Amphotericin B: mechanism, spectrum, pharmacokinetics, uses and side effects

Amphotericin B is a macrocyclic polyene antibiotic derived from Streptomyces nodosus.
It remains the drug of choice for many forms of deep fungal infection.

Mechanism of action of Amphotericin B:

Amphotericin B binds to ergosterol, the principal sterol in the membrane of susceptible fungal cells, causing impairment of membrane barrier function, loss of cell constituents, metabolic disruption and cell death.
In addition to its membrane permeabilizing effects, the drug can cause oxidative damage to fungal cells.
Mammalian cell membranes also contain sterols, and it has been suggested that amphotericin B-induced damage to human and fungal cells shares common mechanisms.

Amphotericin B has a broad spectrum of action including many Aspergillus species, Blastomyces dermatitidis, Candida species, Coccidioides immitis, Cryptococcus neoformans, Histoplasma capsulatum, Paracoccidioides brasiliensis and Penicillium mameffei.
Aspergillus terreus, Fusarium species, Malassezia furfur, Scedosporium species and Trichosporon asahii are often resistant.

Treatment failure attributable to the development of amphotericin B resistance is rare.
Resistant strains of Candida lusitaniae and C. tropicalis, with qualitative and quantitative alterations in membrane sterol composition, including reduced amounts of ergosterol, have been isolated during treatment.
There are a few reports of resistant strains of Cryptococcus neoformans isolated from persons with the acquired immunodeficiency syndrome (AIDS) with relapsed infection.

i. Conventional formulation of amphotericin B:

Amphotericin B is used as micellar suspension formulation.
Administration of the conventional formulation of the drug is associated with harmful side-effects and unpleasant reactions which often limit the amount that can be given.
Parenteral administration of the conventional micellar suspension formulation of amphotericin B is often linked with treatment-limiting toxic effects, in particular renal impairment.

ii. Lipid based formulation of amphotericin B:

Three lipid-based formulations of the Amphotericin B are in use;
- liposomal amphotericin B (AmBisome) in which the drug is encapsulated in phospholipid-containing liposomes
- Amphotericin B lipid complex (Abelcet, ABLC) in which it is complexed with phospholipids to form ribbon-like structures
- Amphotericin B colloidal dispersion (Amphocil, Amphotec, ABCD) in which the drug is complexed with cholesterol sulphate to form small lipid discs.
The lipid-based formulations of amphotericin B are better tolerated than conventional amphotericin B and higher doses can be given over shorter periods with fewer toxic reactions.
These formulations are licensed for the treatment of serious fungal infections in patients who have failed to respond or have developed severe side-effects to conventional amphotericin B or in whom conventional amphotericin B is contraindicated because of renal impairment.
In the USA, AmBisome is also licensed for the empirical treatment of presumed fungal infection in febrile neutropenic patients.

Amphotericin B is not absorbed following mucosal or cutaneous application. Minimal absorption occurs from the gastrointestinal tract.
Oral administration of a 3 g dose will produce serum concentrations in the region of 0.1-0.5 mg/L.

The dose and duration of topical treatment will differ from patient to patient and depend on the nature and extent of infection.
The usual adult dose of the oral suspension for oral forms of candidosis is 1-2ml (100-200mg) at 6-h intervals.
Asthe drug is not absorbed the success of treatment depends on maintaining an adequate concentration in the mouth for as long as possible.
The recommended dosage of the oral suspension for infants and children is 1ml (100mg) at 6-h intervals.

Amphotericin B is present in various forms such as oral, topical and parenteral forms.
Topical amphotericin B preparations can be used to treat mucosal and cutaneous forms of candidosis.
Parenteral amphotericin B is still the drug of choice for many forms of deep fungal infection, including aspergillosis, blastomycosis, candidosis, coccidioidomycosis, cryptococcosis, histoplasmosis and paracoccidioidomycosis.
It is also effective in certain forms of mucormycosis, hyalohyphomycosis and phaeohyphomycosis.
However, it is often ineffective in Scedosporium infection and trichosporonosis, as well as in aspergillosis and candidosis in immunocompromised patients.

i. Side effects of Conventional formulation of amphotericin B:

The immediate side-effects of the intravenous infusion of amphotericin Binclude fever, chills and rigors.
These unpleasant reactions differ from patient to patient, but usually begin 1-3 h after starting the infusion and last for about 1h.
They are most common during the first week of treatment and often diminish thereafter.
Nausea and vomiting are less frequent side-effects and, just as with fever and rigors, often diminish as treatment proceeds.
The most serious toxic effect of amphotericin Bis renal tubular damage.
Infants and children are less susceptible to the nephrotoxic effects of amphotericin B.
The risk of amphotericin B-induced renal impairment can be reduced by pre- and post-infusion hydration and sodium repletion with 500 ml saline, provided the clinical status of the patient will allow sodium loading.
Amphotericin B also causes renal wasting of potassium and magnesium due to renal tubular damage, which can reach symptomatic proportions.
Patients treated for more than 2 weeks often develop a mild normochromic, normocytic anaemia.
Pulmonary reactions, with acute dyspnoea, hypoxaemia and interstitial infiltrates, can occur when treatment with amphotericin B is combined with granulocyte transfusion.
For this reason it is advisable to separate the infusion of the drug from the time of granulocyte transfusion.

ii. Side effects of lipid based formulation of Amphotericin B:

The prevalence of immediate side-effects after administration of ABLC or ABCD is lower than reported for conventional amphotericin B.
Fever and chills tend to occur during the first two infusions and are less frequent with subsequent infusions.
Infusion-related adverse events are more common with ABLC and ABCD treatment than with AmBisome treatment.
Infusion-related hypoxia has been documented in up to 25% of ABLC and ABCD recipients, but is usually reversible.
Infusion- related side-effects can be attenuated or prevented by premedication with acetaminophen, antihistamines, corticosteroids and meperidine.
Patients intolerant of one lipid-based formulation of amphotericin B may tolerate another well.
Renal impairment is less common with all three lipid-based formulations of amphotericin B than with the conventional preparation.
Other adverse events associated with lipid-based formulations of amphotericin B have included elevations in liver transaminases, alkaline phosphatase, and serum bilirubin concentrations.