Chemistry. Amphotericin B is one of a family of some 200 polyene macrolide compounds with antifungal activity. Those studied to date share the characteristics of four to seven conjugated double bonds, an internal cyclic ester, poor aqueous solubility, substantial toxicity on parenteral administration, and a common mechanism of antifungal action. Amphotericin B (see following structure) is a heptaene macrolide containing seven conjugated double bonds in the trans position and 3-amino-3,6-dideoxymannose (mycosamine) connected to the main ring by a glycosidic bond. The amphoteric behavior for which the drug is named derives from the presence of a carboxyl group on the main ring and a primary amino group on mycosamine; these groups confer aqueous solubility at extremes of pH. X-ray crystallography has shown the molecule to be rigid and rod-shaped, with the hydrophilic hydroxyl groups of the macrolide ring forming an opposing face to the lipophilic polyenic portion.
Drug Formulations. There are currently four formulations of amphotericin B commercially available: conventional amphotericin B (C-AMB), liposomal amphotericin B (L-AMB), amphotericin B lipid complex (ABLC), and amphotericin B colloidal dispersion (ABCD). Table 57–2 summarizes the pharmacokinetic properties of these preparations.
C-AMB (Conventional amphotericin B, fungizone). Amphotericin B is insoluble in water but is formulated for intravenous infusion by complexing it with the bile salt deoxycholate. The complex is marketed as a lyophilized powder for injection. C-AMB forms a colloid in water, with particles largely <0.4 μm in diameter. Filters in intravenous infusion lines that trap particles >0.22 μm in diameter will remove significant amounts of drug. Addition of electrolytes to infusion solutions causes the colloid to aggregate.
ABCD. Amphotericin B colloidal dispersion (amphotec, amphocil) contains roughly equimolar amounts of amphotericin B and cholesteryl sulfate formulated for injection. Like C-AMB, ABCD forms a colloidal solution when dispersed in aqueous solution. ABCD provides much lower blood levels than C-AMB in mice and humans. In a study in patients with neutropenic fever comparing daily ABCD (4 mg/kg) with C-AMB (0.8 mg/kg), chills and hypoxia were significantly more common with ABCD than with C-AMB (White et al., 1998). Hypoxia was associated with severe febrile reactions. In a comparison of ABCD (6 mg/kg) and C-AMB (1-1.5 mg/kg) in invasive aspergillosis patients, ABCD was less nephrotoxic than C-AMB (49% vs. 15%) but caused more fever (27% vs. 16%) and chills (53% vs. 30%) (Bowden et al., 2002). Administration of the recommended ABCD dose over 3-4 hours and use of premedication to reduce febrile reactions are advised, particularly with initial infusions. ABCD is approved at a recommended dose of 3-4 mg/kg intravenously daily for patients with invasive aspergillosis who are not responding to or are unable to tolerate C-AMB.
L-AMB. Liposomal amphotericin B is a small, unilamellar vesicle formulation of amphotericin B (ambisome). The drug is supplied as a lyophilized powder, which is reconstituted with sterile water for injection. Blood levels following intravenous infusion are almost equivalent to those obtained with C-AMB, and because l-amb can be given at higher doses, blood levels have been achieved that exceed those obtained with C-AMB (Boswell et al., 1998) (Table 57–2). Amphotericin B accumulation in the liver and spleen is higher with l-amb than with C-AMB. Adverse effects include nephrotoxicity, hypokalemia, and infusion-related reactions, such as fever, chills, hypoxia, hypotension, and hypertension, but these do not commonly lead to drug discontinuation. Infusion-related pain in the back, abdomen, or chest occurs in occasional patients, usually with the first few doses. Anaphylaxis also has been reported. As empirical therapy or prophylaxis in febrile neutropenic patients, CAMB and l-amb are equivalent. As induction therapy of disseminated histoplasmosis in AIDS patients, l-amb 3 mg/kg was superior to C-AMB 0.7 mg/kg (Johnson, 2002). L-AMB is approved for initial therapy of cryptococcal meningitis of AIDS patients and is listed as an alternative to C-AMB for induction therapy of both disseminated histoplasmosis and cryptococcal meningoencephalitis in AIDS patients (Kaplan et al., 2009). l-amb is approved for empirical therapy of fever in the neutropenic host not responding to appropriate antibacterial agents, as well as for salvage therapy of aspergillosis and candidiasis. The recommended daily intravenous dose for empirical therapy is 3 mg/kg; for treatment of mycoses, the dosage is 3-5 mg/kg. l-amb also is effective in visceral leishmaniasis at doses of 3-4 mg/kg daily. The drug is administered in 5% dextrose in water, with initial doses infused over 2 hours. If well tolerated, infusion duration can be shortened to 1 hour. Doses up to 10 mg/kg have been used but are associated with higher toxicity and, in one randomized trial of aspergillosis, no improvement in efficacy (Cornely, 2007a).
ABLC (abelcet). Amphotericin B lipid complex is a complex of amphotericin B with lipids (dimyristoylphosphatidylcholine and dimyristoylphosphatidylglycerol). ABLC is given in a dose of 5 mg/kg in 5% dextrose in water, infused intravenously once daily over 2 hours. Blood levels of amphotericin B 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.
The three lipid formulations collectively appear to reduce the risk of the patient's serum creatinine doubling during therapy by 58% (Barrett et al., 2003). In patients at high risk for nephrotoxicity, ABLC is more nephrotoxic than l-amb (Wingard et al., 2000). In some patients, the additive burden of amphotericin B nephrotoxicity can help precipitate advanced renal failure, with attendant morbidity. Infusion-related reactions are not consistently reduced with the use of lipid preparations. ABCD causes more infusion-related reactions than C-AMB. Although l-amb reportedly causes fewer infusion-related reactions than ABLC during the first dose (Wingard et al., 2000), the difference depends on whether premedication is given and varies considerably between patients. Infusion-related reactions typically decrease with subsequent infusions.
The cost of the lipid formulations of amphotericin B greatly exceeds that of C-AMB, making them unavailable in many countries.
Mechanism of Action. The antifungal activity of amphotericin B depends principally on its binding to a sterol moiety, primarily ergosterol in the membrane of sensitive fungi. By virtue of their interaction with these sterols, polyenes appear to form pores or channels that increase the permeability of the membrane, allowing leakage of a variety of small molecules (Figure 57–1).
Absorption, Distribution, and Excretion. Gastrointestinal (GI) absorption of all amphotericin B formulations is negligible. Pharmacokinetic properties differ markedly between preparations with L-AMB having the highest plasma concentrations at therapeutic doses (Table 57–2). C-AMB is released from its complex with deoxycholate in the bloodstream, and the amphotericin B that remains in plasma is more than 90% bound to proteins, largely β-lipoprotein. Excretion into the urine is negligible with all the formulations. Azotemia, liver failure, or hemodialysis does not have a measurable impact on plasma concentrations. Concentrations of amphotericin B (via C-AMB) in fluids from inflamed pleura, peritoneum, synovium, and aqueous humor are approximately two-thirds of trough concentrations in plasma. Little amphotericin B from any formulation penetrates into cerebrospinal fluid (CSF), vitreous humor, or normal amniotic fluid.
Antifungal Activity. Amphotericin B has useful clinical activity against Candida spp., Cryptococcus neoformans, Blastomyces dermatitidis, Histoplasma capsulatum, Sporothrix schenckii, Coccidioides spp., Paracoccidioides braziliensis, Aspergillus spp., Penicillium marneffei, and the agents of mucormycosis. Amphotericin B has limited activity against the protozoa Leishmania spp. and Naegleria fowleri. The drug has no antibacterial activity.
Fungal Resistance. Some isolates of Candida lusitaniae have been relatively resistant to amphotericin B. Aspergillus terreus and perhaps Aspergillus nidulans may be more resistant to amphotericin B than other Aspergillus species (Steinbach et al., 2004). Mutants selected in vitro for resistance to nystatin (a polyene antifungal discussed later) or amphotericin B replace ergosterol with certain precursor sterols. The rarity of significant amphotericin B resistance arising during therapy has left it unclear whether ergosterol-deficient mutants retain sufficient pathogenicity to survive in deep tissue.
Therapeutic Uses. The recommended doses were given earlier for each formulation. Candida esophagitis responds to much lower doses than deeply invasive mycoses. Intrathecal infusion of C-AMB is useful in patients with meningitis caused by Coccidioides. Too little is known about intrathecal administration of lipid formulations to recommend them. C-AMB can be injected into the CSF of the lumbar spine, cisterna magna, or lateral cerebral ventricle. Fever and headache are common reactions that may be decreased by intrathecal administration of 10-15 mg of hydrocortisone. Local injections of amphotericin B into a joint or peritoneal dialysate fluid commonly produce irritation and pain. Intraocular injection following pars plana vitrectomy has been used successfully for fungal endophthalmitis.
Intravenous administration of amphotericin B is the treatment of choice for mucormycosis and is used for initial treatment of cryptococcal meningitis, severe or rapidly progressing histoplasmosis, blastomycosis, coccidioidomycosis, and penicilliosis marneffei, as well as in patients not responding to azole therapy of invasive aspergillosis, extracutaneous sporotrichosis, fusariosis, alternariosis, and trichosporonosis. Amphotericin B (C-AMB or l-amb) is often given to selected patients with profound neutropenia who have fever that does not respond to broad-spectrum antibacterial agents over 5-7 days.
Untoward Effects. The major acute reactions to intravenous amphotericin B formulations are fever and chills. Infusion-related reactions are worst with ABCD, slightly less with C-C-AMB, even less with ABLC, and least with L-AMB. Tachypnea and respiratory stridor or modest hypotension also may occur, but true bronchospasm or anaphylaxis is rare. Patients with pre-existing cardiac or pulmonary disease may tolerate the metabolic demands of the reaction poorly and develop hypoxia or hypotension. The reaction ends spontaneously in 30-45 minutes; meperidine may shorten it. Pretreatment with oral acetaminophen or use of intravenous hydrocortisone hemisuccinate, 0.7 mg/kg, at the start of the infusion decreases reactions. Febrile reactions abate with subsequent infusions. Infants, children, and patients receiving therapeutic doses of glucocorticoids are less prone to reactions.
Azotemia occurs in 80% of patients who receive C-AMB for deep mycoses (Carlson and Condon, 1994). Lipid formulations are less nephrotoxic, being much less with ABLC, even less with L-AMB, and minimal with ABCD. Toxicity is dose-dependent and usually transient and increased by concurrent therapy with other nephrotoxic agents, such as aminoglycosides or cyclosporine. Although permanent histological changes in renal tubules occur even during short courses of C-AMB, permanent functional impairment is uncommon in adults with normal renal function prior to treatment unless the cumulative dose exceeds 3-4 g. Renal tubular acidosis and renal wasting of K+ and Mg2+ also may be seen during and for several weeks after therapy. Supplemental K+ is required in one-third of patients on prolonged therapy. Saline loading has decreased nephrotoxicity, even in the absence of water or salt deprivation. Administration of 1 L of normal saline intravenously on the day that C-AMB is to be given has been recommended for adults who are able to tolerate the Na+ load and who are not already receiving that amount in intravenous fluids.
Hypochromic, normocytic anemia commonly occurs during treatment with C-AMB. Anemia is less with lipid formulations and usually not seen over the first 2 weeks. The anemia is most likely due to decreased production of erythropoietin. Patients with low plasma erythropoietin may respond to administration of recombinant erythropoietin. Anemia reverses slowly following cessation of therapy. Headache, nausea, vomiting, malaise, weight loss, and phlebitis at peripheral infusion sites are common. Thrombocytopenia or mild leukopenia is observed rarely. Hepatotoxicity is not firmly established with any amphotericin B formulation. Arachnoiditis has been observed as a complication of injecting C-AMB into the CSF.