Amphotericin B

Structural formula
General
Non-proprietary name	Amphotericin B
other names	3- (4-Amino-3,5-dihydroxy-6-methyl-oxan-2-yl) oxy-19,25,27,30,31,33,35,37-octahydroxy-18,20,21-trimethyl -23-oxo-22,39-dioxabicyclo [33.3.1] nonatriaconta-4,6,8,10,12,14,16-heptaen-38-carboxylic acid ( IUPAC )
Molecular formula	C 47 H 73 NO 17
External identifiers / databases
EC number	215-742-2
ECHA InfoCard	100.014.311
PubChem	5280965
ChemSpider	10237579
DrugBank	DB00681
Wikidata	Q412223
Drug information
ATC code	A01 AB04 ; A07 AA07 ; G01 AA03 ; J02 AA01 ;
Drug class	Antibiotic - antifungal agent
properties
Molar mass	924.08 g mol −1
density	1.34 g cm −3 (20 ° C)
boiling point	> 170.0 ° C
solubility	poor in water (1 g l −1 at 20 ° C)
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances Caution
H and P phrases	H: 315-319-335
	P: 280-305 + 351 + 338
Toxicological data	> 5000 mg kg −1 ( LD 50 , rat , oral )
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Amphotericin B is a polyene - macrolactone from Streptomyces nodosum , a actinobacterium from the genus of Streptomycetes . It is used as an antifungal drug to treat fungal infections . Amphotericin B was first described in 1955.

pharmacology

Amphotericin B has long been the primary drug used in the treatment of systemic fungal infections (i.e. fungal infections that affect the blood and internal organs as opposed to superficial fungal infections of the skin and digestive tract). Amphotericin B was used in particular for cryptococcal infections and zygomycoses , but also for histoplasmoses and blastomycoses . The development of resistance of various fungi - with the exception of Aspergillus terreus , here there is a resistance rate of 30% - low.

Amphotericin B has a broad spectrum of activity , but is mainly used to treat fungal infections. It can be used locally (directly at the site of action, e.g. on the skin) or systemically (as an injection, whereby the active substance reaches the target site via the bloodstream). When used orally , Amphotericin B is not absorbed and is only effective in the mouth and throat and in the digestive tract, but does not enter the bloodstream .

The structurally very similar amphotericin A has a single bond between C28 and C29 instead of a double bond. It is not used clinically.

application

For the treatment of superficial fungal infections, Amphotericin B can be given as a cream or ointment for fungal infections of the skin or as a lozenge for fungal infections in the mouth and throat.

Amphotericin B is given as an infusion to treat systemic fungal infections. Because of its high rate of side effects, it is now only used as a reserve antimycotic. However, in recent years various preparations have been developed in which amphotericin B is combined with fat molecules (either in liposomes or as fat-containing solutions). These so-called lipid formulations ( L-AmB , liposomal amphotericin B, or as lipid complex ABLC ) are significantly more expensive than the starting substance or the conventional amphotericin B ( c-AmB ), but this is due to the considerable range of side effects of the non-liposomal formulated amphotericin B.

Amphotericin B is the only treatment option for the very rare and 95% fatal primary amoebic meningoencephalitis (PAM).

Mechanism of action

Amphotericin B interacts with the cell membrane building block ergosterol , which belongs to the sterols and occurs in plants and fungi, but not in vertebrates. This results in an increase in the membrane's permeability for K ⁺ , which, according to the prevailing opinion, is the reason for the fungicidal effect of the antimycotic. However, new studies show that the disruption of membrane permeability does not necessarily have to lead to cell death. The sometimes considerable side effects of amphotericin B result from the fact that the active ingredient in its classic form not only binds to the ergosterol of the fungal cell, but also to human sterols.

Spectrum of activity

Almost all human pathogenic fungi are sensitive to amphotericin B. Also be detected protozoa such as Trichomonas , Leishmania , Trypanosoma , and Entamoeba .

The conventional amphotericin B (c-AmB), which should only be used for special indications or constellations and not for renal insufficiency or additional nephrotoxic therapy, is mainly used for aspergillosis, candidemia, diseases caused by Candida species such as Candida albicans and Candida krusei, the liposomal one Amphotericin B especially in invasive mycoses, empirically in neutropenia and infection with Candida glabrata or Candida krusei. In the case of invasive infections caused by Candida or Aspergillus, the use of amphothericin-B-lipid complex can be considered.

Candida lusitaniae, Paecilomyces, Pseudoallescheria, Acremonium, Aspergillus terreus, Aspergillus flavus and possibly Candida guilermondii show gaps in effectiveness.

Actinomycetes and bacteria are not sensitive .

Side effects

The side effects that occur depend heavily on whether the preparation was applied as a cream or ointment, sucked (and swallowed) as a tablet, or infused as an infusion solution. In general, however, digestive tract complaints and rashes can occur. The occurrence of a Red one syndrome has been reported. With the infusion solution it can u. a. fever, chills, changes in the blood count, hearing loss as well as liver and kidney damage, which is why the use is limited. A test dose should be administered before therapy with amphotericin and the dose should be increased after the start of treatment (especially with conventional c-AmB and liposomal L-AmB ). Caution is advised in the case of impaired renal function : close monitoring of renal function parameters and electrolytes is indicated.

To reduce nephrotoxicity, adequate hydration should be provided after application of amphotericin B. Promethazine , glucocorticoids or pethidine can be given to reduce undesirable side effects . The newly available lipid formulations of amphotericin B are better tolerated and show a slightly better response rate than the original dosage form.

Trade names

Monopreparations

Abelcet (D, A), AmBisome (D, A, CH), Ampho-Moronal (D, A, CH), Amphocil (A), Fungizone (CH), Generika (D, A)

Combination preparations

Mysteclin (D, A)

Individual evidence

↑ ^a ^b ^c data sheet amphotericin B ≥850 IU / mg (PDF) from Carl Roth , accessed on February 1, 2018.
↑ ^a ^b Entry on amphotericin B in the GESTIS substance database of the IFA , accessed on January 8, 2018(JavaScript required) .
↑ Data sheet Amphotericin B from Streptomyces sp. at Sigma-Aldrich , accessed on February 1, 2018 ( PDF ).
Jump up ↑ A. Aszalos, A. Bax, N. Burlinson, P. Roller, C. McNeal: Physico-chemical and microbiological comparison of nystatin, amphotericin A and amphotericin B, and structure of amphotericin A. In: The Journal of antibiotics. Volume 38, Number 12, December 1985, pp. 1699-1713, PMID 3912360 .
↑ Foodborne Pathogenic Microorganisms and Natural Toxins Handbook: Acanthamoeba spp., Naegleria fowleri and other amobae.
↑ Andreas Zumbuehl, Damien Jeannerat u. a .: An Amphotericin B – Fluorescein Conjugate as a Powerful Probe for Biochemical Studies of the Membrane. In: Angewandte Chemie. 116, 2004, pp. 5293-5297, doi : 10.1002 / anie.200460489 .
↑ ^a ^b ^c ^d Marianne Abele-Horn: Antimicrobial therapy. Decision support for the treatment and prophylaxis of infectious diseases. With the collaboration of Werner Heinz, Hartwig Klinker, Johann Schurz and August Stich, 2nd, revised and expanded edition. Peter Wiehl, Marburg 2009, ISBN 978-3-927219-14-4 , p. 270.

[roth-1] ta sheet amphotericin B ≥850 IU / mg (PDF) from Carl Roth , accessed on February 1, 2018.

[GESTIS-2] Entry on amphotericin B in the GESTIS substance database of the IFA , accessed on January 8, 2018(JavaScript required) .

[Sigma-3] Data sheet Amphotericin B from Streptomyces sp. at Sigma-Aldrich , accessed on February 1, 2018 ( PDF ).

[4] Jump up ↑ A. Aszalos, A. Bax, N. Burlinson, P. Roller, C. McNeal: Physico-chemical and microbiological comparison of nystatin, amphotericin A and amphotericin B, and structure of amphotericin A. In: The Journal of antibiotics. Volume 38, Number 12, December 1985, pp. 1699-1713, PMID 3912360 .

[5] Foodborne Pathogenic Microorganisms and Natural Toxins Handbook: Acanthamoeba spp., Naegleria fowleri and other amobae.

[6] Andreas Zumbuehl, Damien Jeannerat u. a .: An Amphotericin B – Fluorescein Conjugate as a Powerful Probe for Biochemical Studies of the Membrane. In: Angewandte Chemie. 116, 2004, pp. 5293-5297, doi : 10.1002 / anie.200460489 .

[Abele-7] Marianne Abele-Horn: Antimicrobial therapy. Decision support for the treatment and prophylaxis of infectious diseases. With the collaboration of Werner Heinz, Hartwig Klinker, Johann Schurz and August Stich, 2nd, revised and expanded edition. Peter Wiehl, Marburg 2009, ISBN 978-3-927219-14-4 , p. 270.