Principles of Antifungal Therapy

Amphotericin B

The prototype of the oldest antifungal class, the polyene macrolides, is amphotericin B deoxycholate. Amphotericin B was once the preferred treatment for most invasive fungal infections as well as the standard of comparison for all newer antifungal agents. Amphotericin B is so named because it is amphoteric, forming soluble salts in both acidic and basic environments. However, because of its insolubility in water, amphotericin B for clinical use is actually amphotericin B mixed with the detergent deoxycholate. Amphotericin B binds to ergosterol, the major sterol found in fungal cytoplasmic membranes, and acts by creating transmembrane channels. The fungicidal activity is due to a damaged barrier and subsequent cell death through leakage of essential nutrients from the fungal cell.

Amphotericin B is released from its carrier and distributes very efficiently with lipoproteins and is then taken up preferentially by organs of the reticuloendothelial system. Following an initial 24-48 hr distributional half-life there is very slow release and a subsequent terminal elimination half-life of up to 15 days. In addition to conventional amphotericin B deoxycholate, 3 fundamentally different lipid-associated formulations have been developed that offer the advantage of an increased daily dosage of the parent drug, better delivery to the primary reticuloendothelial organs (lungs, liver, spleen), and reduced toxicity. Amphotericin B lipid complex (ABLC) is a tightly packed ribbon-like structure of a bilayered membrane, amphotericin B colloidal dispersion (ABCD) is composed of disk-like structures of cholesteryl sulfate complexed with amphotericin B, and liposomal amphotericin B (L-amphotericin B) consists of small uniformly sized vesicles of a lipid bilayer of amphotericin B. Lipid formulations of amphotericin B generally have a slower onset of action, presumably owing to the required disassociation of free amphotericin B from the lipid vehicle. The ability to safely administer higher daily doses of the parent drugs improves their efficacy, comparing favorably with amphotericin B deoxycholate but with less toxicity. Lipid formulations have the added benefit of increased tissue concentrations compared to conventional amphotericin B, specifically in the liver, lungs, and spleen. However, it is not entirely clear if these higher concentrations in tissue are truly available to the microfoci of infection.

Tolerance to amphotericin B deoxycholate is limited by its acute and chronic toxicities. In addition to interacting with fungal ergosterol, the drug also interacts with cholesterol in human cell membranes, likely accounting for its toxicity. Up to 80% of patients receiving amphotericin B develop either infusion-related toxicity or nephrotoxicity, especially with concomitant therapy with nephrotoxic drugs such as aminoglycosides, vancomycin, cyclosporine, or tacrolimus. Renal function usually returns to normal after cessation of amphotericin B, although permanent renal impairment can occur after larger doses. Amphotericin B nephrotoxicity is generally less severe in infants and children than in adults, likely due to the more rapid clearance of the drug in children. Lipid formulations appear to stabilize amphotericin B in a self-associated state so that it is not available to interact with the cholesterol of human cellular membranes.

Unlike older approaches, there is no total dosage of amphotericin B recommended, and the key to success is to give high dosages in the initial phase of therapy and to reduce the frequency of administration (not necessarily the daily dose) if toxicity develops. There are no data or consensus opinions among authorities indicating improved efficacy of any new amphotericin B lipid formulation over conventional amphotericin B deoxycholate. One exception is that L-amphotericin B has shown fewer infusion-related adverse events than the other lipid formulations or conventional amphotericin B.

5-Fluorocytosine

5-Fluorocytosine (5-FC) is a fluorinated analog of cytosine and has antifungal activity results from the rapid conversion into 5-fluorouracil (5-FU) within susceptible fungal cells. Clinical and microbiologic antifungal resistance develops quickly to 5-FC monotherapy, so clinicians have reserved it for combination approaches to augment other more potent antifungals. Fungistatic 5-FC is thought to enhance the antifungal activity of amphotericin B, especially in anatomic sites where amphotericin B penetration is often suboptimal, such as cerebrospinal fluid (CSF), heart valves, and the vitreal body. 5-FC penetrates well into most body sites because it is small, highly water-soluble, and not bound by serum proteins to any great extent. One explanation for the synergy detected with the combination of amphotericin B plus 5-FC is that the membrane-permeabilizing effects of low concentrations of amphotericin B facilitate penetration of 5-FC to the cell interior. 5-FC is only available as an oral formulation in the United States, and the dosage is 150 mg/kg/day in 4 divided doses.

5-FC can exacerbate myelosuppression in patients with neutropenia, and toxic levels can develop when used in combination with amphotericin B, owing to nephrotoxicity of the amphotericin B and decreased renal clearance of 5-FC. Routine serum 5-FC level monitoring is warranted in high-risk patients, and levels should be obtained after 3-5 days of therapy, with a goal to achieve a 2-hr post-dose peak <100 µg/mL (and ideally 30-80 µg/mL). Levels >100 µg/mL are associated with bone marrow aplasia. Toxicities can include azotemia, renal tubular acidosis, leukopenia, thrombocytopenia, and others and appear in approximately 50% of patients in the 1st 2 wk of therapy.

Nearly all clinical studies involving 5-FC are combination antifungal protocols for cryptococcal meningitis, owing to the inherently rather weak antifungal activity of 5-FC monotherapy. The use of 5-FC for Candida meningitis in premature neonates is discouraged. A study evaluating risk factors and mortality rates of neonatal candidiasis among extremely premature infants showed that infants with Candida meningitis who received amphotericin B in combination with 5-FC had a prolonged time to sterilization of the CSF compared to infants receiving amphotericin B monotherapy.