Amphotericin B

Absorption

Bioavailability is 100% for intravenous infusion.

Toxicity

Oral, rat: LD50 = >5 gm/kg. Amphotericin B overdoses can result in cardio-respiratory arrest.

Description

Amphotericin B (1397-89-3) is a powerful antimycotic, effective against a wide variety of fungi, including yeast, via two mechanisms: forming pores in the plasma membrane, leading to leakage and death1, and causing oxidative stress2. Other mechanisms have more recently been proposed, including formation of intracellular amphotericin B-containing vesicular bodies that target vacuoles.3 Amphotericin B is also effective against some parasites, such as Leishmania spp.4 Because of its potency and broad-spectrum activity, it is a common additive used to maintain sterility in cell culture and viral transport media.

Description

Amphotericin B is an antifungal antibiotic produced by the bacterium Streptomyces nodosus. In 1955, it was isolated from soil collected near the Orinoco River of Venezuela by researchers at the Squibb Institute for Medical Research, now part of Bristol-Meyers Squibb (New Brunswick, NJ).
Carl P. Schaffner at Rutgers University (New Brunswick) and coauthors elucidated the complete structure and absolute configuration of amphotericin B in 1965. The molecule’s total synthesis was completed by K. C. Nicolaou, then at the University of Pennsylvania (Philadelphia) and co-workers in 1987. Until the 1980s, the compound was the only effective medication against systemic fungal diseases.
Now amphotericin B could have a new, important medical use. Martin D. Burke and colleagues at the University of Illinois at Urbana–Champaign showed that, when administered to cultured epithelial cells taken from the lung airway linings of cystic fibrosis patients, the drug created new ion channels to replace those blocked by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. This procedure increased the pH and lowered the viscosity of the liquid secreted on the lining surfaces, resulting in improved bicarbonate ion flow.
The authors, together with cystic fibrosis researcher Michael J. Welsh at the University of Iowa (Iowa City), then treated pigs that lacked the CFTR protein with amphotericin B. Again, the pH of the airway surface liquid increased, showing that amphotericin B could be effective against cystic fibrosis when the CFTR protein is mutated or even absent. Clinical trials will follow.

Chemical properties

Crystalline Yellow Solid

Originator

Fungizone,Squibb,US,1958

The Uses of Amphotericin B

Amphotericin B is heptaene polyene antifungal originally discovered as a metabolite of Streptomyces nodosus in 1956. Amphotericin B acts by binding sterols in the cell membrane leading to the formation of transmembrane channels and subsequent ion leakage. Amphotericin B is poorly water soluble so has been developed for therapeutic use as a complex with desoxylate or in liposomes to improve bioavailability. Amphotericin B is widely used as a research reagent in diverse applications with over 15,000 literature citations.

The Uses of Amphotericin B

Polypeptide antibiotic active against gram positive bacteria. Antifungal.

The Uses of Amphotericin B

Amphotericin B (Funizone) is an antifungal macrolide antibiotic produced by Streptomyces nodosus that has been used as an alternative, albeit more toxic, drug to the antimonials. See also Amebiasis (Amebic Dysentery) . It acts as a leishmanicide against the visceral and mucocutaneous forms of the disease. To overcome its potentially severe nephrotoxicity, the drug must be administered over an extended period of time.

Background

Amphotericin B shows a high order of in vitro activity against many species of fungi. Histoplasma capsulatum, Coccidioides immitis, Candida species, Blastomyces dermatitidis, Rhodotorula, Cryptococcus neoformans, Sporothrix schenckii, Mucor mucedo, and Aspergillus fumigatus are all inhibited by concentrations of amphotericin B ranging from 0.03 to 1.0 mcg/mL in vitro. While Candida albicans is generally quite susceptible to amphotericin B, non-albicans species may be less susceptible. Pseudallescheria boydii and Fusarium sp. are often resistant to amphotericin B. The antibiotic is without effect on bacteria, rickettsiae, and viruses.

What are the applications of Application

Amphotericin B trihydrate is an antifungal and antibiotic

What are the applications of Application

Amphotericin B is an antifungal and useful cell culture antibiotic

Indications

Used to treat potentially life threatening fungal infections.

Definition

ChEBI: Amphotericin B is a macrolide antibiotic used to treat potentially life-threatening fungal infections.

Indications

Amphotericin B (Fungizone), a polyene antifungal drug produced by the actinomycete Streptomyces nodosus, consists of a large ring structure with both hydrophilic and lipophilic regions. Polyene antifungal drugs bind to the fungal cell membrane component ergosterol, leading to increased fungal cell membrane permeability and the loss of intracellular constituents. Amphotericin has a lesser affinity for the mammalian cell membrane component cholesterol, but this interaction does account for most adverse toxic effects associated with this drug.

Manufacturing Process

The process for producing amphotericin comprises cultivating a strain of Streptomyces nodosus in an aqueous nutrient medium comprising an assimilable, fermentable carbohydrate and an assimilable organic nitrogen source, under submerged aerobic conditions, until substantial antifungal activity is imparted to the medium and recovering amphotericin from the medium.

brand name

Amphotec (Three Rivers); Fungizone (BristolMyers Squibb).

Therapeutic Function

Antifungal

Antimicrobial activity

The spectrum includes most fungi that cause human disease: A. fumigatus, Blast. dermatitidis, Candida spp., Coccidioides spp., Cryptococcus spp., Hist. capsulatum, Paracocc. brasiliensis and Spor. schenckii. Dermatophytes, Fusarium spp. and some other Aspergillus spp., including A. terreus and A. flavus, may be less susceptible, while Scedosporium spp., Trichosporon asahii (formerly T. beigelii) and some fungi that cause mucormycosis are resistant.

Acquired resistance

Resistant strains of C. tropicalis, C. lusitaniae, C. krusei and C. guilliermondii, with alterations in the cell membrane, including reduced amounts of ergosterol, have occasionally been isolated after prolonged treatment, particularly of infections in partially protected sites, such as the vegetations of endocarditis. Significant resistance in yeasts, including C. albicans and C. glabrata, has been reported in isolates from cancer patients with prolonged neutropenia. In some cases resistant strains have caused disseminated infection. There are a few reports of amphotericin-resistant strains of Cryp. neoformans recovered from AIDS patients with relapsed meningitis.

Hazard

May have undesirable side effects.

Pharmaceutical Applications

A fermentation product of Streptomyces nodosus available for intravenous infusion or oral administration. The traditional micellar suspension formulation is often associated with serious toxic effects, in particular renal damage, and this has stimulated efforts to develop chemical modifications and new formulations.

Biochem/physiol Actions

Amphotericin B is used for primary treatment of acute invasive fungal infections, such as aspergillosis.

Pharmacokinetics

Amphotericin B shows a high order of in vitro activity against many species of fungi. Histoplasma capsulatum, Coccidioides immitis, Candida species, Blastomyces dermatitidis, Rhodotorula, Cryptococcus neoformans, Sporothrix schenckii, Mucor mucedo, and Aspergillus fumigatus are all inhibited by concentrations of amphotericin B ranging from 0.03 to 1.0 mcg/mL in vitro. While Candida albicans is generally quite susceptible to amphotericin B, non-albicans species may be less susceptible. Pseudallescheria boydii and Fusarium sp. are often resistant to amphotericin B. The antibiotic is without effect on bacteria, rickettsiae, and viruses.

Pharmacokinetics

Less than 10% of a parenteral dose of the conventional micellar suspension of amphotericin B remains in the blood 12 h after administration. The remainder is thought to bind to tissue cell membranes, the highest concentrations being found in the liver (up to 40% of the dose). Levels in the CSF are less than 5% of the simultaneous blood concentration. The conventional formulation has a terminal half-life of about 2 weeks. About 75% of a given dose is excreted unchanged in the urine and feces. No metabolites have been identified.
The pharmacokinetics of lipid-based formulations are quite diverse. Maximal serum concentrations of the liposomal formulation are much higher than those of the conventional micellar formulation, while levels of colloidal dispersion and lipid complex formulations are lower due to more rapid distribution of the drug to tissue. Administration of lipid-associated formulations of amphotericin B results in much higher drug concentrations in the liver and spleen than are achieved with the conventional formulation. Renal concentrations of the drug are much lower and its nephrotoxic side effects are greatly reduced.
Blood concentrations are unchanged in hepatic or renal failure. Hemodialysis does not influence serum concentrations unless the patient is hyperlipidemic, in which case there is some drug loss due to adherence to the dialysis membrane.

Pharmacology

This compound has a broad spectrum of antifungal activity, including Candida albicans, Leishmania brasiliensis, Mycobacterium leprae, Histoplasma capsulatum, Blastomyces dermatitidus, and Coccidioides immitis. It possesses fungistatic and fungicidal activity depending on the dose used. The antifungal activity of amphotericin B is exhibited because it binds with sterols, in particular with ergosterol in the cellular membrane of sensitive fungi. This reaction makes pores in the membrane and increases the permeability of the membrane to small molecules, thus reducing the function of the membrane as an osmotic barrier and making the cells more sensitive to being destroyed.
Amphotericin B is active against growing cells and cells that are dormant. However, this compound is not highly selective and reacts with host mammalian cells. Despite the many side effects, amphotericin B remains the primary drug for treating severe, acute systemic fungal infections. It is used for generalized fungal infections, such as candidomycosis, aspergillosis, histoplasmosis, cryptococcosis, coccidioidomycosis, blastomycosis, and pulmonary mycoses. Synonyms of this drug are amphocyclin, fungisone, fungilin, and others.

Clinical Use

Aspergillosis
Systemic mycoses with dimorphic fungi (blastomycosis, coccidioidomycosis, histoplasmosis, paracoccidioidomycosis, penicilliosis)
Candidosis
Cryptococcosis
Hyalohyphomycosis, mucormycosis, phaeohyphomycosis
Visceral leishmaniasis

Clinical Use

Amphotericin B is most commonly used to treat serious disseminated yeast and dimorphic fungal infections in immunocompromised hospitalized patients. As additional experience has been gained in the treatment of fungal infections with the newer azoles, the use of amphotericin B has diminished; if azole drugs have equivalent efficacy, they are preferred to amphotericin B because of their reduced toxicity profile and ease of administration. For the unstable neutropenic patient with Candida albicans fungemia, amphotericin B is the drug of choice.
Amphotericin B remains the drug of choice in the treatment of invasive aspergillosis, locally invasive mucormycosis, and many disseminated fungal infections occurring in immunocompromised hosts (the patient population most at risk for serious fungal infections). For example, the febrile neutropenic oncology patient with persistent fever despite empirical antibacterial therapy is best treated with amphotericin B for possible Candida spp. sepsis.

Side Effects

Common side effects of conventional amphotericin B include hypotension, fever, rigors, chills, headache, backache, nausea, vomiting, anorexia, anemia, disturbances in renal function (including hypokalemia and hypomagnesemia), renal toxicity, abnormal liver function (discontinue treatment), rash and anaphylactoid reactions. Risk factors for nephrotoxicity include average daily dose, concomitant treatment with other nephrotoxic drugs and elevated baseline serum creatinine.
The lipid-associated formulations all lower the risk of amphotericin B-induced renal failure. However, infusionrelated side effects, such as fever, rigors and hypotension, develop in up to 40% of patients treated with the colloidal dispersion, and hypoxic events also occur; as a result this formulation is not widely used. In contrast, infusionrelated reactions are uncommon with liposomal amphotericin B or the lipid complex. Patients who have developed renal impairment while receiving the conventional formulation of amphotericin B have improved or stabilized when lipid-associated amphotericin B was substituted, even when the dose was increased. Renal function should be measured at regular intervals, particularly in patients receiving other nephrotoxic drugs.

Safety Profile

Poison by intravenous and intraperitoneal routes. Human systemic effects by intravenous route: leukopenia, lung changes, and cardiac changes.Experimental reproductive effects. Mutation data reported. When heated to decomposition it emits toxic fumes of NOx.

Synthesis

Amphotericin B, is a large polyene antibiotic made from the cultural fluid of the actinomycete Streptomyces nodosus.

Veterinary Drugs and Treatments

Amphotericin B has been used topically and subconjunctivally to treat cases of equine fungal keratitis. Amphotericin B is fungistatic or fungicidal depending on the concentration obtained in body fluids and the susceptibility of the fungus. The drug acts by binding to sterols in the cell membrane of susceptible fungi with a resultant change in membrane permeability allowing leakage of intracellular components. Mammalian cell membranes also contain sterols and it has been suggested that the damage to human cells and fungal cells may share common mechanisms. Amphotericin B has been shown to be effective against the following fungi: Histoplasma capsulatum, Coccidioides immitis, Candida species, Blastomyces dermatitidis, Rhodotorula, Cryptococcus neoformans, Sporothrix schenckii, Mucor mucedo, and Aspergillus fumigatus. While Candida albicans is generally quite susceptible to amphotericin B, non-albicans species may be less susceptible. Pseudallescheria boydii and Fusarium spp. are often resistant to amphotericin B. The major action of amphotericin B is to bind ergosterol in the fungal plasma cell membrane, making the membrane more permeable and resulting in leakage of cell electrolytes and cell death. At high concentrations, amphotericin B is thought to cause oxidative damage to the fungal cell or disruption of fungal cell enzymes.

in vitro

amphotericin b was the most effective drug for treating many life-threatening fungal infections. in cells expressing tlr2 and cd14, amphotericin b induced signal transduction and inflammatory cytokine release. in primary murine macrophages and human cell lines expressing tlr2, cd14, and the adapter protein myd88, amphotericin induced nf-κb-dependent reporter activity and cytokine release, whereas cells deficient in any of these failed to respond. cells with tlr4 mutation were less responsive to amphotericin b stimulation than cells expressing normal tlr4 [1]. amphotericin b could interact with cholesterol, the major sterol of mammal membranes, thus limiting the usefulness of amphotericin b due to its relatively high toxicity [2]. low amb concentrations (≤ 0.1 μm) induced a polarization potential in kcl-loaded liposomes suspended in an iso-osmotic sucrose solution, indicating k+ leakage. amb (＞ 0.1 μm) allowed cations and anions movements. lps suspended in an iso-osmotic nacl solution and exposed to amb (0.05 μm) exhibited a nearly total collapse of the negative membrane potential, indicated that na+ entered into the cells [3].

in vivo

amphotericin b prolonged the incubation time and decreased prpsc accumulation in the hamster scrapie model. amphotericin b markedly resulted in reduction of prpsc levels in mice with transmissible subacute spongiform encephalopathies (tsse) [4].

Metabolism

Exclusively renal

storage

Store at -20°C

References

Kinsky et al. (1970), Antibiotic interaction with model membranes; Annu. Rev. Pharmacol., 10 119 Sokol-Anderson et al. (1986), Amphotericin B-Induced Oxidative Damage and Killing of Candida Albicans; Infect. Dis., 154 75 Grela et al. (2019), Modes of the antibiotic activity of amphotericin B against Candida albicans; Rep., 9 17029 Paila et al. (2010), Amphotericin B inhibits entry of Leishmaniz donovani into primary macrophages; Biophys. Res. Commun., 399 429