Amphotericin B

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Amphotericin B
Clinical data
Trade namesFungizone, Mysteclin-F, AmBisome and other
AHFS/Drugs.comMonograph
MedlinePlusa682643
License data
Pregnancy
category
Intravenous infusion
ATC code
Legal status
Legal status
  • US: WARNING Rx-only[2]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability100% (IV)
Metabolismkidney
Elimination half-life
  • Initial phase: 24 hours
  • Second phase: approximately 15 days
Excretion
  • 40% found in urine after single cumulated over several days
  • Biliary excretion is also important
Identifiers
  • (1R,3S,5R,6R,9R, 11R,15S,16R,17R,18S,19E,21E, 23E,25E,27E,29E,31E,33R,35S,36R,37S)- 33-[(3-amino- 3,6-dideoxy- β-D-mannopyranosyl)oxy]- 1,3,5,6,9,11,17,37-octahydroxy- 15,16,18-trimethyl- 13-oxo- 14,39-dioxabicyclo [33.3.1] nonatriaconta- 19,21,23,25,27,29,31-heptaene- 36-carboxylic acid
JSmol)
Melting point170 °C (338 °F)
SMILES
  • O=C(O)[C@@H]3[C@@H](O)C[C@@]2(O)C[C@@H](O)C[C@@H](O)[C@H](O)CC[C@@H](O)C[C@@H](O)CC(=O)O[C@@H](C)[C@H](C)[C@H](O)[C@@H](C)C=CC=CC=CC=CC=CC=CC=C[C@H](O[C@@H]1O[C@H](C)[C@@H](O)[C@H](N)[C@@H]1O)C[C@@H]3O2
  • InChI=1S/C47H73NO17/c1-27-17-15-13-11-9-7-5-6-8-10-12-14-16-18-34(64-46-44(58)41(48)43(57)30(4)63-46)24-38-40(45(59)60)37(54)26-47(61,65-38)25-33(51)22-36(53)35(52)20-19-31(49)21-32(50)23-39(55)62-29(3)28(2)42(27)56/h5-18,27-38,40-44,46,49-54,56-58,61H,19-26,48H2,1-4H3,(H,59,60)/b6-5+,9-7+,10-8+,13-11+,14-12+,17-15+,18-16+/t27-,28-,29-,30+,31+,32+,33-,34-,35+,36+,37-,38-,40+,41-,42+,43+,44-,46-,47+/m0/s1 checkY
  • Key:APKFDSVGJQXUKY-INPOYWNPSA-N checkY
  (verify)

Amphotericin B is an

intravenously.[4]

Common side effects include a reaction with

kidney problems.[4] Allergic symptoms including anaphylaxis may occur.[4] Other serious side effects include low blood potassium and myocarditis (inflammation of the heart).[3] It appears to be relatively safe in pregnancy.[4] There is a lipid formulation that has a lower risk of side effects.[4] It is in the polyene class of medications and works in part by interfering with the cell membrane of the fungus.[3][4]

Amphotericin B was isolated from

generic medication.[4][10]

Medical uses

Antifungal

One of the main uses of amphotericin B is treating a wide range of systemic

immunocompromised patients. It is considered first line therapy for invasive mucormycosis infections, cryptococcal meningitis, and certain aspergillus and candidal infections.[11][12] It has been a highly effective drug for over fifty years in large part because it has a low incidence of drug resistance in the pathogens it treats. This is because amphotericin B resistance requires sacrifices on the part of the pathogen that make it susceptible to the host environment, and too weak to cause infection.[13]

Antiprotozoal

Amphotericin B is used for life-threatening

primary amoebic meningoencephalitis.[15]

Spectrum of susceptibility

The following table shows the amphotericin B susceptibility for several medically important fungi.

Species MIC[clarification needed] breakpoint
(mg/L)
Aspergillus fumigatus 1[16]
Aspergillus terreus Resistant[16][17]
Candida albicans 1[16]
Candida glabrata
 		1[16]
Candida krusei
 		1[16]
Candida lusitaniae
 		Intrinsically resistant[17]
Cryptococcus neoformans 2[18]
Fusarium oxysporum 2[18]

Available formulations

Intravenous

Amphotericin B alone is insoluble in normal saline at a pH of 7. Therefore, several formulations have been devised to improve its intravenous bioavailability.[19] Lipid-based formulations of amphotericin B are no more effective than conventional formulations, although some evidence suggests lipid-based formulations may be better tolerated and have fewer adverse effects.[20]

Deoxycholate

The original formulation uses sodium deoxycholate to improve solubility.[17] Amphotericin B deoxycholate (ABD) is administered intravenously.[21] As the original formulation of amphotericin, it is often referred to as "conventional" amphotericin.[22]

Liposomal

To improve the tolerability of amphotericin and reduce toxicity, researchers developed several lipid formulations.[17] Liposomal formulations have been found to have less renal toxicity than deoxycholate,[23][24] and fewer infusion-related reactions.[17] They are more expensive than amphotericin B deoxycholate.[25]

AmBisome (liposomal amphotericin B; LAMB) is a liposomal formulation of amphotericin B for injection and consists of a mixture of phosphatidylcholine, cholesterol and distearoyl phosphatidylglycerol that in aqueous media spontaneously arrange into unilamellar vesicles that contain amphotericin B.[17][26] It was developed by NeXstar Pharmaceuticals (acquired by Gilead Sciences in 1999). It was approved by the FDA in 1997.[27] It is marketed by Gilead in Europe and licensed to Astellas Pharma (formerly Fujisawa Pharmaceuticals) for marketing in the US, and Sumitomo Pharmaceuticals in Japan.[citation needed]

Lipid complex formulations

Several lipid complex preparations are also available. Abelcet was approved by the FDA in 1995.[28] It consists of amphotericin B and two lipids in a 1:1 ratio that form large ribbon-like structures.[17] Amphotec is a complex of amphotericin and sodium cholesteryl sulfate in a 1:1 ratio. Two molecules of each form a tetramer that aggregates into spiral arms on a disk-like complex.[26] It was approved by the FDA in 1996.[28]

By mouth

An oral preparation exists but is not widely available.

amphipathic nature of amphotericin along with its low solubility and permeability has posed major hurdles for oral administration given its low bioavailability. In the past it had been used for fungal infections of the surface of the GI tract such as thrush, but has been replaced by other antifungals such as nystatin and fluconazole.[30]

However, recently novel nanoparticulate drug delivery systems such as AmbiOnp,[31] nanosuspensions, lipid-based drug delivery systems including cochleates, self-emulsifying drug delivery systems,[32] solid lipid nanoparticles[31] and polymeric nanoparticles[33]—such as amphotericin B in pegylated polylactide coglycolide copolymer nanoparticles[34]—have demonstrated potential for oral formulation of amphotericin B.[35] The oral lipid nanocrystal amphotericin by Matinas Biopharma is furthest along, having completed a successful phase 2 clinical trial in cryptococcal meningitis.[36]

Side effects

Amphotericin B is well known for its severe and potentially lethal side effects, earning it the nickname "amphoterrible".

drowsiness, and generalized weakness. The violent chills and fevers have caused the drug to be nicknamed "shake and bake".[39][40] The precise etiology of the reaction is unclear, although it may involve increased prostaglandin synthesis and the release of cytokines from macrophages.[41][42] Deoxycholate formulations (ABD) may also stimulate the release of histamine from mast cells and basophils.[43] Reactions sometimes subside with later applications of the drug. This nearly universal febrile response necessitates a critical (and diagnostically difficult) professional determination as to whether the onset of high fever is a novel symptom of a fast-progressing disease or merely the effect of the drug. To decrease the likelihood and severity of the symptoms, initial doses should be low and increased slowly. Paracetamol, pethidine, diphenhydramine, and hydrocortisone have all been used to treat or prevent the syndrome, but the prophylactic use of these drugs is often limited by the patient's condition.[44]

Intravenously administered amphotericin B in therapeutic doses has also been associated with multiple organ damage. Kidney damage, including Type I (distal) renal tubular acidosis, is a frequently reported side effect, and can be severe and/or irreversible.[45] Less kidney toxicity has been reported with liposomal formulations (such as AmBisome) and it has become preferred in patients with preexisting renal injury.[46][47] The integrity of the liposome is disrupted when it binds to the fungal cell wall, but is not affected by the mammalian cell membrane,[48] so the association with liposomes decreases the exposure of the kidneys to amphotericin B, which explains its less nephrotoxic effects.[49]

In addition, electrolyte imbalances such as

cardiac failure have been reported. Skin reactions, including serious forms, are also possible.[citation needed
]

The analogue AM-2-19 has been engineered to be less toxic to the kidneys.[51]

Interactions

Drug-drug interactions may occur when amphotericin B is coadministered with the following agents:[52]

  • Flucytosine: The toxicity of flucytosine is increased and allows for a lower dose of amphotericin B. Amphotericin B may also facilitate entry of flucytosine into the fungal cell by interfering with the permeability of the fungal cell membrane.
  • Diuretics or cisplatin: Increased renal toxicity and increased risk of hypokalemia
  • Corticosteroids: Increased risk of hypokalemia
  • Imidazole Antifungals: Amphotericin B may antagonize the activity of ketoconazole and miconazole. The clinical significance of this interaction is unknown.
  • Neuromuscular-blocking agents: Amphotericin B-induced hypokalemia may potentiate the effects of certain paralytic agents.
  • tenofovir, adefovir
    : The risk of hematological and kidney side effects of amphotericin B is increased
  • Zidovudine: Increased the risk of kidney and hematological toxicity.
  • Other nephrotoxic drugs (such as aminoglycosides): Increased risk of serious renal damage
  • Cytostatic drugs: Increased risk of kidney damage, low blood pressure, and airway spasms
  • Transfusion of leukocytes: There is a risk that pulmonary (lung) damage may occur. Space the intervals between the application of amphotericin B and the transfusion, and monitor pulmonary function

Mechanism of action

Amphotericin B binds with

Scedosporium prolificans, without affecting the cell wall.[citation needed
]

Two amphotericins, amphotericin A and amphotericin B, are known, but only B is used clinically, because it is significantly more active in vivo. Amphotericin A is almost identical to amphotericin B (having a C=C double bond between the 27th and 28th carbons), but has little antifungal activity.[19]

Mechanism of toxicity

Mammalian and fungal membranes contain sterols, a primary membrane target for amphotericin B. Because mammalian and fungal membranes are similar in structure and composition, this is one mechanism by which amphotericin B causes cellular toxicity. Amphotericin B molecules can form pores in the host membrane as well as the fungal membrane. This impairment in membrane barrier function can have lethal effects.[56][57][58] Ergosterol, the fungal sterol, is more sensitive to amphotericin B than cholesterol, the common mammalian sterol. Reactivity with the membrane is also sterol concentration dependent.[59] Bacteria are not affected as their cell membranes do not usually contain sterols.[citation needed]

Amphotericin B administration is limited by infusion-related toxicity. This is thought to result from innate immune production of proinflammatory cytokines.[57][60]

Biosynthesis

The natural route to synthesis includes polyketide synthase components.[61] The carbon chains of amphotericin B are assembled from sixteen 'C2' acetate and three 'C3'propionate units by polyketide syntheses (PKSs).[62] Polyketide biosynthesis begins with the decarboxylative condensation of a dicarboxylic acid extender unit with a starter acyl unit to form a β-ketoacyl intermediate. A series of Claisen reactions constructs the growing chain. The extender units are loaded onto the current ACP domain by acetyl transferase (AT) within each module. The ACP-bound elongation group reacts in a Claisen condensation with the KS-bound polyketide chain. Ketoreductase (KR), dehydratase (DH), and enoyl reductase (ER) enzymes may also be present to form alcohol, double bonds, or single bonds.[63] After cyclisation, the macrolactone core undergoes further modification by hydroxylation, methylation and glycosylation. The order of these three post-cyclization processes is unknown.[63]

History

It was originally extracted from

Orinoco River region of Venezuela.[19][64] Two antifungal substances were isolated from the soil culture, amphotericin A and amphotericin B, but B had better antifungal activity. For decades, it remained the only effective therapy for invasive fungal disease until the development of the azole antifungals in the early 1980s.[21]

Its complete stereo structure was determined in 1970 by an X-ray structure of the N-iodoacetyl derivative.

K. C. Nicolaou.[65]

Amphotericin B was used to treat a patient with disseminated coccidioidomycosis who was admitted to the U.S. Public Health Service Hospital, Seattle, Washington, on January 16, 1957. "The course was rapidly downhill with a grim prognosis as manifested by positive blood cultures, rising complement fixation titers, and failure of the skin to react to intradermal coccidioidin. Amphotericin B was started eight weeks following the onset of his illness. Following this, there was a remarkable improvement both objectively and subjectively. A fourteen-month follow-up after drug discontinuation revealed stabilization of all laboratory studies except for a re-elevation of the complement fixation titer from 1 to 16 to 1 to 32. The patient was completely asymptomatic except for the sputum production containing a few spherules. The clinical effect of this drug in this patient has been most encouraging and agrees with results obtained by others. The lasting effect of the drug seems suggested by the patient's complete well-being after fourteen months of cessation of treatment. It is reasonable to assume that this drug will play a major part in the specific treatment of this disease." [66]

Formulations

It is a subgroup of the macrolide antibiotics and exhibits similar structural elements.[67] Currently, the drug is available in many forms. Either "conventionally" complexed with sodium deoxycholate (ABD), as a cholesteryl sulfate complex (ABCD), as a lipid complex (ABLC), and as a liposomal formulation (LAMB). The latter formulations have been developed to improve tolerability and decrease toxicity, but may show considerably different pharmacokinetic characteristics compared to conventional amphotericin B.[17]

Names

Amphotericin's name originates from the chemical's amphoteric properties.[68]

It is commercially known as Fungilin, Fungizone, Abelcet, AmBisome, Fungisome, Amphocil, Amphotec, and Halizon.[69]


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