Common side effects include a reaction withfever, chills, andheadaches soon after the medication is given, as well askidney problems.[4] Allergic symptoms includinganaphylaxis may occur.[4] Other serious side effects includelow blood potassium andmyocarditis (inflammation of the heart).[3] It appears to be relatively safe inpregnancy.[4] There is a lipid formulation that has a lower risk of side effects.[4] It is in thepolyene class of medications and works in part by interfering with thecell membrane of the fungus.[3][4]
One of the main uses of amphotericin B is treating a wide range of systemicfungal infections. Due to its extensive side effects, it is often reserved for severe infections in critically ill orimmunocompromised patients. It is considered first line therapy for invasivemucormycosis infections,cryptococcal meningitis, and certainaspergillus andcandidal infections.[11][12] It has been a highly effective drug for over fifty years in large part because it has a low incidence ofdrug 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]
Amphotericin B alone isinsoluble innormal saline at apH 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]
The original formulation uses sodiumdeoxycholate to improve solubility.[17] Amphotericin B deoxycholate (ABD) is administeredintravenously.[21] As the original formulation of amphotericin, it is often referred to as "conventional" amphotericin.[22]
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 forinjection and consists of a mixture ofphosphatidylcholine,cholesterol and distearoyl phosphatidylglycerol that in aqueous media spontaneously arrange intounilamellar vesicles that contain amphotericin B.[17][26] It was developed by NeXstar Pharmaceuticals (acquired byGilead Sciences in 1999). It was approved by the United StatesFood and Drug Administration (FDA) in 1997.[27] It is marketed by Gilead in Europe and licensed toAstellas Pharma (formerly Fujisawa Pharmaceuticals) for marketing in the US, andSumitomo Pharmaceuticals in Japan.[28]
Several lipid complex preparations are also available. Abelcet was approved by the FDA in 1995.[29] 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.[29]
An oral preparation exists but is not widely available.[30] Theamphipathic nature of amphotericin along with its low solubility and permeability has posed major hurdles for oral administration given its lowbioavailability. In the past it had been used for fungal infections of the surface of the GI tract such asthrush, but has been replaced by other antifungals such asnystatin andfluconazole.[31]
However, recently novel nanoparticulate drug delivery systems such as AmbiOnp,[32] nanosuspensions, lipid-based drug delivery systems including cochleates, self-emulsifying drug delivery systems,[33] solid lipidnanoparticles[32] and polymeric nanoparticles[34]—such as amphotericin B in pegylated polylactide coglycolide copolymer nanoparticles[35]—have demonstrated potential for oral formulation of amphotericin B.[36] The oral lipid nanocrystal amphotericin by Matinas Biopharma is furthest along, having completed a successful phase 2 clinical trial in cryptococcal meningitis.[37]
Amphotericin B is well known for its severe and potentially lethalside effects, earning it the nickname "amphoterrible".[38][39] Very often, it causes a serious reaction soon after infusion (within 1 to 3 hours), consisting of high fever, shaking chills,hypotension,anorexia,nausea,vomiting,headache,dyspnea andtachypnea,drowsiness, and generalized weakness. The violent chills and fevers have caused the drug to be nicknamed "shake and bake".[40][41] The precise etiology of the reaction is unclear, although it may involve increasedprostaglandin synthesis and the release ofcytokines frommacrophages.[42][43] Deoxycholate formulations (ABD) may also stimulate the release ofhistamine frommast cells andbasophils.[44] 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, andhydrocortisone 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.[45]
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.[46] Less kidney toxicity has been reported with liposomal formulations (such as AmBisome) and it has become preferred in patients with preexisting renal injury.[47][48] The integrity of the liposome is disrupted when it binds to the fungal cell wall, but is not affected by the mammalian cell membrane,[49] so the association with liposomes decreases the exposure of the kidneys to amphotericin B, which explains its less nephrotoxic effects.[50]
In very rare instances, amphotericin B has also been shown to cause reversibleototoxicity causingtinnitus,vertigo, and temporary hearing loss. While there have been only a few reported cases, the hearing loss was temporary in all of them, with hearing showing improvement two weeks after discontinuing the drug.[54][55]
The analogueAM-2-19 has been engineered to be less toxic to the kidneys.[56]
Drug-drug interactions may occur when amphotericin B is coadministered with the following agents:[57]
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 orcisplatin: Increased renal toxicity and increased risk of hypokalemia
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
Amphotericin B binds withergosterol, a component of fungal cell membranes, forming pores that cause rapid leakage ofmonovalent ions (K+,Na+,H+ andCl−) and subsequent fungal cell death. This is amphotericin B's primary effect as an antifungal agent.[58][59] It has been found that the amphotericin B/ergosterol bimolecular complex that maintains these pores is stabilized by Van der Waals interactions.[60] Researchers have found evidence that amphotericin B also causesoxidative stress within the fungal cell,[50] but it remains unclear to what extent this oxidative damage contributes to the drug's effectiveness.[58] The addition offree radical scavengers orantioxidants can lead to amphotericin resistance in some species, such asScedosporium prolificans,[61] without affecting the cell wall.[62][63]
Two amphotericins, amphotericin A and amphotericin B, are known, but only B is used clinically, because it is significantly more activein 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]
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.[50][64][65] 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.[66] Bacteria are not affected as their cell membranes do not usually contain sterols.[67][68]
Amphotericin B administration is limited by infusion-related toxicity. This is thought to result from innate immune production of proinflammatory cytokines.[64][68]
The natural route to synthesis includespolyketide synthase (PKS) components.[69] The carbon chains of amphotericin B are assembled from sixteen 'C2' acetate and three 'C3' propionate units by polyketide syntheses.[70] 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.[71] After cyclisation, the macrolactone core undergoes further modification by hydroxylation, methylation and glycosylation. The order of these three post-cyclization processes is unknown.[71]
It was originally extracted fromStreptomycesnodosus, afilamentousbacterium, in 1955, at the Squibb Institute for Medical Research from cultures of an undescribed streptomycete isolated from the soil collected in theOrinoco River region ofVenezuela.[19][72] 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 theazole antifungals in the early 1980s.[21]
Its complete stereo structure was determined in 1970 by an X-ray structure of the N-iodoacetyl derivative.[70] The first synthesis of the compound's naturally occurring enantiomeric form was achieved in 1987 byK. C. Nicolaou.[73]
Amphotericin B was used to treat a patient with disseminatedcoccidioidomycosis 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."[74]
It is a subgroup of the macrolide antibiotics and exhibits similar structural elements.[75] 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 aliposomal formulation (LAMB). The latter formulations have been developed to improve tolerability and decrease toxicity, but may show considerably differentpharmacokinetic characteristics compared to conventional amphotericin B.[17]
^abcControl of the leishmaniasis: report of a meeting of the WHO Expert Committee on the Control of Leishmaniases. Geneva: World Health Organization. March 2010. pp. 55, 88, 186.hdl:10665/44412.ISBN978-92-4-120949-6.
^abcdefgh"Amphotericin B". The American Society of Health-System Pharmacists.Archived from the original on 2015-01-01. RetrievedJanuary 1, 2015.
^World Health Organization model list of essential medicines: 21st list 2019. Geneva:World Health Organization. 2019.hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^Bennett JE, Dolin R, Blaser MJ (28 August 2014).Drugs Active against Fungi, Pneumocystis, and Microsporidia. Elsevier Health Sciences. pp. 479–494.e4.ISBN978-1-4557-4801-3.
^Moen MD, Lyseng-Williamson KA, Scott LJ (2012-09-17). "Liposomal amphotericin B: a review of its use as empirical therapy in febrile neutropenia and in the treatment of invasive fungal infections".Drugs.69 (3):361–392.doi:10.2165/00003495-200969030-00010.PMID19275278.S2CID34340503.
^Steimbach, Laiza M., Fernanda S. Tonin, Suzane Virtuoso, Helena HL Borba, Andréia CC Sanches, Astrid Wiens, Fernando Fernandez-Llimós, and Roberto Pontarolo. "Efficacy and safety of amphotericin B lipid-based formulations—A systematic review and meta-analysis." Mycoses 60, no. 3 (2017): 146-154.
^abPatel PA, Patravale VB (October 2011). "AmbiOnp: solid lipid nanoparticles of amphotericin B for oral administration".Journal of Biomedical Nanotechnology.7 (5):632–639.doi:10.1166/jbn.2011.1332.PMID22195480.
^Wasan EK, Bartlett K, Gershkovich P, Sivak O, Banno B, Wong Z, et al. (May 2009). "Development and characterization of oral lipid-based amphotericin B formulations with enhanced drug solubility, stability and antifungal activity in rats infected with Aspergillus fumigatus or Candida albicans".International Journal of Pharmaceutics.372 (1–2):76–84.doi:10.1016/j.ijpharm.2009.01.003.PMID19236839.
^Italia JL, Yahya MM, Singh D, Ravi Kumar MN (June 2009). "Biodegradable nanoparticles improve oral bioavailability of amphotericin B and show reduced nephrotoxicity compared to intravenous Fungizone".Pharmaceutical Research.26 (6):1324–1331.doi:10.1007/s11095-009-9841-2.PMID19214716.S2CID8612917.
^Hartsel SC."Studies on Amphotericin B"(PDF).Chem 491, Chemistry Department. University of Wisconsin-Eau Claire.Archived(PDF) from the original on 20 December 2016. Retrieved8 December 2016.
^Gigliotti F, Shenep JL, Lott L, Thornton D (November 1987). "Induction of prostaglandin synthesis as the mechanism responsible for the chills and fever produced by infusing amphotericin B".The Journal of Infectious Diseases.156 (5):784–789.doi:10.1093/infdis/156.5.784.PMID3309074.
^Baronti R, Masini E, Bacciottini L, Mannaioni PF (May 2002). "Differential effects of amphotericin B and liposomal amphotericin B on inflammatory cells in vitro".Inflammation Research.51 (5):259–264.doi:10.1007/pl00000302.PMID12056514.S2CID2124507.
^Goodwin SD, Cleary JD, Walawander CA, Taylor JW, Grasela TH (April 1995). "Pretreatment regimens for adverse events related to infusion of amphotericin B".Clinical Infectious Diseases.20 (4):755–761.doi:10.1093/clinids/20.4.755.PMID7795069.
^Douglas JB, Healy JK (January 1969). "Nephrotoxic effects of amphotericin B, including renal tubular acidosis".The American Journal of Medicine.46 (1):154–162.doi:10.1016/0002-9343(69)90067-9.PMID4951424.
^Jill Adler-Moore,* and Richard T. liposomal formulation, structure, mechanism of action and pre-clinical experience.Journal of Antimicrobial Chemotherapy (2002) 49, 21–30
^abcBaginski M, Czub J (June 2009). "Amphotericin B and its new derivatives - mode of action".Current Drug Metabolism.10 (5):459–469.doi:10.2174/138920009788898019.PMID19689243.
^Zietse R, Zoutendijk R, Hoorn EJ (April 2009). "Fluid, electrolyte and acid-base disorders associated with antibiotic therapy".Nature Reviews. Nephrology.5 (4):193–202.doi:10.1038/nrneph.2009.17.PMID19322184.S2CID24486546.
^O'Keeffe J, Doyle S, Kavanagh K (December 2003). "Exposure of the yeast Candida albicans to the anti-neoplastic agent adriamycin increases the tolerance to amphotericin B".The Journal of Pharmacy and Pharmacology.55 (12):1629–1633.doi:10.1211/0022357022359.PMID14738588.S2CID38893122.
^Baran M, Borowski E, Mazerski J (May 2009). "Molecular modeling of amphotericin B-ergosterol primary complex in water II".Biophysical Chemistry.141 (2–3):162–168.doi:10.1016/j.bpc.2009.01.010.PMID19233539.
^Blatzer M, Jukic E, Posch W, Schöpf B, Binder U, Steger M, et al. (December 2015). "Amphotericin B Resistance in Aspergillus terreus Is Overpowered by Coapplication of Pro-oxidants".Antioxidants & Redox Signaling.23 (18). SAGE Publications Ltd.:1424–1438.doi:10.1089/ars.2014.6220.PMID26054424.
^Vertut-Croquin A, Bolard J, Chabbert M, Gary-Bobo C (June 1983). "Differences in the interaction of the polyene antibiotic amphotericin B with cholesterol- or ergosterol-containing phospholipid vesicles. A circular dichroism and permeability study".Biochemistry.22 (12):2939–2944.doi:10.1021/bi00281a024.PMID6871175.
