Continuing Education Activity

Amphotericin B deoxycholate, an esteemed member of the polyene class of antifungals, has been a cornerstone in therapy against invasive fungal infections for over 5 decades. This drug has witnessed significant advancements by introducing novel lipid formulations that exhibit a reduced nephrotoxic profile compared to the traditional formulation. This comprehensive activity is designed to meticulously elucidate the indications, contraindications, pharmacological activity, adverse events, and toxicity associated with amphotericin B, equipping members of the interprofessional healthcare team with essential insights for adeptly managing mycotic infections in diverse clinical settings. Participants gain a profound understanding of the antifungal applications of amphotericin B, empowering them to contribute effectively to the collaborative care of patients grappling with fungal infections.

Objectives:

• Identify the appropriate indications for amphotericin B therapy based on the type of fungal infection and patient characteristics.

• Implement proper dosing and administration strategies for amphotericin B to ensure optimal therapeutic outcomes while minimizing toxicity.

• Assess the patient's response to amphotericin B therapy by regularly monitoring clinical symptoms, laboratory parameters, and adverse effects.

• Determine a plan with other healthcare professionals, such as infectious disease specialists and pharmacists, to optimize amphotericin B therapy and ensure comprehensive patient care.

Indications

Amphotericin B deoxycholate belongs to the polyene class of antifungals. The drug is also known as amphotericin B and has been used to treat invasive fungal infections for over 50 years. Amphotericin B was first isolated as a natural product of a soil Actinomycete species.[1][2]

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

• Amphotericin B liposomal, which is a liposomal formulation and exhibits increased tolerability and a reduced toxicity profile
• An amphotericin B lipid complex (ABLC) 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 to conventional amphotericin B, and are less nephrotoxic.[4]

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

FDA-Approved Indications

FDA-approved indications of amphotericin B deoxycholate are listed below:

• Aspergillosis
• Cryptococcosis 
• Severe blastomycosis
• Systemic candidiasis (effective against Candida albicans, Candida krusei, Candida tropicalis, and Candida parapsilosis)
• Coccidioidomycosis
• Histoplasmosis (disseminated disease)
• Zygomycosis (including mucormycosis) due to susceptible Absidia, Mucor, and Rhizopus spp species.
• Infections due to related susceptible species of Conidiobolus and Basidiobolus
• Severe cases of sporotrichosis [5]

Liposomal amphotericin B has been FDA-approved for the following indications:

• Empirical therapy for fungal infection in febrile, neutropenic patients.
• Treatment of infections caused by refractory Aspergillus, Candida, and Cryptococcus species that are unresponsive to amphotericin B deoxycholate or in cases where renal impairment or unacceptable toxicity prohibits the use of amphotericin B deoxycholate.
• Visceral leishmaniasis (higher relapse rates in immunocompromised patients)
• Cryptococcal meningitis in patients with HIV [6]

Amphotericin B lipid complex (ABLC) has received FDA approval for treating invasive fungal infections in patients who have shown resistance to or intolerance of conventional amphotericin B therapy.

According to the IDSA (Infectious Diseases Society of America), amphotericin B deoxycholate and lipid formulations are recommended for treating aspergillus infections when voriconazole is not feasible. Amphotericin B deoxycholate is suitable for resource-limited settings, while lipid formulations are preferred in cases of azole intolerance or contraindication.

Aerosolized amphotericin B can be used as a prophylactic measure in specific patient populations, such as those with prolonged neutropenia, patients undergoing induction/reinduction therapy for acute leukemia, recipients of allogeneic hematopoietic stem cell transplantation during conditioning or graft-vs-host disease treatment and lung transplant recipients.[7] 

IDSA guidelines endorse amphotericin B for visceral and cutaneous leishmaniasis.[8] A lipid formulation of amphotericin B for candidemia is a reasonable alternative for intolerance, limited availability, or resistance to other antifungal agents. For chorioretinitis with vitreous, intravitreal amphotericin B deoxycholate should be considered. Cystitis due to Candida glabrata or Candida krusei can be treated with endoscopic lesion removal and amphotericin B bladder irrigation.[9]

Off-Label Uses

Off-label indications for amphotericin B include severe paracoccidioidomycosis (South American blastomycosis).[10] Liposomal amphotericin B demonstrates effectiveness against filamentous fungi, including Fusarium spp., Scopulariopsis spp., and Penicillium spp.[11] 

When prescribing amphotericin B, the clinician should consider the indication, the patient's immune status, and the adverse effect profile. Amphotericin is used in cerebral cryptococcosis along with flucytosine for induction therapy. 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. Amphotericin-B has been extensively used COVID-19 associated mucormycosis.[12]

Mechanism of Action

Amphotericin B acts by binding to ergosterol in the cell membrane of most fungi. After binding with ergosterol, amphotericin B causes the formation of ion channels, leading to the loss of protons and monovalent cations, which results in depolarization and concentration-dependent cell killing.[13][14]

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

Pharmacokinetics

Absorption: Amphotericin B is given parenterally due to poor oral absorption. The pharmacokinetics of amphotericin B lipid complex and amphotericin B liposomal are non-linear, characterized by a dose-dependent increase in the volume of distribution and clearance. Amphotericin B demonstrates concentration-dependent fungicidal activity and post-antifungal effect.[15]

Distribution: Amphotericin B achieves high concentrations in tissues such as the liver, spleen, bone marrow, kidneys, and lungs. The amphotericin B lipid complex has a higher volume of distribution than liposomal amphotericin B due to its uptake by the reticuloendothelial system. 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. Liposomal amphotericin B achieves higher concentrations in the blood, liver, and spleen but lower levels in the kidneys and lungs compared to conventional formulations. The plasma protein binding of amphotericin B is approximately 90%.[16]

Metabolism: According to the current evidence, amphotericin B is not metabolized in the liver. The primary route of elimination for amphotericin B is through the kidneys.[17]

Elimination: The kidneys gradually eliminate conventional amphotericin B, with only a small percentage (2% to 5%) of the dose excreted in its active form over a prolonged period. Liposomal amphotericin B is primarily eliminated from the body through unchanged excretion in feces and urine, with less than 10% of the administered dose being excreted over 7 days. The amphotericin B lipid complex (ABLC) excretion in urine over 24 hours amounts to approximately 0.9% of the administered dose. The clearance of amphotericin B lipid complex and liposomal amphotericin B follows non-linear kinetics, with a dose-dependent increase in the elimination of the drug.[11]

Administration

Amphotericin B is amphoteric (can act as both an acid and a base) and water-insoluble. The drug is not absorbable via oral or intramuscular administration.[18]

Dosage and Strengths

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

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

Amphotericin B deoxycholate: The recommended dosage is 0.5 to 1 mg/kg/d. The maximum recommended dose is 1.5 mg/kg/d.

Amphotericin B lipid complex (ABLC): The recommended dosage is 5 mg/kg/d.

Liposomal amphotericin B: For empirical therapy, the initial dose is 3 mg/kg/d. In systemic fungal infections caused by Aspergillus, Candida, and Cryptococcus, the initial dose ranges from 3 to 5 mg/kg/d. In the case of cryptococcal meningitis in HIV-infected patients, the recommended initial dose is 6 mg/kg/d.[19]

Mucormycosis: Amphotericin B and its lipid formulations, including liposomal amphotericin and the amphotericin lipid complex, are superior to conventional amphotericin for treating mucormycosis. For COVID-19-associated mucormycosis, liposomal amphotericin (5 mg/kg/d) is the preferred treatment. A high dose of liposomal amphotericin or the amphotericin lipid complex (10 mg/kg/d) is recommended for CNS involvement or solid organ transplant recipients. The continuation of high-dose treatment is appropriate for stable or partially responsive cases, while the progressive disease may require combination therapy with liposomal amphotericin with posaconazole. In cases of treatment-related toxicity, a low dose of liposomal amphotericin or the amphotericin lipid complex (5 mg/kg/d) is recommended. In resource-limited settings, amphotericin B deoxycholate can be used.[20]

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

Specific Patient Populations

Hepatic impairment: There is limited clinical data regarding the effect of hepatic impairment on the pharmacokinetics of amphotericin B.

Renal impairment: Nephrotoxicity is higher with amphotericin B deoxycholate than with lipid-based formulations.

Pregnancy Considerations: Amphotericin B should be used during pregnancy only if indicated. According to IDSA guidelines, amphotericin B is the drug of choice for invasive candidiasis in pregnancy.[9] Using ideal body weight instead of total body weight can reduce potential adverse effects on the fetus. Liposomal amphotericin B is preferred due to its minimal risk of teratogenicity during pregnancy.[21]

Breastfeeding Considerations: Limited information is available regarding the presence of amphotericin B in human milk. However, due to its high protein binding, large molecular weight, and poor oral absorption, the use of amphotericin B during lactation is considered probably safe. Therefore, most experts consider it acceptable for use in breastfeeding mothers.[22]

Pediatric Patients: The safety and efficacy of amphotericin B in patients <1 month of age have not been established. However, successful treatment of systemic fungal infections in pediatric patients with amphotericin B deoxycholate has been observed without any unusual adverse effects. Amphotericin B lipid complex (ABLC) has shown efficacy in treating hepatosplenic candidiasis. Liposomal amphotericin B has demonstrated positive outcomes in pediatric patients with systemic fungal infections or visceral leishmaniasis.[23]

Older Patients: In older adults, amphotericin B lipid complex has been administered at a dose of 5 mg/kg/d, and no significant unexpected adverse events were reported.

Adverse Effects

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

• Hypokalemia [24]
• Hypomagnesemia 
• Anaphylaxis
• Nephrotoxicity: Renal toxicity correlates with conventional amphotericin B use and can lead to renal failure and the 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. Systematic review and meta-analysis suggests that liposomal formulation is associated with substantially lower nephrotoxicity compared to conventional amphotericin B.[25]
• Other potential uncommon adverse effects include demyelinating encephalopathy in patients with bone marrow transplants with total body irradiation or receiving cyclosporine.
• The long-term administration is associated with normochromic, normocytic anemia due to low erythropoietin concentrations.[26]
• Fever, headache, chills, hypotension, tachypnea, and vomiting typically occur within 1 to 3 hours after initiating an intravenous infusion of amphotericin B. These reactions are usually more encountered with the initial doses.[27]

Drug-Drug Interactions

• Antineoplastic agents: Concurrent use may increase the risk of bronchospasm, nephrotoxicity, and hypotension. Caution is advised when using antineoplastic agents (especially nitrogen mustard) with amphotericin B.
• Corticosteroids: Concomitant steroid use should be reconsidered to reduce the risk of hypokalemia. 
• Digoxin: Hypokalemia can potentiate digoxin toxicity and can cause rhabdomyolysis. Monitoring of serum potassium levels is necessary, and electrolytes should be replenished.[28]
• Flucytosine: Simultaneous use of amphotericin B may increase the toxicity of flucytosine, possibly affecting its cellular uptake and renal excretion. Careful monitoring is required when using amphotericin B and flucytosine together.
• Azoles (ketoconazole, miconazole, clotrimazole, fluconazole): In vitro and preclinical studies suggest that imidazoles may induce fungal resistance to amphotericin B. Combination therapy should be administered with caution, especially in immunocompromised patients.[6]
• Nephrotoxic drugs: Drugs such as aminoglycosides, cyclosporine, and pentamidine may increase the risk of nephrotoxicity when used concomitantly with amphotericin B. Monitoring of renal function is required.[29]
• Skeletal muscle relaxants: Amphotericin B-induced hypokalemia can increase the effect of skeletal muscle relaxants like tubocurarine. Use with caution.
• Leukocyte transfusions: Simultaneous infusion of amphotericin B and granulocytes correlates with acute pulmonary reactions, and clinicians should avoid the combination.[30]

Drug-Laboratory Interaction

• Liposomal amphotericin B can cause pseudo-hyperphosphatemia due to interference with the PHOSm assay.[31]

Contraindications

Absolute contraindications include a history of anaphylactic reaction to amphotericin B.[32]

Boxed Warning

Use caution to prevent overdosage of amphotericin B, as it can lead to cardiopulmonary arrest.[33] The product name and formulation should be verified, especially if the prescribed dose of amphotericin B exceeds the suggested maximum of 1.5 mg/kg. Amphotericin B is primarily indicated for treating progressive and potentially life-threatening fungal infections. Amphotericin B should not be in patients with normal neutrophil counts to treat noninvasive fungal diseases, such as vaginal candidiasis, oral thrush, and esophageal candidiasis.

Precautions

Do not administer amphotericin B by rapid intravenous infusion due to the possibility of hypotension, hypokalemia, arrhythmias, and shock. Amphotericin B use has been linked to leukoencephalopathy; total body irradiation increases the risk.[34]

Monitoring

Monitoring 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 been adequately researched. Monitoring is a recommendation to evaluate for the presence of adverse effects. Initially, a daily electrolyte panel, including potassium and magnesium concentrations, is required until the dose increases to its therapeutic concentration, and after that, weekly electrolyte concentrations are sufficient.[35]

Clinicians should obtain potassium concentrations immediately if the patient presents with signs of hypokalemia, such as muscle weakness, cramps, drowsiness, or ECG changes of hypokalemia. Renal function should also be monitored closely due to the risk of nephrotoxicity and distal renal tubular acidosis.[35]

Toxicity

Amphotericin exhibits infusion-related toxicity, which accounts for its extended administration times. Infuse slowly over 3 hours; rapid infusion can cause cardiotoxicity. Amphotericin B deoxycholate overdose can cause ventricular arrhythmias and bradycardia in patients with preexisting cardiac conditions.[36]

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. In the suspected overdose of amphotericin B, treatment should be discontinued. Supportive therapy should be administered as required. Amphotericin B and its formulations are not effectively removed by dialysis.

Enhancing Healthcare Team Outcomes

Healthcare professionals, including physicians and advanced practice practitioners prescribing amphotericin B, should know its indications, administration, and adverse effects. Close to 80% of the patients will develop either infusion-related or renal toxicity. Before the infusion, consider pretreatment with acetaminophen, diphenhydramine, or hydrocortisone to attenuate adverse effects. Meperidine treatment may decrease the duration of rigors.[11] Following infusion, the patient's renal function requires periodic monitoring.

Given the drug's interaction and adverse event profile, it is unsurprising that amphotericin B use is cautiously used. However, prescribers may need to employ it for recalcitrant infections, and consultation with the pharmacist is necessary to ensure no drug-drug interactions exist or that a different agent might achieve the desired therapeutic result. Nurses also need to understand the side effect profile of this drug and the potential for infusion reactions; if there are any concerns, the nursing staff should immediately alert the prescribing clinician. A robust, collaborative, interprofessional healthcare team effort involving physicians, infectious disease specialists, advanced practice practitioners, nurses, and pharmacists must achieve desired patient outcomes with minimal adverse effects.