|Year : 2021 | Volume
| Issue : 2 | Page : 104-108
Amphotericin B Revisited
Sahil Kumar, Vandana Roy
Department of Pharmacology, Maulana Azad Medical College, New Delhi, India
|Date of Submission||19-Jul-2021|
|Date of Acceptance||05-Aug-2021|
|Date of Web Publication||27-Aug-2021|
Department of Pharmacology, Maulana Azad Medical College, New Delhi 110002
Source of Support: None, Conflict of Interest: None
Amphotericin B, one of the first systemic antifungal agents, has been in use since the past six decades. In light of the recent outbreak of mucormycosis (black fungus) cases during the second coronavirus disease 2019 wave in India, the relevance of knowing the chief aspects of this drug has been renewed. This drug review attempts to revisit the important details available about this agent, which will be of use to the clinician.
Keywords: Amphotericin B, antifungals, mucormycosis
|How to cite this article:|
Kumar S, Roy V. Amphotericin B Revisited. MAMC J Med Sci 2021;7:104-8
| Introduction|| |
Amphotericin B (AMB) was among the first antifungal agents available for systematic use in 1958. It was isolated from Streptomyces nodosus in 1955, at the Squibb for Medical Research Institute from cultures isolated from the streptomycete obtained from the soil of Orinoco riverbed in Venezuela. The name “amphotericin” comes from the chemical’s amphoteric properties (acting both as an acid and as a base). Two antifungal substances were isolated from the soil culture, amphotericin A and AMB, but B had better antifungal activity. For decades, it remained the only effective therapy for invasive fungal disease until the development of the imidazole antifungals in the 1970s. As new antifungals have been developed, AMB although discovered more than six decades ago, still remains the gold standard of systemic antifungal pharmacotherapy.
It is an amphoteric polyenemacrolide with the broadest spectrum of antifungal activity of currently available antifungal drugs.
Mechanism of Action
The AMB has a high affinity for ergosterol, a component of fungal cell membranes. It forms pores that increase membrane permeability causing rapid leakage of ions and subsequent fungal cell death. In addition, it sequesters ergosterol from lipid bilayer resulting in fungal cell death. The polyenes also bind to cholesterol present in host cell membranes, which resemble ergosterol. Thus, selectivity of action of AMB is low and is responsible for systemic toxicity. As bacteria do not have sterols, it does not have antibacterial action.
The AMB has a broad range of activity against fungi, including Candida spp., Cryptococcus neoformans, Blastomyces dermatitidis, Histoplasma capsulatum, Sporothrix schenckii, Coccidioides spp., Paracoccidioides braziliensis, Aspergillus spp., Penicillium marneffei, Fusarium spp., Torulopsis, Rhodotorula, and Mucorales.,
It is fungistatic at low and fungicidal at high concentrations. Dermatophytes are inhibited in vitro but concentrations achieved in skin are ineffective.
It has limited activity against protozoa − Leishmania spp. and Naegleria fowleri. No antibacterial activity exists.
Resistance to AMB, while present, is rare and not a problem in clinical use of the drug. Resistance is noted in Candida lusitaniae isolates, Aspergillus terreus, and Aspergillus nidulans.
The AMB is not absorbed orally. When administered intravenously, it gets widely distributed in the body but penetration in the cerebrospinal fluid is poor. Due to binding with sterols in tissues and lipoproteins in plasma, it stays in the body for a long time. In plasma, AMB is more than 90% bound to proteins. It has a terminal elimination half-life of 15 days. About 60%, AMB is metabolized in liver and excretion occurs via bile and urine slowly. No dose adjustment is needed in patients with kidney or liver disease.
Differences in pharmacokinetics are there among AMB formulations.
Currently, the drug is available in four formulations [Table 1]. The AMB alone is not absorbed orally and is insoluble in normal saline at a pH of 7. Therefore, several formulations have been devised to improve its intravenous bioavailability.
- Conventional amphotericin B (C-AMB): Pure AMB is insoluble in water; hence, it is formulated with bile salt deoxycholate, so it can be given by intravenous infusion. It is available as a lyophilized powder for injection. In water, C-AMB forms a colloid, with particles largely less than 0.4 µm in diameter. Filters in intravenous infusion lines that trap particles larger than 0.22 µm in diameter will remove significant amounts of drug. Electrolytes in infusion solutions can cause the colloid to aggregate.
- Liposomal amphotericin B (LAMB) − In this, AMB is incorporated within a small, unilamellar liposomal vesicle formulation. Comparable blood levels to C-AMB are achieved with it. As LAMB can be given at higher doses, blood levels have been achieved that exceed those obtained with C-AMB.
- Amphotericin B colloidal dispersion (ABCD) − This contains roughly equimolar amounts of AMB and cholesteryl sulfate formulated for injection. In aqueous solution, it forms a colloidal solution when reconstituted. ABCD provides much lower blood levels than C-AMB in humans. More fever (27% vs. 16%) and chills (53% vs. 30%) were observed in comparison with C-AMB but ABCD was less nephrotoxic than C-AMB (15% vs. 49%).
- Amphotericin B lipid complex (ABLC) − This consists of AMB with two phospholipids dimyristoylphosphatidylcholine and dimyristoylphosphatidylglycerol in a 1:1 ratio that forms a large ribbon-like structure. Blood levels of AMB are much lower with ABLC than with the same dose of C-AMB. ABLC is effective in a variety of mycoses, with the possible exception of cryptococcal meningitis. The drug is approved for salvage therapy of deep mycoses.
- Topical formulations − LAMB 0.5% (w/v) eye drop (AmBisome™, Gilead Sciences), ABLC solution (5 mg/ml), AMB (liposomal) gel 0.1% w/w (Fungisome™, Lifecare Innovations Pvt Ltd.), Vaginal tablets of 50 mg AMB (Talsutin™, Nicholas Piramal India Ltd.).
|Table 1 Dose, pharmacokinetics, availability, and cost of amphotericin formulations,|
Click here to view
The therapeutic uses are as follows,,:
- It is considered first-line therapy for invasive mucormycosis infections, rapidly progressive histoplasmosis, blastomycosis, coccidioidomycosis, penicilliosis, cryptococcal meningitis (in combination with 5-flucytosine), and certain aspergillus and candidal infections.
- Salvage therapy for patients not responding to azole therapy for invasive aspergillosis, extracutaneous sporotrichosis, fusariosis, alternariosis, or trichosporonosis.
- Empirical therapy for presumed fungal infection in immunocompromised hosts, febrile, neutropenic patients. (Azoles and echinocandins are generally the drugs of choice because of reduced toxicity.)
- Treatment of visceral leishmaniasis.
- Intraocular injection following pars plana vitrectomy has been used to treat fungal endophthalmitis.
- Topical uses (otomycosis, keratitis, vaginitis, rhinomaxillary mucomycosis, and cutaneous leishmaniasis).
Mucormycosis therapy, includes starting dosage of 5 mg/kg per day for LAMB and ABLC are given to adults and children. Dose escalation of LAMB to 7.5 or 10 mg/kg per day for central nervous system (CNS) mucormycosis may be considered in light of the limited penetration of polyenes into the brain. LAMB is preferred to ABLC for management of CNS infection on the basis of retrospective survival data and superior brain penetration. There is no advantage to escalating the LAMB dose above 10 mg/kg per day, and doses of 5 mg/kg per day are probably adequate for non-CNS infections. ABLC dose escalation above 5 mg/kg per day is not advisable given the lack of relevant data and the drug’s potential toxicity.
The C-AMB can also be used to treat mucormycosis, particularly when other formulations prove too costly. The typical dose is 1 to 1.5 mg/kg per day. The total dose given over the course of therapy is usually 2.5 to 3 g. High doses of this drug are required, and nephrotoxicity may result. This is of particular concern since many patients who develop mucormycosis have pre-existing renal disease (e.g., diabetics, transplant recipients).
- Acute effects
- Infusion-related fever, chills, aches and pain all over, nausea, vomiting, and dyspnea lasting for 2 to 5 hours probably due to the release of inflammatory cytokines. These are most prominent with ABCD, less with LAMB. Tachypnea, respiratory stridor, and modest hypotension can occur; frank bronchospasm and anaphylaxis are rare. Patients with pre-existing cardiac or pulmonary disease may tolerate the metabolic demands of the reaction poorly and develop hypoxia or hypotension. Pretreatment with oral acetaminophen or ibuprofen or use of intravenous hydrocortisone sodium succinate (hemisuccinate), 0.7 mg/kg, at the start of the infusion decreases reactions.
- Long-term effects
- Nephrotoxicity − It is dose dependent. Azotemia occurs in 80% patients who receive C-AMB for deep mycoses. The lipid formulations are significantly less nephrotoxic than C-AMB. Reduced glomerular filtration rate, renal tubular acidosis, hypokalemia (supplemental K+ is required in one-third patients), loss of magnesium, and inability to concentrate urine may occur. Nephrotoxicity reverses slowly and often incompletely after stoppage of therapy. It is recommended that 1 l of normal saline be administered intravenously on the day C-AMB is to be administered in those who are able to tolerate the Na+ load.,
- Anemia − Hypochromic, normocytic anemia commonly occurs during treatment with C-AMB. Anemia is less with lipid formulations. It is due to bone marrow depression and largely reversible. It often responds to administration of erythropoietin.
- CNS toxicity − It occurs only on intrathecal administration of C-AMB − headache, vomiting, arachnoiditis, nerve palsies, etc. may occur. These reactions may be decreased by intrathecal administration of 10 to 15 mg of hydrocortisone.,
- Malaise, weight loss, and thrombophlebitis at peripheral infusion sites are other common reactions.
The interactions include the following:
- Drug interactions due to AMB-induced hypokalemia:
- Diuretics like furosemide may exacerbate hypokalemia.
- Digitalis glycosides − Concurrent use may potentiate digitalis toxicity.
- Corticosteroids and corticotropin (ACTH) − Concurrent use may potentiate hypokalemia which could predispose the patient to cardiac dysfunction.
- Skeletal muscle relaxants − AMB-induced hypokalemia may enhance the curariform effect of skeletal muscle relaxants (e.g., tubocurarine).
- Drugs increasing the risk of nephrotoxicity and other toxicities:
- Antineoplastic agents − Concurrent use may enhance the potential for renal toxicity, bronchospasm, and hypotension.
- Other nephrotoxic medications − Concurrent use of other nephrotoxic medications (such as aminoglycosides, vancomycin, cyclosporine, etc.) may enhance the potential for drug-induced renal toxicity.
- Leukocyte transfusions − Acute pulmonary toxicity has been reported in patients simultaneously receiving intravenous AMB and leukocyte transfusions.
- Flucytosine − Concurrent use may increase the toxicity of flucytosine by possibly increasing its cellular uptake and/or impairing its renal excretion.
- Drugs increasing resistance to AMB:
- Azoles (e.g., ketoconazole, miconazole, clotrimazole, fluconazole, etc.) − In vitro and in vivo animal studies of the combination of AMB and imidazoles suggest that imidazoles may induce fungal resistance to AMB. Combination therapy should be administered with caution, especially in immunocompromised patients.
Reconstitution and Storage of LAMB
The steps and precautions involved in the reconstitution and storage of LAMB are as follows:
- Aseptically add 12 ml of sterile water for injection, to a vial (containing 50 mg AMB) to yield a preparation containing 4 mg AMB/ml.
- Immediately after the addition of water, shake the vial vigorously for 30 seconds to completely disperse the drug. It forms a yellow, translucent suspension. Visually inspect the vial for particulate matter and continue shaking until completely dispersed.
- Calculate the amount of reconstituted (4 mg/ml) LAMB to be further diluted.
- Withdraw this amount of reconstituted LAMB into a sterile syringe.
- Attach the 5-micron filter provided to the syringe. Inject the syringe contents through the filter, into the appropriate amount of 5% dextrose injection (use only one filter per vial).
- LAMB must be diluted with 5% dextrose injection to a final concentration of 1 to 2 mg/ml prior to administration. Discard partially used vials.
- For example:
- For a patient weighing 60 kg, the daily total dose is calculated to be 5mg/kg/day × 60 kg = 300 mg/day.
- On reconstitution, 4 mg AMB is present in 1 ml sterile water. Therefore, 300 mg AMB will be present in 75 ml sterile water. To bring the final concentration with 5% dextrose to 2 mg/ml, we add 75 ml of 5% dextrose to this, so the total volume becomes (75 + 75 = 150 ml) which contains 300 mg AMB.
- Do not reconstitute with saline or add saline to the reconstituted concentration, or mix with other drugs as it may cause precipitation.
- 5% dextrose must be used to flush an existing intravenous line prior to infusion. If this is not feasible, it must be administered through a separate line.
- Intravenous infusion should be given over a period of approximately 2 to 6 hours (depending on the dose). Infusion time may be reduced to approximately 60 minutes in patients in whom the treatment is well-tolerated. If the patient experiences discomfort during infusion, the duration of infusion may be increased.
- Unopened vials of lyophilized material are to be stored at temperatures up to 25°C.
- The reconstituted product concentrate may be stored for up to 24 hours at 2°C to 8°C following reconstitution with sterile water for injection. Do not freeze.
- Injection should commence within 6 hours of dilution with 5% dextrose injection.
Clinically Relevant Aspects
The following clinical information should be taken note of:
- History of
- Concomitant medications (see “Interactions” above), including herbal medications, supplements
- Pre-existing kidney/liver disease (involved in elimination, though dose adjustments usually not required)
- Diabetes (risk of nephrotoxicity increases)
- Recipient of transplant (risk of nephrotoxicity increases due to concomitant drugs)
- Hypersensitivity to any medication
- Investigations and monitoring
- Serum electrolytes, serum magnesium
- Blood urea, serum creatinine
- Alanine aminotransferase, aspartate aminotransferase, serum proteins, serum bilirubin
- Complete hemogram
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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