Continuing Education Activity

Amphotericin B deoxycholate belongs to the polyene class of antifungals. It is also known by the conventional name amphotericin B and has been used for the treatment of invasive fungal infections for more than 50 years. Newer lipid formulations that are less nephrotoxic as compared with conventional amphotericin B are available. This activity reviews the indications, contraindications, activity, adverse events, toxicity, and other key elements of antifungal uses of amphotericin B in the clinical setting as relates to the essential points needed by members of an interprofessional team managing the care of patients who present with mycotic infections.

Objectives:

• Identify the approved indications of amphotericin B.
• Review the mechanism of action of amphotericin B.
• Describe the adverse of amphotericin B.
• Summarize interprofessional team strategies for improving care coordination and communication to advance appropriate clinical outcomes with amphotericin B therapy to treat mycotic infections to optimal patient outcomes and mitigate toxicity and adverse events.

Indications

Amphotericin B deoxycholate belongs to the polyene class of antifungals. It is also known by the conventional name amphotericin B and has been in use for the treatment of invasive fungal infections for more than 50 years. It was first isolated as a natural product of a soil Actinomycete sp.[1][2]

Newer lipid formulations that are less nephrotoxic as compared with conventional amphotericin B are available.[3] These include:

• Amphotericin B, which is more commonly administered in a liposomal formulation and exhibits increased tolerability and a reduced toxicity profile
• An amphotericin B lipid complex in which amphotericin B is tightly packed in a ribbon-like structure
• Amphotericin B cholesteryl sulfate complex

These lipid formulations permit a higher daily dose, provide better delivery to organs within the reticular endothelial system such as the lungs, liver, and spleen, have similar efficacy when compared to conventional amphotericin B, and are less nephrotoxic.[4]

With the advancement of newer antifungals, such as azoles (e.g., voriconazole) and Echinocandins (e.g., caspofungin), amphotericin B is typically only reserved for selected invasive fungal infections. 

Common indications in yeast and invasive mold infections are listed below:

1. Invasive candidiasis (FDA approved). It is effective against the majority of the Candida species, including Candida albicans, Candida krusei, Candida tropicalis, and Candida parapsilosis. 
2. In neonatal candidiasis, conventional amphotericin B is less toxic than in adults and well-tolerated.
3. Opportunistic fungal infections in immunocompromised children, including HIV
4. Life-threatening fungal infections in both normal and immunocompromised hosts
5. Empiric treatment in a persistently febrile neutropenic host.
6. Cerebral cryptococcosis along with flucytosine for induction therapy
7. Mucormycosis and other molds, including Fusarium spp. and penicilliosis
8. Severe cases of sporotrichosis
9. Coccidioidomycosis and paracoccidioidomycosis, especially in severe disease
10. Histoplasmosis, for disseminated disease
11. Blastomycosis, for severe disease
12. Aspergillosis, for salvage therapy in cases not responding to voriconazole
13. Visceral and cutaneous leishmaniasis (a protozoan infection)

Dose: The recommended daily dose depends upon the type of infection, the organ involved, the host (immunocompetent versus immunocompromised), and ranges from 0.7 to 1 mg/kg per day over 2 to 4 hours as tolerated.

When prescribing amphotericin B, the clinician should take into consideration: the indication, immune status of the patient, and side effect profile. Also, the resistance to amphotericin B remains low for Candida species except for Candida lusitaniae. Aspergillus spp. and opportunistic molds have a more variable susceptibility pattern. Secondary resistance is uncommon and is not usually a clinical problem. Clinicians should consider in vitro susceptibility testing in cases of clinical failure, and when treating pathogens such as Candida lusitaniae, Trichosporon species, Fusarium species, or Psudoallescheria boydii.

Clinicians should recall that amphotericin B exerts a concentration-dependent fungicidal activity against susceptible fungi such as Candida spp., Cryptococcus spp., and Aspergillus spp. It also has a prolonged post-antifungal effect of up to 12 hours.

Mechanism of Action

Amphotericin B acts by binding to ergosterol in the cell membrane of most fungi. After binding with ergosterol, it causes the formation of ion channels leading to loss of protons and monovalent cations, which results in depolarization and concentration-dependent cell killing.[5][6]

Additionally, amphotericin B also produces oxidative damage to the cells with the formation of free radicals and subsequently increased membrane permeability. Additionally, amphotericin B has a stimulatory effect on phagocytic cells, which assists in fungal infection clearance.

The half-life of amphotericin B is from 24 hours to 15 days.

Administration

Amphotericin B is amphoteric (can act as both an acid and a base) and virtually water-insoluble. It is not absorbable via oral or intramuscular administration.[7]

Amphotericin B intravenous (IV) infusion administration is over 2 to 6 hours. If the patient experiences any of the following; fever, hypertension, chills, or nausea, premedication 30 to 60 minutes before administration with a combination of acetaminophen/ibuprofen plus diphenhydramine and/or hydrocortisone should merit consideration.  The risk of nephrotoxicity increases at doses greater than 1 mg/kg, and there is no evidence supporting doses greater than 1.5 mg/kg per day. Pretreating the patient with 1 liter of normal saline can attenuate nephrotoxicity.

Topical use of amphotericin B for peritoneal or bladder wash has been reported in the literature but not recommended. Topical amphotericin B is irritating to the skin; therefore, the decision to use topical amphotericin B should be made based on expert consultation.

Amphotericin B achieves high concentrations in tissue such as the liver, spleen, bone marrow, kidney, and lungs. Although concentrations in cerebrospinal fluid (CSF) are low (5% of serum), it is effective in the treatment of fungal infections of the central nervous system (CNS) when given intrathecally (higher risk of toxicity).

A high interindividual variability characterizes the reported pharmacokinetic data in children. Children seem to clear the drug from plasma more rapidly than adults.

Adverse Effects

About 80% of the patients will develop either infusion-related or renal toxicity. Amphotericin B also interacts with cholesterol in human cell membranes, which is responsible for its toxicity. The most common side effects of amphotericin B include:

1. Loss of potassium
2. Loss of magnesium
3. Anaphylaxis
4. Fevers
5. Nephrotoxicity: Renal toxicity correlates with conventional amphotericin B use and can lead to renal failure and requirement for dialysis. But the azotemia often stabilizes with therapy and renal damage is reversible after discontinuation of amphotericin B. Avoiding concomitant use of other nephrotoxic agents, and appropriate hydration with normal saline may significantly decrease the likelihood and severity of azotemia associated with amphotericin B.
6. Other potential uncommon side effect includes demyelinating encephalopathy in patients with bone marrow transplant with total body irradiation or who are receiving cyclosporine.
7. The long-term administration is associated with normochromic, normocytic anemia due to low erythropoietin concentrations.

Contraindications

Absolute contraindications include a history of anaphylactic reaction to amphotericin B.

Before potential administration, drug-drug interactions require a thorough review. Concomitant steroid use should be reconsidered to reduce the risk of hypokalemia. Hypokalemia can also potentiate digoxin toxicity and can cause rhabdomyolysis. Simultaneous infusion of amphotericin B and granulocytes has correlations with acute pulmonary reactions, and clinicians should avoid the combination.

Monitoring

The monitoring of amphotericin B concentrations in the serum or CSF is of little value because the relationships between plasma and tissue concentrations and clinical efficacy or toxicity have not had adequate research performed.

Monitoring is a recommendation to evaluate for the presence of side effects. Initially, a daily electrolyte panel, including potassium and magnesium concentrations until the dose increases to its therapeutic concentration, and after that, weekly electrolyte concentrations are sufficient. Clinicians should obtain potassium concentrations immediately if the patient presents with any signs of hypokalemia, such as muscle weakness, cramps, drowsiness, or ECG changes of hypokalemia.

Toxicity

Amphotericin exhibits infusion-related toxicity, which accounts for its extended administration times. Infuse slowly over 3 hours; rapid infusion can cause cardiotoxicity.

Due to the similarity of mammalian and fungal membranes, which both contain sterols (the therapeutic target for amphotericin B), amphotericin B can exhibit cellular toxicity.

Enhancing Healthcare Team Outcomes

Healthcare professionals, including physicians, physician assistants, and nurse practitioners who prescribe amphotericin B, should be very familiar with its administration and side effects. Close to 80% of the patients will develop either infusion-related or renal toxicity. Consider pretreatment with acetaminophen, diphenhydramine, and/or hydrocortisone before the infusion to attenuate side effects. Meperidine treatment may decrease the duration of rigors. Following infusion, the renal function requires monitoring.

Given its interaction and adverse event profile, it is not surprising that amphotericin B use is cautiously used. However, physicians may need to employ it for recalcitrant infections, and consultation with the pharmacist is necessary to ensure there will be no drug-drug interactions, or that a different agent might achieve the desired therapeutic result. Nurses also need to understand the side effect profile of this drug, as well as the potential for infusion reactions; in the event of any concerns, the nursing staff should immediately alert the treating physician. This drug may have been around for many years. Still, its use requires a robust, collaborative interprofessional healthcare team effort to be able to achieve desired patient outcomes with minimal adverse effects. [Level V]

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References

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Rybak JM, Fortwendel JR, Rogers PD. Emerging threat of triazole-resistant Aspergillus fumigatus. J Antimicrob Chemother. 2019 Apr 01;74(4):835-842. [PMC free article: PMC6657284] [PubMed: 30561652]

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Pruthi HS. When to Initiate Antifungal Treatment in COVID-19 Patients with Secondary Fungal Co-infection. Curr Clin Microbiol Rep. 2022;9(4):60-68. [PMC free article: PMC9630809] [PubMed: 36345368]

Disclosure: Asif Noor declares no relevant financial relationships with ineligible companies.

Disclosure: Charles Preuss declares no relevant financial relationships with ineligible companies.