Amphotericin B lipid complex in the treatment of invasive fungal infections: results of the Collaborative Exchange of Antifungal Research (CLEAR), an industry-supported patient registry.

Reprints or correspondence: Dr. Peter G. Pappas, Dept. of Medicine, Div. of Infectious Diseases, University of Alabama at Birmingham, 229 THT, 1900 University Blvd., Birmingham, AL 35294 (pappas@uab.edu). Clinical Infectious Diseases 2005; 40:S379–83 2005 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2005/4009S6-0001$15.00 Many factors confound the conduct, reproducibility, and interpretation of prospective therapeutic trials of antifungal agents. In general, clinical trials of antifungal agents involve relatively small numbers of patients, owing to the relative rarity of certain mycoses, strict eligibility criteria, and the complexity of the comorbid conditions encountered among patients who develop invasive fungal infections. Compounding these problems is the relative lack of diagnostic methods that permit accurate identification of potential study candidates early enough during the course of the infection to facilitate study enrollment. In recognition of these substantial obstacles, some investigators have advocated the use of a more innovative approach to the study of invasive mycoses— for example, the use of surrogate markers and nonculture techniques to identify potential study candidates and to assess response [1]. Finally, despite the growing size of the population of at-risk patients and the recognition of new and emerging fungal pathogens, the study of the diagnosis and treatment of invasive fungal infections is underfunded at all levels. The Collaborative Exchange of Antifungal Research (CLEAR) database was developed in the mid-1990s in response to some of these unresolved issues. The database has enhanced our understanding of the epidemiology of invasive fungal infections and clinical experience with amphotericin B lipid complex (ABLC) injection (Enzon Pharmaceuticals). ABLC is a composition of amphotericin B and 2 phospholipids (dimyristoylphosphatidylcholine and dimyristoylphosphatidylglycerol) in a 1:1 drug-to-lipid molar ratio [2]. ABLC was developed to reduce the nephrotoxicity associated with the conventional formulation of amphotericin B deoxycholate (AmB), thus allowing for administration of higher doses of ABLC than AmB for longer therapeutic courses [3]. Although conventional AmB has been considered as the reference standard of antifungal therapy for many invasive mycoses, the high incidence of renal toxicity and other side effects associated with its use have resulted in a recent reevaluation of its position as first-line therapy for many mycoses [4–7]. ABLC is rapidly absorbed by the reticuloendothelial system, resulting in a lower concentration of amphotericin B in the plasma and kidneys and a greater distribution of active drug at tissue sites. Therefore, ABLC may be beneficial in the treatment of fungal infections when renal dysfunction is a concern or as second-line therapy when AmBinduced nephrotoxicity occurs. The CLEAR database provides data on efficacy and renal safety for 3514 patients treated with ABLC from 1996 to 2000 at 1160 institutions in the United States and Canada. One of the strengths of the CLEAR database is that it reflects a broad spectrum of patients treated for invasive fungal infections in North America and avoids the risk of excluding particular groups of patients, which often occurs during recruitment of patients for phase 3 clinical trials. Similar to other observational and retrospective studies of antifungal therapy, the CLEAR database has its distinct limitations: it was retrospective, the data collection method was based on voluntary reporting and, thus, was subject to potential enrollment bias, objectively defined response criteria were lacking, and follow-up was limited to completion of therapy with ABLC or discharge from the hospital, whichever was sooner. However, this database has value because it provides a unique opportunity to examine various aspects of therapy with ABLC among a broad scope of patients with various invasive fungal infections. Table 1 depicts the demographic char-