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Actions and Uses |
Amphotericin B is a highly lipophilic, polyene antifungal substance (molecular weight = 924) synthesized by Streptomyces nodosus, an organism found in the soil. It exerts a fungicidal effect by binding irreversibly to ergosterol, a component of the fungal cell membrane, disrupting fungal membrane and causing cell death.
Amphotericin B remains the gold standard for the treatment of serious fungal infections. It is a broad spectrum antifungal agent that shows little resistance development. It is effective against many pathogens including:
- Aspergillus sp.
- Blastomyces sp.
- Candida sp. (albicans, glabrata, krusei, lusitaniae, parapsilosis, tropicalis, , , etc)
- Coccidioidomyces
- Cryptococcus sp.
- Histoplasma sp.
- Leishmania
- Mucorales
However, serious side effects such infusion-related reactions and nephrotoxicity have significantly limited its clinical utility. Efforts to overcome these problems led to the development of several lipid-based amphotericin B [LBAB] formulations which have proven to be as effective and significantly safer than the conventional preparation [for review see: Pharmacotherapy 1999; 19(3):306-323]. Conventional amphotericin B (AmB) is supplied in combination with Na deoxycholate for IV administration. Hence, it is referred to as amphotericin B deoxycholate. Before being infused, the combination of AmB and bile salt is reconstituted and diluted in 5% dextrose solution (D5W) where it forms a stable micellar dispersion. None of the AmB product should be mixed with NaCl solutions
In addition of the conventional formulation, there are at least 3 lipid-based amphotericin B products:
- Amphotericin B lipid complex (ABLC) (Abelcet®)
- Truly liposomal amphotericin B (LamB) (AmBisome®)
- Amphotericin B colloidal dispersion (ABCD) (Amphotec®).
Table 1 describes the three lipid-based products and table 2 lists the FDA approved indications of the two most widely used lipid products together with the indications of the conventional product:
Table 1
Lipid-based Amphotericin B Products
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Lipid Complex
Flattened, ribbon-like mutilamellar vesicle/structure.
Molecular ratio (drug:lipid) = 1:2
Particle size = 1600-11,000 nm
|
Abelcet® |
Liposome company; Princeton, NJ |
Colloidal Dispersion
Elongated disk structure
Particle diameter = 115 nm
Molecular ratio (drug:lipid) = 1:1 |
Amphotec® |
Sequus Pharmaceuticals; Melno Park, CA |
Liposomal
Closed fluid-filled unilamellar liposome made of a single phospholipid bilayer
Molecular ratio (drug:lipid) = 1:9)
Particle size = 45-80 nm |
AmBisome® |
NeXstar Pharmaceuticals; Boulder CO & Fujisama USA; Deerfield, IL |
Table 2
FDA Approved Indications |
| Abelcet® (ABLC) |
Treatment of invasive fungal infections in patients who are refractory to or intolerant of conventional amphotericin B |
| Conventional Amphotericin B (deoxycholate) (ABDC) |
Treatment of potentially life-threatening fungal infections: aspergillosis, cryptococcosis (torulosis), N. American blasmomycosis, systemic candidiasis, coccidioidomycosis, histoplasmosis, zgomycosis including mucormycosis due to susceptible species of the genera Absidia, Mucor, and Rhizopus and infections due to related susceptible species of Conidiobolus and Basidiobolus, and sporotrichosis. AmB may be useful in the treatment of American mucocutaneous leishmaniasis, but is not the drug of choice for this pathogen (drug of choice is stibogluconate or meglumine antimoniate). |
AmBisome®
(LAmB) |
- Empiric therapy for presumed fungal infections in febrile neutropenic patients.
- Treatment of patients with Aspergillus species, Candida species and/or infections due to Cryptococcus species refractory to conventional AmB or in patients with marked renal impairment or when severe toxicity precludes the
use of conventional AmB.
- Treatment of visceral leishmaniasis.
|
| Amphotec |
Treatment of invasive aspergillosis in patients who are refractory to or intolerant of conventional amphotericin B |
ABLC (Abelcet) consists of amphotericin B complexed with two phospholipids in a 1:2 drug-to-lipid molar ratio. The complex assumes a flattened, ribbon-like mutilamellar structure with a particle size ranging from 1600 to 11,000 nm. The two phospholipids, L-a-dimyristoylphosphatidylcholine (DMPC) and L-a-dimyristoylphosphatidylglycerol (DMPG), are present in a 7:3 molar ratio. In contrast, AmBisome consists of closed fluid-filled unilamellar liposomes made of a single phospholipid bilayer with drug-to-lipid molecular ratio of 1:9. The liposome particle size ranges from 45 to 80 nm
The actions and uses of the lipid preparations (LBAB) are similar to those of the conventional amphotericin B deoxycholate. However, due to their high cost, the use of LBAB in most hospitals requires the approval of the Infectious Disease Unit. The patient must meet at least one of the following criteria to qualify for therapy with LBAB:
- Significant Renal Impairment: Scr ³ 2.4 mg/dL or CLcr < 50 mL/min, or a rise in Scr by 1 mg/dL over the baseline level while on regular AmB.
- Patient is unable to tolerate the infusion-related reactions to the regular Amphotericin B
- In some centers, transplant recipients (SOT and BMT) are exempt from these restrictions.
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Available As |
| Product (NDC #) | | Dilution |
Amphotericin Deoxycholate (Fungizone®)
(0000-0000-00) | | Lyophilized powder for injection (50-mg vials) to be diluted in D5W (for iv route) or SWFI (for bladder irrigation; 50 mg/L) |
Abelcet® (ABLC)
(61799-0101-41) | Injectable suspension (100 mg / 20 mL) to be diluted in 5% dextrose in water to a final concentration of about 1 mg /mL (maximum 2 mg/mL). |
AmBisome®
(00469-3051-30) | 50 mg vial. Reconstitue with 12 mL of H2O (SWFI) to yield 4 mg/mL. Transfer to D5W bag using 5 micron filter. Final concentration should be 1 to 2 mg/mL. Infuse dose over 2 hours. |
| Amphotec® | Injectable suspension (50 mg/20 mL or 100 mg/100mL) to be diluted in 5% dextrose in water to a final concentration of about 1 mg /mL (maximum 2 mg/mL). |
|
Dose and Administration |
- A test dose is recommended for conventional amphotericin, but not with the lipid-based products.
- Premedication (diphenhydramine + acetaminophen + iv hydrocortisone) are recommend before administring conventional amphotericin and should be used also before the 1st dose of Abelcet.
| Product | Recommended Dose |
| Conventional AmB |
- Test dose= 0.1 mg/kg with a mximum of 1 mg infused over 60 min for children and 20 min for adults.
- Maintenance dose ranges from 0.5 to 1.5 mg/kg iv q24h infused over 2 - 4 hours.
- After the first 5 - 7 days of therapy, AmB may be administered on a q48h basis because of its relatively long half-life.
- Prophylactic dose for neutropenic patients is 0.1 - 0.2 mg/kg iv q24h.
|
| Abelcet® (ABLC) |
The recommended daily dosage for adults and children (regardless of indication) is 5 mg/kg iv qd given as a single infusion. Abelcet® should be administered by IV infusion at a rate of 2.5 mg/kg/h. However, doses of 3 mg/kg iv qd have been used for impiric treatment and doses as high as 16 mg/kg have been used for the treatment of severe mucormycoses infections. If the infusion time exceeds 2 hours, mix the contents of the bag by shaking it every 2 hours.
|
| AmBisome®
|
| Empirical therapy | 3 mg/kg iv qd |
Documented systemic fungal infections
involving Aspergillus, Candida, or Cryptococcus | 3 - 5 mg/kg iv qd |
| Cryptococcal meningitis in HIV infected patients | 6 mg/kg iv qd |
|
| Amphotec® |
- Premedications (acetaminophen, diphenhydramine, hydrocortisone) are highly recommended.
- The recommended daily dosage for adults and children 3 - 5 mg/kg iv qd (max 7.5 mg/kg/day) infused at the rate of 1 mg/kg/hr.
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Pharmacokinetics |
- Amphotericin B is not reabsorbed through the GI and is used orally only for gut decontamination.
- Amphotericin B is widely distributed in tissues, but has a poor CSF penetration (CSF/Blood levels ratio < 5%). Therefore, intrathecal administration of conventional amphotericin may be necessary for the treatment of fungal meningitis. Lipid-based products have been used (exclusively intravenously) for the treatment of CNS infections with mixed results. No dose escalation study has been conducted to establish an effective dose of LBAB for CNS infections
- Amphotericin B is >95% protein bound and is not removed by hemodialysis.
- ABLC has a much larger volume of distribution than ampho B deoxycholate. Hence larger doses are required
| Product | Vd
L/kg1 | Initial
t1/2 (hrs) | Terminal
t1/2 (hrs)2 | Pref. Tiss Distrib3 |
| AmB | 5 | 24 | >100 | Extensive |
| Abelcet | 130 | 24 | 173 | Lungs |
| AmBisome | 0.1 - 0.4 | 6 - 12 | 100 - 150 | Extensive |
| Amphotec | 4 | 28 | 100 - 150 | Liver |
1 Vd increases with increasing dose representing increased tissue penetration
2 This reflects the release of amphotericin from tissue depot.
3 The tissue that shows the highest concentrations of amphotericin following the administration of the amphotericin product.
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Main Side Effects |
- Amphotericin is a toxic drug and should be used with care.
- On rare occasion, severe hypersesitivity reactions or anaphylaxis may occur.
- Headache, generalized pain, and (rarely) seizures
- Orthostatic hypotension, tachycardia, and hypertension.
- Anorexia, nausea, and vomiting.
- Rash
- The incidences of infusion-related reactions (fever, chills, rigors, etc) associated with Abelcet and conventional amphotericin B (CAB) are similar. However, the incidence and the severity of nephrotoxicity associated with the use of CAB are markedly higher than observed with the lipid-based products.
- Hypokalemia, hypomagnesemia, and tubular acidosis may occur particularly with conventional amphotericin.
- Hematologic: thrombocytopenia, agranulcytosis, and anemia.
- Elevated liver indeces.
- Recent data indicate that Abelcet® is associated with significantly higher incidence of nephrotoxicity and infusion-related adverse reactions (chills, fever, rigors) than the liposomal amphotericin product (AmbiSome).
| Frequency (% of patients) of infusion-related reactions on day 1 of treatment with lipid formulations of amphotericin B |
| | Liposomal amphotericin B | Amphotericin B lipid complex |
|---|
| Infusion-related reaction | 3 mg/kg/day | 5 mg/kg/day | 5 mg/kg/day |
|---|
| Chills/rigors | 18.8 | 23.5 | 79.5 | | Fever* | 23.5 | 19.8 | 57.7 | | Vomiting | 5.9 | 6.2 | 14.1 | | Nausea | 10.6 | 8.6 | 11.5 | | Other reactions** | 18.8 | 25.9 | 41 | | Total | 51.8 | 48.1 | 88.5 |
* defined as a temperature increase of ≥ 1°C from baseline
** including pain, chest pain, tachycardia, hypertension, hypotension and vasodilation
Wingard JR, White MH, Anaissie E, Raffalli J, L Amph/ABLC Collaborative Study Group, et al. A randomized, double-blind comparative trial evaluating the safety of liposomal amphotericin B versus amphotericin B lipid complex in the empirical treatment of febrile neutropenia. Clinical Infectious Diseases 31: 1155-1163, Nov 2000 |
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Drug Interactions |
- Most of the interactions involving AmB are pharmacodynamic in nature.
- Potentially nephrotoxic drugs can exacerbate AmB induced nephrotoxicity.
- Steroids may exacerbate electrolyte disturbances, particularly hypokalemia
- Hypokalemia caused by AmB may enhance the risk of digoxin cardiac toxicity.
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References |
- Product Information Abelcet
- Product Information AmBisome
- Robinson RF, Nahata MC. A comparative review of conventional and lipid formulations of amphotericin B. J Clin Pharm Ther. 1999;24(4):249-57.
- Arikan S, Rex JH. Lipid-based antifungal agents: current status. Curr Pharm Des. 2001;7(5):393-415.
- Tiphine M. Amphotericin B and its new formulations: pharmacologic characteristics, clinical efficacy, and tolerability. Transpl Infect Dis. 1999;1(4):273-83.
- Ellis M. Amphotericin B preparations: a maximum tolerated dose in severe invasive fungal infections? Transpl Infect Dis. 2000;2(2):51-61.
- Kam LW, Lin JD. Management of systemic candidal infections in the intensive care unit.
Am J Health Syst Pharm. 2002 Jan 1;59(1):33-41.
- Razzaque MS, Hossain MA, et al. Lipid formulations of polyene antifungal drugs and attenuation of associated nephrotoxicity. Nephron. 2001;89(3):251-4.
- Hann IM, Prentice HG. Lipid-based amphotericin B: a review of the last 10 years of use.
Int J Antimicrob Agents. 2001;17(3):161-9.
- Adedoyin A. et al. A pharmacokinetic study of amphotericin B lipid complex injection (Abelcet) in patients with definite or probable systemic fungal infections. Antimicrob Agents Chemother. 2000;44(10):2900-2.
- Walsh TJ et al. Amphotericin B lipid complex for invasive fungal infections: analysis of safety and efficacy in 556 cases. Clin Infect Dis. 1998;26(6):1383-96.
- Wingard JR et al. A randomized, double-blind comparative trial evaluating the safety of liposomal amphotericin B versus amphotericin B lipid complex in the empirical treatment of febrile neutropenia. Clinical Infectious Diseases 2000; 31: 1155-1163.
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