Amphotericin B

What is Amphotericin B?

Amphotericin B is one of the most popular anti-fungal drugs. Chemically it is a macrolide polyene that is derived from a soil actinomycete named Streptomyces nodosus, through a fermentative process. It was FDA approved in 1959 and has been clinically used since then.

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Chemistry

Chemically amphotericin B is a macrolide polyene. It is insoluble in saline at a normal pH. This is why it is formulated as a mixture of 50 mg amphotericin B pure drug with 41 mg of the detergent and sodium deoxycholate. This helps in the formation of a mixed colloidal dispersion.

Amphotericin B is formulated as amphotericin B deoxycholate, liposomal amphotericin B (L-AmB), amphotericin B lipid complex (ABLC) and amphotericin B colloidal dispersion (ABCD). Their respective half-lives are 24h, 8.6 ± 3.1h, 173.4h and 28.2h, with their typical dosage of 1.0 mg/kg, 5.0 mg/kg, 5.0 mg/kg and 4.0 mg/kg, respectively.

Drug Administration

Amphotericin B can be administered by intravenous infusion using an injection. The drug comes as a solid powder cake, which is then required to be made into a solution before injecting intravenously (generally injected slowly and intravenously over a period of 2 to 6 hours once daily). Administration of this drug should be done only after consultation with a doctor with proper prescription of the dosage and duration of administration.

Mechanism of Activity

Fungal cell walls have a peculiar precursor of steroid called ergosterol as an important constituent. Amphotericin B preferentially binds to ergosterol. The amphotericin B molecule consists of two domains, namely, a hydrophobic polyene hydrocarbon chain and a hydrophilic polyhydroxyl chain, which makes it act just like a detergent.

Each amphotericin B molecule hydrophobically interacts with a hydrophobic ergosterol molecule via its polyene chain. Eight of such interactions result in the formation of barrel-like pores in the fungal cell wall, with hydrophilic polyhydroxyl chains of amphotericin B facing the interior of the pores.

These pores result in the rapid efflux of potassium ions that inhibits fungal glycolysis, followed by
subsequent magnesium ion efflux and proton influx. This detrimental effect on the fungal cell wall brought about by amphotericin B causes acidification of the fungal cell interior that leads to precipitation of their cytoplasmic constituents and ultimate cell death.

Alternatives of Amphotericin B used

Posaconazole, itraconazole, isavuconazole and echinocandin-based antifungal drugs, reportedly, are currently considered as the clinical alternatives of amphotericin B. However, these options still come secondary to the use of amphotericin B as the primary medication for fungal diseases.

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References:

  • Hamill, R. J. (2013). Amphotericin B Formulations: A Comparative Review of Efficacy and Toxicity. Drugs, 73(9), 919–934. doi: 10.1007/s40265-013-0069-4

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