Overview of Antifungal Agents
George R.Thompson III, MD, FACPa,b,*, Jose Cadena, MDa,b, Thomas F. Patterson, MDa,b KEYWORDS
Fungal infection Invasive mycoses Triazoles Echinocandins Amphotericin Flucytosine
The number of agents available to treat fungal infections has increased by 30% since the year 2000, yet still only 15 agents are currently approved for clinical use. The greater number of medications now available allows for therapeutic choices; however, differences in antifungal spectrum of activity, bioavailability, formulation, drug interactions, and side effects necessitates a detailed knowledge of each drug class.
Amphotericin B (AMB) and nystatin are the currently available polyenes, although differing safety profiles have limited nystatin to topical use.1 The polyenes bind to ergosterol present within the fungal cell wall membrane. This process disrupts cell wall permeability by forming oligodendromes functioning as pores with the subsequent efflux of potassium and intracellular molecules causing fungal death.2 There is also evidence that AMB acts as a proinflammatory agent and further serves to stimulate innate host immunity. This process involves the interaction of AMB with toll-like receptor 2 (TLR-2), the CD14 receptor, and by stimulating the release of cytokines, chemokines, and other immunologic mediators. It has been suggested that AMB may interact with host humoral immunity after the observation of synergistic activity of AMB and antibodies directed at heat shock protein 90 (hsp90), although further confirmatory data are needed.2
When AMB resistance occurs, it is generally attributed to reductions in ergosterol biosynthesis or the synthesis of alternative sterols with a reduced affinity for AMB. Resistance to AMB is common in Aspergillus terreus, Scedosporium apiospermum, Scedosporium prolificans, Trichosporon spp, and Candida lusitaniae (Table 1). Resistance has been reported with several other species, however.3 The peak serum level to mean inhibitory concentration (MIC) ratio is the best pharmacologic predictor of outcomes with polyene therapy. Drug levels are infrequently measured, nor are they necessary, and they are typically available only in the research setting.4 AMB is primarily used intravenously (IV) or through the inhalational route. In attempts to avoid the nephrotoxicity seen with amphotericin B deoxycholate (AmBd; Fungizone) several other formulations have been developed. The lipid preparations include: liposomal amphotericin B (L-AMB; Ambisome), amphotericin B lipid complex, (ABLC; Abelcet), and amphotericin B colloidal dispersion (ABCD; Amphotec, Amphocil). All currently available formulations are highly protein bound (>95%, primarily to albumin) and have long halflives. AMB exhibits poor cerebrospinal fluid levels (1 mg/mL) have been obtained. Fluconazole levels are infrequently monitored because of the excellent bioavailability of this agent. Clinical circumstances may dictate drug monitoring when therapeutic levels are uncertain (ie, concurrent use of rifampin, rifampicin, and so forth). The newer triazoles, posaconazole and voriconazole, have received increased attention because of their erratic absorption (posaconazole) or concerns for toxicity and the interpatient variability of serum levels (voriconazole). No guidelines exist for posaconazole TDM; however, past
Thompson et al
evidence supports a relationship between posaconazole serum drug level and efficacy.80 TDM should also be considered when drug interactions are of concern, such as the aforementioned potential for acid-suppressive agents to reduce absorption. Although goal levels remain to be determined, most advocate trough concentrations 0.5 mg/mL or greater when given for antifungal prophylaxis. The interpatient variability of voriconazole also warrants consideration of TDM during use. Low concentrations (1 mg/mL) when Candida parapsilosis and Candida guilliermondii are...
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