Polyenes

Classification

Polyenes are one of the original classes of antifungal Antifungal Azoles 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. Skin: Structure and Functions, 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 Toxicity Dosage Calculation compared with other antifungal Antifungal Azoles 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 Ergosterol A steroid occurring in fungi. Irradiation with ultraviolet rays results in formation of ergocalciferol (vitamin d2). Azoles
    • Removal of mycosamine group results in the loss of antifungal Antifungal Azoles 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 Ergosterol A steroid occurring in fungi. Irradiation with ultraviolet rays results in formation of ergocalciferol (vitamin d2). Azoles; however, the exact mechanism of action is unclear.

• Ergosterol Ergosterol A steroid occurring in fungi. Irradiation with ultraviolet rays results in formation of ergocalciferol (vitamin d2). Azoles: a critical component of fungal cell membranes (the equivalent of cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism in human cell membranes)
• Polyenes bind BIND Hyperbilirubinemia of the Newborn to ergosterol Ergosterol A steroid occurring in fungi. Irradiation with ultraviolet rays results in formation of ergocalciferol (vitamin d2). Azoles 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 Free radicals Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. Ischemic Cell Damage 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 Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response, chemokines Chemokines Class of pro-inflammatory cytokines that have the ability to attract and activate leukocytes. They can be divided into at least three structural branches: c; cc; and cxc; according to variations in a shared cysteine motif. Adaptive Cell-mediated Immunity, and prostaglandins Prostaglandins A group of compounds derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway. They are extremely potent mediators of a diverse group of physiological processes. Eicosanoids → ↑ phagocytic action
  • Upregulates the 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 involved in angiogenesis Angiogenesis Bartonella
  • Induces accumulation of nitric oxide Nitric Oxide A free radical gas produced endogenously by a variety of mammalian cells, synthesized from arginine by nitric oxide synthase. Nitric oxide is one of the endothelium-dependent relaxing factors released by the vascular endothelium and mediates vasodilation. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic gmp. Pulmonary Hypertension Drugs (or free radicals Free radicals Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. Ischemic Cell Damage)

Amphotericin B preparations: deoxycholate versus liposomal

• Amphotericin B deoxycholate or conventional amphotericin B (C-AMB):
  • Conventional preparation in which amphotericin B is in a colloidal suspension
  • High toxicity Toxicity Dosage Calculation: Amphotericin can bind BIND Hyperbilirubinemia of the Newborn to mammalian cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism and create similar pores in cells in humans.
• Lipid-based formulations (liposomal amphotericin B and amphotericin B lipid complex):
  • Developed to reduce toxicity Toxicity Dosage Calculation
  • Liposomal amphotericin B (L-AMB) preparation:
    • Packaged within lipid drug-delivery vehicles
    • Binds to lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids with an affinity that is in between that of fungal ergosterol Ergosterol A steroid occurring in fungi. Irradiation with ultraviolet rays results in formation of ergocalciferol (vitamin d2). Azoles and human cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism
  • Amphotericin B lipid complex (ABLC):
    • Amphotericin B is complexed with 2 phospholipids Phospholipids Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. Lipid Metabolism
    • Carries higher risk of nephrotoxicity Nephrotoxicity Glycopeptides compared to L-AMB
  • Effects:
    • Less nonspecific binding to human cell membranes → ↓ toxicity Toxicity Dosage Calculation 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 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:
  • 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. Skin: Structure and Functions
  • Oral suspensions are poorly absorbed.
• Excretion (oral suspension only): fecal, as unchanged drug

Amphotericin B

• 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: 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
  • Oral amphotericin is only effective on fungi Fungi A kingdom of eukaryotic, heterotrophic organisms that live parasitically as saprobes, including mushrooms; yeasts; smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi, commonly known as molds, refer to those that grow as multicellular colonies. Mycology present within the lumen of the GI tract (it is no longer used to treat these 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).
  • IV administration is required for systemic infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease.
• Distribution:
  • Protein binding > 90%, primarily bound to lipoproteins Lipoproteins Lipid-protein complexes involved in the transportation and metabolism of lipids in the body. They are spherical particles consisting of a hydrophobic core of triglycerides and cholesterol esters surrounded by a layer of hydrophilic free cholesterol; phospholipids; and apolipoproteins. Lipoproteins are classified by their varying buoyant density and sizes. Lipid Metabolism
  • 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: Anatomy, 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: Anatomy, and bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy
    • Aqueous humor Humor Defense Mechanisms
  • Only 2% of drug in the serum reaches the CSF. Intrathecal therapy may be required when used to treat fungal meningitis Fungal meningitis Meningitis caused by fungal agents which may occur as opportunistic infections or arise in immunocompetent hosts. Meningitis.
  • Crosses the placenta Placenta A highly vascularized mammalian fetal-maternal organ and major site of transport of oxygen, nutrients, and fetal waste products. It includes a fetal portion (chorionic villi) derived from trophoblasts and a maternal portion (decidua) derived from the uterine endometrium. The placenta produces an array of steroid, protein and peptide hormones (placental hormones). Placenta, Umbilical Cord, and Amniotic Cavity, but considered relatively safe in all trimesters of pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care (Category B: no evidence of risk in studies)
• Metabolism and excretion:
  • No metabolites have been identified.
  • Elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy is unclear: Only 5% of an administered dose is accounted for in urine and fecal 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: 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 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:

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

Amphotericin B

Owing to its toxicity Toxicity Dosage Calculation and the availability of less toxic agents, amphotericin B should be used only for individuals with severe, life-threatening, invasive fungal infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease, 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 Aspergillus A genus of mitosporic fungi containing about 100 species and eleven different teleomorphs in the family trichocomaceae. Echinocandins spp.
• 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
• 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 Mycoses Diseases caused by fungi. Mycology:
  • Blastomycosis Blastomycosis Blastomycosis is an infection caused by inhalation of the spores of the fungus, Blastomyces. Blastomyces species thrive in moist soil and decaying material and are common in the Ohio and Mississippi River valleys and the Great Lakes regions of the United States and Canada. Although most patients are asymptomatic, some can develop pneumonia. Blastomyces/Blastomycosis
  • 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 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:

Organisms with intrinsic 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 amphotericin B:

• A. terreus A. terreus Aspergillus/Aspergillosis
• 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 Allergy An abnormal adaptive immune response that may or may not involve antigen-specific IgE Type I Hypersensitivity Reaction.

• Topical: contact dermatitis Contact dermatitis A type of acute or chronic skin reaction in which sensitivity is manifested by reactivity to materials or substances coming in contact with the skin. It may involve allergic or non-allergic mechanisms. Male Genitourinary Examination
• Oral: 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 (1%‒10% of individuals)
• Contraindication: hypersensitivities

Amphotericin B

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

Infusion-related toxicity Toxicity Dosage Calculation:

• Near-universal effects during administration:
  • 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 and chills Chills The sudden sensation of being cold. It may be accompanied by shivering. Fever
  • Myalgias Myalgias Painful sensation in the muscles. Tick-borne Encephalitis Virus and muscle spasms Spasms An involuntary contraction of a muscle or group of muscles. Spasms may involve skeletal muscle or smooth muscle. Ion Channel Myopathy
  • 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
  • Headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess
  • 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 Normal saline A crystalloid solution that contains 9. 0g of sodium chloride per liter of water. It has a variety of uses, including: as a contact lens solution, in ophthalmic solutions and nasal lavage, in wound irrigation, and for fluid therapy. Intravenous Fluids 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 Corticosteroids Chorioretinitis
  • A test dose may be administered before starting therapy to gauge the severity of reactions and tolerability.

Cumulative toxicity Toxicity Dosage Calculation:

• Nephrotoxicity Nephrotoxicity Glycopeptides:
  • 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 Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome due to amphotericin B alone is uncommon.
  • The degree of azotemia Azotemia A biochemical abnormality referring to an elevation of blood urea nitrogen and creatinine. Azotemia can be produced by kidney diseases or other extrarenal disorders. When azotemia becomes associated with a constellation of clinical signs, it is termed uremia. Acute Kidney Injury 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 Oliguria Decreased urine output that is below the normal range. Oliguria can be defined as urine output of less than or equal to 0. 5 or 1 ml/kg/hr depending on the age. Renal Potassium Regulation/ anuria Anuria Absence of urine formation. It is usually associated with complete bilateral ureteral (ureter) obstruction, complete lower urinary tract obstruction, or unilateral ureteral obstruction when a solitary kidney is present. Acute Kidney Injury
    • Renal tubular acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory 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 Hypomagnesemia A nutritional condition produced by a deficiency of magnesium in the diet, characterized by anorexia, nausea, vomiting, lethargy, and weakness. Symptoms are paresthesias, muscle cramps, irritability, decreased attention span, and mental confusion, possibly requiring months to appear. Deficiency of body magnesium can exist even when serum values are normal. In addition, magnesium deficiency may be organ-selective, since certain tissues become deficient before others. Electrolytes
    • 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: due to ↓ erythropoietin Erythropoietin Glycoprotein hormone, secreted chiefly by the kidney in the adult and the liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. Erythrocytes: Histology production
  • Management:
    • Consider ↓ dose or switching agents
    • Sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia loading via normal saline Normal saline A crystalloid solution that contains 9. 0g of sodium chloride per liter of water. It has a variety of uses, including: as a contact lens solution, in ophthalmic solutions and nasal lavage, in wound irrigation, and for fluid therapy. Intravenous Fluids 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). Peritoneal Dialysis and Hemodialysis may be required.
• Hepatic toxicity Toxicity Dosage Calculation:
  • ↑ 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 
  • Hepatitis
  • Acute 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 (rare)
• Cardiac toxicity Toxicity Dosage Calculation:
  • Heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR) due to direct myocardial toxicity Toxicity Dosage Calculation
  • 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 Anaphylaxis An acute hypersensitivity reaction due to exposure to a previously encountered antigen. The reaction may include rapidly progressing urticaria, respiratory distress, vascular collapse, systemic shock, and death. Type I Hypersensitivity Reaction
• 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 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 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 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 amphotericin B is rare but emerging. The primary mechanisms 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 include:

• ↓ Ergosterol Ergosterol A steroid occurring in fungi. Irradiation with ultraviolet rays results in formation of ergocalciferol (vitamin d2). Azoles 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 Ergosterol A steroid occurring in fungi. Irradiation with ultraviolet rays results in formation of ergocalciferol (vitamin d2). Azoles synthesis Synthesis Polymerase Chain Reaction (PCR) pathway
  • Use of sterol Sterol Steroids with a hydroxyl group at c-3 and most of the skeleton of cholestane. Additional carbon atoms may be present in the side chain. Mycoplasma intermediates
• Changes in 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 structure
• Exposure of certain yeasts to subinhibitory concentrations of fluconazole Fluconazole Triazole antifungal agent that is used to treat oropharyngeal candidiasis and cryptococcal meningitis in aids. Azoles can induce 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 oxidative stress Oxidative stress A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products. Cell Injury and Death, leading to some 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 against amphotericin B.

Comparison of Antifungal Medications