Amphotericin: Action as Polyene Antifungal
Amphotericin B is a polyene antifungal isolated from the bacterium Streptomyces nodosus and has been established since the 1950s in the therapy of severe systemic fungal infections. In Germany, amphotericin B is available as a conventional form (amphotericin B deoxycholate) and as a liposomal form (AmBisome) as well as a lipid complex (amphotericin B lipid complex, ABLC). Despite the development of modern antifungals such as echinocandins and triazoles, amphotericin B remains an indispensable reserve agent in infectiology due to its broad spectrum of activity and high efficacy against severe systemic fungal infections.
The liposomal form (AmBisome) has significantly changed the practice of amphotericin B therapy. By encapsulation in liposomes, the concentration in tissues with mononuclear phagocyte systems is optimized and nephrotoxicity is significantly reduced. This allows liposomal amphotericin B to be safely administered at higher doses and is today the standard in many indications such as invasive aspergillosis, mucormycosis, and severe visceral leishmaniasis. Administration is exclusively in clinical settings under intensive care or infectious disease supervision.
Mechanism of Action
Amphotericin B selectively binds to ergosterol, a major component of the fungal cell membrane. This binding leads to the formation of pores in the fungal cell membrane through which potassium and other cellular components escape from the fungal cell. This causes the fungal cell to lose its membrane integrity and die. Since human cell membranes contain cholesterol instead of ergosterol, selectivity for fungal cells is higher than for human cells. However, there is some affinity for cholesterol, which explains the toxicity in mammalian cells, especially in erythrocytes and in the renal tubule cells.
Amphotericin B is fungicidal (cell killing) against most clinically relevant fungi. The spectrum of activity includes Candida species, Cryptococcus neoformans, Aspergillus species, Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis, Mucorales (causative agents of mucormycosis), and Leishmania species. Resistance is rare but can occur in Candida lusitaniae and some Aspergillus terreus strains.
Pharmacokinetically, amphotericin B is not orally absorbed (oral use only for local effects in the gastrointestinal tract). Intravenous administration results in very high plasma protein binding. The elimination half-life of the conventional form is 24 to 48 hours, of the liposomal form about 100 to 150 hours. The substance accumulates in liver, spleen, kidney, and lung, where it can persist for weeks to months. Renal excretion is low.
Indications
- Invasive aspergillosis as reserve therapy in case of failure or intolerance of voriconazole or isavuconazole
- Mucormycosis (zygomycosis) as first line therapy, especially in combination with surgical debridement
- Invasive candidiasis and candidemia in case of failure or intolerance of echinocandins or azoles
- Cryptococcus meningitis, especially in HIV positive patients in combination with flucytosine
- Severe visceral leishmaniasis (kala azar), liposomal amphotericin B as first line therapy
- Histoplasmosis, blastomycosis, coccidioidomycosis in severe form
- Empirical antifungal therapy in febrile neutropenia with inadequate response to antibiotics
- Local in tablets for therapy of oral candidiasis, in suspensions for oral hygiene
Dosage and Administration
Conventional amphotericin B deoxycholate: 0.5 to 1 mg per kg per day intravenously as an infusion over 4 hours, individual dose escalation depending on tolerability. Today largely replaced by the liposomal form.
Liposomal amphotericin B (AmBisome): 3 to 5 mg per kg per day intravenously as an infusion over 30 to 60 minutes. For mucormycosis 5 to 10 mg per kg per day.
Amphotericin B lipid complex (ABLC): 5 mg per kg per day intravenously as an infusion.
Cryptococcus meningitis: liposomal amphotericin B 3 to 4 mg per kg per day plus flucytosine 100 mg per kg per day in 4 divided doses for 2 weeks, followed by fluconazole consolidation.
Visceral leishmaniasis: liposomal amphotericin B 3 mg per kg on days 1 to 5, 14, and 21 (total dose 21 mg per kg) in immunocompetent patients.
Pediatric: similar dosing as in adults per kg, individual adjustment in pediatric infectious disease.
Administration: exclusively intravenous in clinical settings. Before each infusion, check patient parameters (vital signs, renal and liver function, electrolytes). Premedication with paracetamol and antihistamine, possibly pethidine for chills.
Renal insufficiency: caution and close monitoring, possibly dose reduction. Liposomal form significantly less nephrotoxic. Hepatic insufficiency: caution in severe impairment.
Adverse Effects
Very frequent (conventional form): chills, fever, headache, muscle pain during infusion, nausea, vomiting, hypokalemia, hypomagnesemia, increase in renal values (creatinine), increase in liver values, anemia.
Frequent: hypotension, tachycardia, thrombophlebitis at the infusion site, pancreatitis, chest pain, shortness of breath.
Occasional: renal tubular acidosis with hypokalemia and hypomagnesemia, acute renal failure (especially conventional form), cardiac arrhythmias such as bradycardia or torsade de pointes, severe hypersensitivity reactions, hepatic damage, seizures.
Liposomal form: significantly less frequent nephrotoxicity, in rare cases infusion reactions with shortness of breath and chest pain.
With local oral use: bitter taste, gastrointestinal discomfort when swallowing.
Note: very severe hyperkalemia possible with too rapid infusion, can lead to cardiac arrest.
Drug Interactions
- Other nephrotoxic substances (aminoglycosides, vancomycin, cyclosporine, tacrolimus, cisplatin, NSAIDs): additive nephrotoxicity, caution and monitoring.
- Diuretics (furosemide, hydrochlorothiazide): enhancement of hypokalemia and renal toxicity.
- Glucocorticoids, cortisone: enhancement of hypokalemia and risk of cardiac arrhythmias.
- Digitalis glycosides: hypokalemia enhances digitalis toxicity, caution and monitoring.
- Muscle relaxants (non-depolarizing): enhanced effect due to hypokalemia.
- Antiarrhythmics and QT prolonging substances: risk of torsade de pointes enhanced by electrolyte disturbances.
- Flucytosine: synergistic effect in Cryptococcus meningitis, standard combination therapy.
Special Precautions
Pregnancy: in case of life-threatening fungal infection and lack of alternative, amphotericin B can be used in pregnancy, previous data show no increased risk. Breastfeeding: limited data, individual assessment.
Children: established in specialized pediatric infectious disease settings.
Contraindications: known hypersensitivity. Relatively contraindicated in severe renal insufficiency or anuria without dialysis.
Before use: renal and liver function, electrolytes (potassium, magnesium, calcium), complete blood count, coagulation, ECG, allergy history.
During therapy: daily electrolyte and renal function tests, regular complete blood count and liver values, ECG in high-risk patients, clinical follow-up assessment, tolerability of infusion.
Lifestyle: therapy takes place in clinical settings, therefore no specific recommendations outside of direct application.
Ability to drive: generally not recommended during therapy due to accompanying symptoms such as fatigue, dizziness, weakness, and concomitant medication.
You May Also Be Interested In
- Voriconazole, triazole in invasive aspergillosis
- Isavuconazole, triazole with broad spectrum
- Fluconazole, triazole in Candida and Cryptococcus
- Caspofungin, echinocandin in Candida and aspergillosis
- Posaconazole, triazole with broad spectrum in mucormycosis
Frequently Asked Questions
What distinguishes liposomal amphotericin B from the conventional form?
In liposomal amphotericin B (AmBisome), the active substance is packaged in liposomes. This encapsulation leads to altered pharmacokinetics with higher concentrations in tissues and lower concentrations in the kidney. This results in significantly lower nephrotoxicity with comparable or higher antifungal efficacy. The liposomal form is today the preferred variant in most clinical indications.
Why is amphotericin B called a "reserve antifungal"?
Because toxicity, especially nephrotoxicity of the conventional form, is a major disadvantage. Therefore, in many indications other antifungals such as echinocandins or triazoles are used first, and amphotericin B is used when these fail or are intolerant, or when the pathogen spectrum requires it (e.g., mucormycosis).
What is mucormycosis?
Mucormycosis is a rare but life-threatening fungal infection caused by Mucorales fungi that occurs mainly in severely immunosuppressed patients, such as in diabetic ketoacidosis, hematologic malignancies, hematopoietic stem cell transplantation, or steroid therapy. Treatment requires rapid diagnosis, surgical debridement of affected tissue, and systemic antifungal therapy with liposomal amphotericin B at high dose as first line treatment.
Which electrolyte disturbances occur with amphotericin B?
Hypokalemia is the most common electrolyte disturbance and occurs through renal tubular acidosis. Hypomagnesemia and hypocalcemia are also frequent. These electrolyte disturbances can lead to muscle weakness, cardiac arrhythmias, and tetany. Therefore, daily electrolyte monitoring and, if necessary, supplementation is part of standard surveillance. With the liposomal form, these complications are less frequent but not excluded.
Sources
- Gelbe Liste, amphotericin B active substance profile
- BfArM, Federal Institute for Drugs and Medical Devices
- German Society for Infectiology (DGI)
- AWMF S3 guideline on invasive fungal infection
- European Medicines Agency, EPAR AmBisome
Legal Notice and Disclaimer
The information provided on this page is for general informational purposes only and does not constitute medical advice, diagnosis, or treatment recommendation. It does not replace the advice of an approved physician or pharmacist. Amphotericin B is administered exclusively in specialized clinical settings under infectious disease and intensive care supervision. All information is based on expert information and recognized scientific sources published at the time of creation, with the currently valid package insert of the manufacturer being authoritative at all times. Sanoliste assumes no liability for completeness, timeliness, or accuracy of the information presented. In medical emergencies, call emergency number 112.