oxidative damage within the cell
  • Considered fungicidal
  • Other effects of amphotericin B (mechanism is not fully understood):
    • Immunomodulatory effects: ability to alter the transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription of cytokines, chemokines, and prostaglandins
    • Upregulates the genes involved in angiogenesis
    • Induces accumulation of NO
Antifungal agents and mechanisms of action

Antifungal agents and mechanisms of action

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

Amphotericin B preparations: deoxycholate versus liposomal

  • Amphotericin B deoxycholate:
    • Conventional preparation in which amphotericin B is in a colloidal suspension
    • High toxicity: Amphotericin can bind to mammalian cholesterol and create similar pores in cells in humans.
  • Liposomal amphotericin B:
    • Developed to reduce toxicity
    • Liposomal amphotericin B preparation:
      • Packaged within lipid drug-delivery vehicles
      • Binds to lipids with an affinity that is in between that of fungal ergosterol and human cholesterol
    • Effects:
      • Less nonspecific binding to human cell membranes → ↓ toxicity without reduced efficacy
      • Larger doses can be administered.
    • Significantly more expensive than amphotericin deoxycholate

Pharmacokinetics

Nystatin

Nystatin is only used topically and as an oral suspension (administered with instructions to “swish and swallow”).

  • Absorption:
    • Not absorbed through mucous membranes or intact 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
    • Oral suspensions are poorly absorbed.
  • Excretion (oral suspension only): fecal, as unchanged drug

Amphotericin B

  • Absorption: poor oral absorption
    • Oral amphotericin is only effective on fungi Fungi Fungi belong to the eukaryote domain and, like plants, have cell walls and vacuoles, exhibit cytoplasmic streaming, and are immobile. Almost all fungi, however, have cell walls composed of chitin and not cellulose. Fungi do not carry out photosynthesis but obtain their substrates for metabolism as saprophytes (obtain their food from dead matter). Mycosis is an infection caused by fungi. Mycology: Overview present within the lumen of the GI tract (it is no longer used to treat these infections).
    • IV administration is required for systemic infections.
  • Distribution:
    • Protein binding > 90%, primarily bound to lipoproteins
    • Widely distributed in most tissues, including:
      • Pleural, peritoneal, pericardial, and synovial fluids
      • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver, spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen, and bile
      • Aqueous humor
    • Only 2% of drug in the serum reaches the CSF. Intrathecal therapy may be required when used to treat fungal 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.
    • Crosses the placenta Placenta The placenta consists of a fetal side and a maternal side, and it provides a vascular communication between the mother and the fetus. This communication allows the mother to provide nutrients to the fetus and allows for removal of waste products from fetal blood. Placenta, Umbilical Cord, and Amniotic Cavity, but considered relatively safe in all trimesters of pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care (Category B: no evidence of risk in studies)
  • Metabolism and excretion: 
    • No metabolites have been identified.
    • Elimination is unclear: Only 5% of an administered dose is accounted for in urine and fecal excretion.
    • Half-life: approximately 15 days
    • No dosing adjustments required in hepatic or renal impairment

Indications

Nystatin

Nystatin is used for susceptible 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 species that cause fungal infections in:

  • Skin
  • Mucous membranes
  • Oral cavity (oral suspension given as “swish and swallow”)

Amphotericin B

Owing to its toxicity and the availability of less toxic agents, amphotericin B should be used only for individuals with severe, life-threatening, invasive fungal infections, or those unable to tolerate alternative agents.

Spectrum of activity:

Amphotericin B is active against:

  • 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.
  • Most Aspergillus spp.
  • 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
  • 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
  • Leishmania Leishmania Leishmania species are obligate intracellular parasites that are transmitted by an infected sandfly. The disease is endemic to Asia, the Middle East, Africa, the Mediterranean, and South and Central America. Clinical presentation varies, dependent on the pathogenicity of the species and the host's immune response. Leishmania/Leishmaniasis spp.
  • Endemic mycoses:
    • 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
    • Sporotrichosis
  • Black and brown molds

Resistance:

Organisms with intrinsic resistance to amphotericin B:

  • A. terreus
  • C. lusitaniae
  • Scedosporium spp.
  • Some Fusarium spp.

Adverse Events and Contraindications

Nystatin

Topical and oral nystatin have very few adverse effects. The only contraindication is a known allergy.

  • Topical: contact dermatitis
  • Oral: 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 (1%‒10% of individuals)
  • Contraindication: hypersensitivities

Amphotericin B

Therapy with amphotericin B is often limited by its toxicity, especially drug-induced renal impairment. Adverse events can be divided into immediate infusion-related reactions and effects due to cumulative toxicity.

Infusion-related toxicity:

  • Near-universal effects during administration:
    • Fever and chills
    • Myalgias and muscle spasms
    • Nausea/vomiting
    • Headache
    • 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
  • Management:
    • Pretreatment:
      • Normal saline infusion
      • Antipyretics
      • Antihistamines Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Antihistamines
      • With/without corticosteroids
    • A test dose may be administered before starting therapy to gauge the severity of reactions and tolerability.

Cumulative toxicity:

  • Nephrotoxicity:
    • Most clinically significant reaction
    • Some degree of renal impairment is noted in up to 80% of individuals:
      • Deoxycholate is more toxic than liposomal preparations.
      • Severe renal failure due to amphotericin B alone is uncommon.
    • The degree of azotemia is 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 (typically stabilizes during therapy).
    • May be:
      • Reversible, when due to ↓ prerenal perfusion
      • Permanent, when due to renal tubular injury
    • Presentation:
      • Oliguria/anuria
      • Renal tubular acidosis Renal Tubular Acidosis Renal tubular acidosis (RTA) is an imbalance in physiologic pH caused by the kidney's inability to acidify urine to maintain blood pH at physiologic levels. Renal tubular acidosis exist in multiple types, including distal RTA (type 1), proximal RTA (type 2), and hyperkalemic RTA (type 4). Renal Tubular Acidosis
      • 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
      • Hypomagnesemia
      • 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: due to ↓ erythropoietin production
    • Management:
      • Consider ↓ dose or switching agents
      • Sodium loading via normal saline infusion given with amphotericin B
      • Dialysis Dialysis Renal replacement therapy refers to dialysis and/or kidney transplantation. Dialysis is a procedure by which toxins and excess water are removed from the circulation. Hemodialysis and peritoneal dialysis (PD) are the two types of dialysis, and their primary difference is the location of the filtration process (external to the body in hemodialysis versus inside the body for PD). Overview and Types of Dialysis may be required.
  • Hepatic toxicity:
    • ↑ Transaminases 
    • Hepatitis
    • Acute hepatic failure (rare)
  • Cardiac toxicity:
    • Heart failure due to direct myocardial toxicity
    • Cardiac arrest Cardiac arrest Cardiac arrest is the sudden, complete cessation of cardiac output with hemodynamic collapse. Patients present as pulseless, unresponsive, and apneic. Rhythms associated with cardiac arrest are ventricular fibrillation/tachycardia, asystole, or pulseless electrical activity. Cardiac Arrest
    • Arrhythmias
  • Hypersensitivity reactions/anaphylaxis
  • After transthecal therapy:
    • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
    • Chemical arachnoiditis may lead to serious neurologic sequelae.

Contraindications and Precautions:

  • Hypersensitivity (the only absolute contraindication)
  • CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease or concurrent use with other nephrotoxic medications

Mechanisms of Resistance

Secondary resistance to amphotericin B is rare but emerging. The primary mechanisms of resistance include:

  • ↓ Ergosterol content in 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 through:
    • Alterations in the ergosterol synthesis pathway
    • Use of sterol intermediates
  • Changes in cell wall structure
  • Exposure of certain yeasts to subinhibitory concentrations of fluconazole can induce resistance to oxidative stress, leading to some resistance against amphotericin B.

Comparison of Antifungal Medications

Table: Comparison of antifungal 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, 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 (Amphotericin B, Nystatin) Binds to ergosterol in the fungal cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane creating artificial pores in the membrane → results in leakage of cellular components and leads to cell lysis (death) Amphotericin B:
  • Reserved for life-threatening fungal infections
  • Broad spectrum of activity
  • Relatively ↑ toxicity (especially nephrotoxicity)
  • Overall less toxic than amphotericin B

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

References

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  7. 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 
  8. Cox, G.M. (2021). Mucormycosis (zygomycosis). In Bond, S. (Ed.), UpToDate. Retrieved July 21, 2021, from https://www.uptodate.com/contents/mucormycosis-zygomycosis 
  9. 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 
  10. 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 
  11. 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

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