Amphotericin B

SYSTEMIC ANTIFUNGAL DRUGS FOR SYSTEMIC INFECTIONS

AMPHOTERICIN B

Amphotericin A and B are antifungal antibiotics produced by Streptomyces nodosus. Amphotericin A is not in clinical use.

Chemistry & Pharmacokinetics

Amphotericin B is an amphoteric polyene macrolide (polyene = containing many double bonds; macrolide = containing a large lactone ring of 12 or more atoms). It is nearly insoluble in water and is therefore prepared as a colloidal suspension of amphotericin B and sodium desoxycholate for intravenous injection. Several formulations have been developed in which amphotericin B is packaged in a lipid-associated delivery system (Table 48–1 and Box: Liposomal Amphotericin B).

Amphotericin B is poorly absorbed from the gastrointestinal tract. Oral amphotericin B is thus effective only on fungi within the lumen of the tract and cannot be used for treatment of systemic disease. The intravenous injection of 0.6 mg/kg/d of amphotericin B results in average blood levels of 0.3–1 mcg/mL; the drug is more than 90% bound by serum proteins. Although it is mostlymetabolized, some amphotericin B is excreted slowly in the urine over a period of several days. The serum half-life is approximately 15 days. Hepatic impairment, renal impairment, and dialysis have little impact on drug concentrations, and therefore no dose adjust-ment is required. The drug is widely distributed in most tissues, but only 2–3% of the blood level is reached in cerebrospinal fluid, thus occasionally necessitating intrathecal therapy for certain types of fungal meningitis.

Mechanisms of Action & Resistance

Amphotericin B is selective in its fungicidal effect because it exploits the difference in lipid composition of fungal and mammalian cell membranes. Ergosterol, a cell membrane sterol, is found in the cell membrane of fungi, whereas the predominant sterol of bacteria and human cells is cholesterol. Amphotericin B binds to ergosterol and alters the permeability of the cell by forming amphotericin B-associated pores in the cell membrane (Figure 48–1).

Liposomal Amphotericin B

Therapy with amphotericin B is often limited by toxicity, espe-cially drug-induced renal impairment. This has led to the devel-opment of lipid drug formulations on the assumption that lipid-packaged drug binds to the mammalian membrane less readily, permitting the use of effective doses of the drug with lower toxicity. Liposomal amphotericin preparations package the active drug in lipid delivery vehicles, in contrast to the colloidal suspensions, which were previously the only available forms. Amphotericin binds to the lipids in these vehicles with an affinity between that for fungal ergosterol and that for human choles-terol. The lipid vehicle then serves as an amphotericin reservoir, reducing nonspecific binding to human cell membranes. This preferential binding allows for a reduction of toxicity without sacrificing efficacy and permits use of larger doses. Furthermore,some fungi contain lipases that may liberate free amphotericin B directly at the site of infection.

Three such formulations are now available and have differing pharmacologic properties as summarized in Table 48–1. Although clinical trials have demonstrated different renal and infusion-related toxicities for these preparations compared with regular amphotericin B, there are no trials comparing the different for-mulations with each other. Limited studies have suggested at best a moderate improvement in the clinical efficacy of the lipid formulations compared with conventional amphotericin B. Because the lipid preparations are much more expensive, their use is usually restricted to patients intolerant to, or not respond-ing to, conventional amphotericin treatment.

As sug-gested by its chemistry, amphotericin B combines avidly with  lipids (ergosterol) along the double bond-rich side of its structure and associates with water molecules along the hydroxyl-rich side. This amphipathic characteristic facilitates pore formation by mul-tiple amphotericin molecules, with the lipophilic portions around the outside of the pore and the hydrophilic regions lining the inside. The pore allows the leakage of intracellular ions and mac-romolecules, eventually leading to cell death. Some binding to human membrane sterols does occur, probably accounting for the drug’s prominent toxicity.

Resistance to amphotericin B occurs if ergosterol binding is impaired, either by decreasing the membrane concentration of ergosterol or by modifying the sterol target molecule to reduce its affinity for the drug.

Antifungal Activity & Clinical Uses

Amphotericin B remains the antifungal agent with the broadest spectrum of action. It has activity against the clinically significant yeasts, including Candida albicans and Cryptococcus neoformans; the organisms causing endemic mycoses, including Histoplasmacapsulatum, Blastomyces dermatitidis, and Coccidioides immitis;and the pathogenic molds, such as Aspergillus fumigatus and the agents of mucormycosis. Some fungal organisms such as Candidalusitaniae and Pseudallescheria boydii display intrinsic amphoteri-cin B resistance.

Owing to its broad spectrum of activity and fungicidal action, amphotericin B remains a useful agent for nearly all life-threatenin mycotic infections, although newer, less toxic agents have largely replaced it for most conditions. Amphotericin B is often used as the initial induction regimen to rapidly reduce fungal burden and then replaced by one of the newer azole drugs (described below) for chronic therapy or prevention of relapse. Such induction therapy is especially important for immunosup-pressed patients and those with severe fungal pneumonia, severe cryptococcal meningitis, or disseminated infections with one of the endemic mycoses such as histoplasmosis or coccidioidomy-cosis. Once a clinical response has been elicited, these patients then often continue maintenance therapy with an azole; therapy may be lifelong in patients at high risk for disease relapse. For treatment of systemic fungal disease, amphotericin B is given by slow intravenous infusion at a dosage of 0.5–1 mg/kg/d. It is usually continued to a defined total dose (eg, 1–2 g), rather than a defined time span, as used with other antimicrobial drugs.

Intrathecal therapy for fungal meningitis is poorly tolerated and fraught with difficulties related to maintaining cerebrospinal fluid access. Thus, intrathecal therapy with amphotericin B is being increasingly supplanted by other therapies but remains an option in cases of fungal central nervous system infections that have not responded to other agents.

Local or topical administration of amphotericin B has been used with success. Mycotic corneal ulcers and keratitis can be cured with topical drops as well as by direct subconjunctival injec-tion. Fungal arthritis has been treated with adjunctive local injection directly into the joint. Candiduria responds to bladder irrigation with amphotericin B, and this route has been shown to produce no significant systemic toxicity.

Adverse Effects

The toxicity of amphotericin B can be divided into two broad categories: immediate reactions, related to the infusion of the drug, and those occurring more slowly.

A. Infusion-Related Toxicity

Infusion-related reactions are nearly universal and consist of fever, chills, muscle spasms, vomiting, headache, and hypoten-sion. They can be ameliorated by slowing the infusion rate or decreasing the daily dose. Premedication with antipyretics, anti-histamines, meperidine, or corticosteroids can be helpful. When starting therapy, many clinicians administer a test dose of 1 mg intravenously to gauge the severity of the reaction. This can serve as a guide to an initial dosing regimen and premedication strategy.

B. Cumulative Toxicity

Renal damage is the most significant toxic reaction. Renal impair-ment occurs in nearly all patients treated with clinically significant doses of amphotericin. The degree of azotemia is variable and often stabilizes during therapy, but it can be serious enough to necessitate dialysis. A reversible component is associated with decreased renal perfusion and represents a form of prerenal renal failure. An irreversible component results from renal tubular injury and subsequent dysfunction. The irreversible form of amphotericin nephrotoxicity usually occurs in the setting of pro-longed administration (> 4 g cumulative dose). Renal toxicity commonly manifests as renal tubular acidosis and severe potas-sium and magnesium wasting. There is some evidence that the prerenal component can be attenuated with sodium loading, and it is common practice to administer normal saline infusions with the daily doses of amphotericin B.

Abnormalities of liver function tests are occasionally seen, as is a varying degree of anemia due to reduced erythropoietin produc-tion by damaged renal tubular cells. After intrathecal therapy with amphotericin, seizures and a chemical arachnoiditis may develop, often with serious neurologic sequelae.