Amphotericin B

Amphotericin B is a drug used to treat fungal infections (antifungal). It is used for local and systemic treatment of fungal diseases.

Use and indications

Amphotericin B is an antifungal agent that has high activity against a large number of fungi. It is most commonly used for particularly severe systemic infections in patients with neutropenia or HIV. Amphotericin B is effective for the following fungal diseases:

• Candida mycoses
• Cryptococcoses
• Aspergilloses
• Coccidioidomycoses
• Histoplasmosis
• North American blastomycosis
• Paracoccidioidomycosis

Amphotericin B also shows activity against protozoa such as Leishmania or Trichomonas and is the only therapeutic option for primary amebic meningoencephalitis.

Amphotericin B can be given as a cream for superficial infections or as a lozenge for infections of the mouth and throat. For systemic fungal infections, it is administered exclusively in the form of infusions. A distinction must be made between conventional amphotericin B (c-AmB) and liposomal amphotericin B (L-AmB). Infusions of conventional AmB are now used only as a reserve antifungal because, although it has good efficacy and low resistance rates, it has too great a potential for side effects. Liposomal AmB is a more recent development, which is much more costly to produce but causes far fewer side effects due to the packaging of the active ingredient in small fat globules. The dosage depends on the type of disease and the weight of the patient (dosage 5mg/kg body weight). Lozenges usually contain 10mg of the active ingredient, tablets for oral use usually contain 100mg.

History

Amphotericin B was originally extracted from Streptomyces nodosus, a filamentous bacterium, at the Squibb Institute for Medical Research in 1955. The bacterium was isolated from soil in the Orinoco River region of Venezuela. Two antifungal compounds were isolated from the soil culture, amphotericin A and amphotericin B, with B having better antifungal activity. Amphotericin B remained the only effective therapy for invasive fungal disease for decades from this time until the group of azole antifungals was developed in the early 1980s. These have largely displaced AmB for most applications.

Its complete structure was determined by X-ray structural analysis in 1970. The first synthesis, of the naturally occurring enantiomeric form of the compound was achieved by K. C. Nicolaou in 1987.

Pharmacodynamics and mechanism of action

Amphotericin B is fungistatic or fungicidal, depending on the concentration reached at the target site and the type of pathogen. The drug acts by binding to sterols (ergosterol) in the cell membrane. These have an important structuring and stabilizing function for the fungal cell. Binding to ergosterol creates a transmembrane channel, resulting in a change in membrane permeability. This allows leakage of intracellular components, which subsequently leads to disruption of membrane integrity and ultimately cell death.

Pharmacokinetics

Bioavailability is 100% after intravenous infusion. Amphotericin B is highly bound to plasma proteins (>90%). The initial plasma half-life is approximately 24 hours. This is followed by a second phase in which the elimination half-life is approximately 15 days.

Newer formulations, such as liposomal amphotericin B, may exhibit markedly different pharmacokinetics.

Drug Interactions

Taking the drug together with other drugs may cause interactions.

There may be an increased risk of renal impairment with the following agents:

• Ciclosporin
• Aminoglycoside antibiotics (gentamicin, neomycin, and streptomycin).
• Pentamidine

Use with the following medications may lower potassium levels, increasing the risk of cardiac arrhythmias, convulsions, and weakness and tremors:

• Corticosteroids
• Diuretics
• Digitalis glycosides
• Muscle relaxants

Other interactions:

When taken together with flycytosine, the ability to form new blood cells may be impaired.

When taken together with cytostatic drugs such as methotrexate, doxorubicin, carmustine, and cyclophosphamide, respiratory problems, kidney damage, and hypotension may occur.

Severe pulmonary problems may occur if leukocytes are transfused together.

Contraindications and precautions

Amphotericin B must not be used if there is an allergy to the active substance.

The following things should be considered when using Amphotericin B:

• In case of concomitant use of drugs that damage the kidneys, kidney function should be closely monitored
• If blood potassium levels are low, additional potassium should be substituted
• In case of simultaneous transfusion of white blood cells, a large time interval between the infusions should be observed.

Side effects

Amphotericin B can potentially cause the following serious side effects:

• pale skin, easy bruising
• blood in the stool
• severe dizziness
• seizures (convulsions)
• jaundice (yellowing of the skin or eyes)
• Fluid buildup in the lungs - signs include anxiety, sweating, shortness of breath, coughing with foamy mucus, chest pain, fast or irregular heartbeat
• Kidney damage - signs include little or no urination, painful or difficult urination, swelling in the feet or ankles, fatigue or shortness of breath
• Potassium deficiency - signs include confusion, irregular heartbeat, extreme thirst, increased urination, leg discomfort, muscle weakness, or general tiredness

Common side effects of amphotericin B may include:

• Nausea
• vomiting
• stomach pain
• Diarrhea
• Stomach upset
• Loss of appetite
• muscle or joint pain
• headache
• ringing in the ears
• pain, bruising, or swelling where the medicine was injected
• weight loss
• redness (warmth, flushing, or tingling sensation)

The frequency of side effects depends on the dosage form and whether the drug is used superficially or systemically.

Pregnancy and lactation

Clinical studies on the use of amphotericin B in pregnancy are lacking, so the safety of its use has not been established. However, previous experience obtained from case reports argues against a teratogenic risk. It is not known whether amphotericin B passes into breast milk or whether it could harm a nursing child. Therefore, breastfeeding should not be undertaken during use.