Usage
Amphotericin B is prescribed for the treatment of progressive, potentially life-threatening invasive fungal infections. It is particularly effective against a broad spectrum of fungi including Aspergillus, Candida, Cryptococcus, Coccidioides, Histoplasma, Mucor, and Rhizopus. It is also used in the treatment of leishmaniasis.
Amphotericin B is classified as an antifungal agent, specifically a polyene antifungal.
Its mechanism of action involves binding to ergosterol, a key component of fungal cell membranes. This binding disrupts membrane integrity, leading to increased permeability and ultimately fungal cell death.
Alternate Names
While “Amphotericin B” is the universally recognized generic name, various formulations exist including:
- Conventional Amphotericin B: Amphotericin B deoxycholate
- Lipid formulations: Liposomal amphotericin B, Amphotericin B lipid complex, Amphotericin B cholesteryl sulfate complex
Brand names include:
- Fungizone (conventional)
- AmBisome (liposomal)
- Abelcet (lipid complex)
- Amphotec (cholesteryl sulfate complex)
How It Works
Pharmacodynamics: Amphotericin B primarily exerts its antifungal effect by binding to ergosterol in the fungal cell membrane. This interaction creates pores, increasing membrane permeability and causing leakage of intracellular contents, leading to cell death. Some binding to cholesterol in human cell membranes also occurs, accounting for some of its toxicity.
Pharmacokinetics:
- Absorption: Poorly absorbed from the gastrointestinal tract. Administered intravenously for systemic infections.
- Distribution: Concentrates in liver, spleen, and kidney. Limited penetration into cerebrospinal fluid (CSF), necessitating intrathecal administration for some CNS infections.
- Metabolism: Partially metabolized, but the exact metabolic pathways are not fully elucidated.
- Elimination: Primarily renal excretion, with a prolonged terminal half-life. Lipid formulations exhibit altered pharmacokinetics with higher tissue concentrations and slower clearance.
Mode of Action: Binds to ergosterol in fungal cell membranes, disrupting membrane integrity and function. It forms pores that increase permeability, leading to cell death.
Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: The primary mechanism is ergosterol binding. No significant interaction with human receptors, enzymes, or neurotransmitters.
Elimination Pathways: Primarily renal excretion, with minimal hepatic metabolism. Lipid formulations have reduced renal clearance compared to conventional amphotericin B.
Dosage
Standard Dosage
Adults:
- Conventional: Test dose: 1 mg IV over 20-30 minutes. Initial dose: 0.25 mg/kg/day IV, slowly increased as tolerated to a maximum of 1.5 mg/kg/day or on alternate days. Infuse over 2-6 hours.
- Liposomal: 3-5 mg/kg/day IV infused over 30-60 minutes. Can be increased to a maximum of 7.5-10 mg/kg/day in severe cases or for mucormycosis.
Children:
- Conventional: Similar dosing to adults, starting at a lower dose and escalating based on tolerance and therapeutic response.
- Liposomal: Similar dosing to adults, based on mg/kg body weight.
Special Cases:
- Elderly Patients: Close monitoring of renal function is crucial, dosage adjustments may be needed.
- Patients with Renal Impairment: Dose reduction or alternate-day dosing may be necessary for conventional amphotericin B. Liposomal formulations are generally preferred in renal impairment.
- Patients with Hepatic Dysfunction: Limited data exists, close monitoring is recommended.
- Patients with Comorbid Conditions: Adjust dosages cautiously in patients with cardiac, electrolyte, or other relevant comorbidities.
Clinical Use Cases
Dosage recommendations are based on specific infection and patient factors. The clinician should refer to the latest guidelines for specific recommendations in clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, and emergency situations.
Dosage Adjustments
Dose modifications are often necessary based on renal function, hepatic function, concomitant medications, and individual patient tolerance. Therapeutic drug monitoring may be helpful in optimizing therapy and minimizing toxicity.
Side Effects
Common Side Effects
Fever, chills, rigors, headache, nausea, vomiting, anorexia, muscle pain, hypotension, infusion-related reactions (flushing, fever, chills), electrolyte imbalances (hypokalemia, hypomagnesemia), renal impairment.
Rare but Serious Side Effects
Anaphylaxis, nephrotoxicity (acute kidney injury, renal failure), hepatotoxicity, cardiac arrhythmias, bone marrow suppression, seizures, pulmonary toxicity.
Long-Term Effects
Chronic renal insufficiency, electrolyte disturbances (hypokalemia, hypomagnesemia).
Adverse Drug Reactions (ADR)
Nephrotoxicity, anaphylaxis, infusion reactions.
Contraindications
Hypersensitivity to amphotericin B. Caution in patients with pre-existing renal impairment.
Drug Interactions
Nephrotoxic drugs (aminoglycosides, cyclosporine, tacrolimus), digoxin, antineoplastic agents, corticosteroids, flucytosine, azole antifungals.
Pregnancy and Breastfeeding
Amphotericin B is generally considered safe during pregnancy, especially lipid formulations. It is not known whether amphotericin B is excreted in human milk. The decision to breastfeed should consider the potential risks to the infant and the benefits of breastfeeding.
Drug Profile Summary
- Mechanism of Action: Binds to ergosterol in fungal cell membranes, causing cell death.
- Side Effects: Nephrotoxicity, infusion reactions, electrolyte disturbances.
- Contraindications: Hypersensitivity to amphotericin B.
- Drug Interactions: Nephrotoxic drugs, digoxin, antineoplastic agents, corticosteroids, flucytosine.
- Pregnancy & Breastfeeding: Generally considered safe during pregnancy. Data on breastfeeding is limited.
- Dosage: Varies depending on formulation and clinical situation.
- Monitoring Parameters: Renal function, electrolytes (potassium, magnesium), liver function tests, complete blood count.
Popular Combinations
Flucytosine is sometimes used in combination with amphotericin B for synergistic effects, particularly in cryptococcal meningitis.
Precautions
Close monitoring of renal function, electrolytes, and hepatic function is essential. Prehydration with normal saline may reduce nephrotoxicity. Administer infusions slowly to minimize infusion reactions. Caution in patients with pre-existing renal or hepatic impairment.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Amphotericin B?
A: Dosage depends on the formulation (conventional vs. lipid-based) and the specific infection being treated. Consult specific guidelines and package inserts for detailed dosing recommendations.
Q2: What are the most serious side effects of Amphotericin B?
A: Nephrotoxicity and anaphylaxis are the most serious potential side effects.
A: Premedication with antipyretics, antihistamines, and corticosteroids can reduce the severity of infusion reactions. Slowing the infusion rate may also be helpful.
Q4: Can Amphotericin B be used in patients with renal impairment?
A: Conventional amphotericin B requires careful dose adjustment in patients with renal impairment. Lipid formulations are generally preferred.
Q5: Is Amphotericin B safe during pregnancy?
A: Amphotericin B, particularly liposomal formulations, is generally considered safe during pregnancy when the benefits outweigh the potential risks.
Q6: What monitoring is required during Amphotericin B therapy?
A: Renal function, electrolytes (potassium, magnesium), liver function, and complete blood count should be monitored regularly.
A: Conventional amphotericin B (deoxycholate), liposomal amphotericin B, amphotericin B lipid complex, and amphotericin B cholesteryl sulfate complex.
Q8: How is Amphotericin B administered?
A: Amphotericin B is typically administered intravenously.
Q9: What is the mechanism of action of Amphotericin B?
A: It binds to ergosterol in fungal cell membranes, disrupting membrane integrity and leading to fungal cell death.
