Australasian Society for Infectious Diseases

Guidelines for use of antifungal agents in treatment of invasive fungal infection (July 2003)

ANTIFUNGAL AGENTS

Background

For 30 years, amphotericin B (amphotericin B deoxycholate) has been the gold standard for treatment of invasive fungal infections (IFIs). Most fungi are susceptible to amphotericin B, although fungi with reduced susceptibility or resistance include Trichosporon beigelii, Fusarium spp and the dematiaceous fungi such as Alternaria spp. Pseudallescheria boydii and Scedosporium spp [1]. In many clinical settings such as invasive aspergillosis in neutropenic or immunosuppressed patients the response to amphotericin B is poor. This may relate to late diagnosis, host defects or dose limiting toxicity.

The narrow therapeutic window and attendant toxicities of amphotericin B are well recognised. Infusional toxicity occurs in 60% of patients and renal impairment in 80% of patients receiving a 2 week course of amphotericin B [2]. Although strategies to manage these toxicities have been developed (eg. saline loading, potassium sparing diuretics and premedication with antihistamines, steroids and pethidine), amphotericin B is often poorly tolerated particularly in patients requiring prolonged courses at doses above 0.5 mg/kg/day. Multivariate analysis of amphotericin B use and renal failure in over 200 transplant patients, showed that the degree of nephrotoxicity tolerated was secular with HSCT recipients most at risk of requiring hemodialysis [3], In another study of adults with amphotericin B associated renal failure, the mortality rate was higher and the mean length of stay was longer than in those without acute renal failure [4].

The number of available antifungals is increasing. Amphotericin B deoxycholate, three lipid formulations of amphotericin B, three triazoles as well as caspofungin are available in Australia. Different methods of administration such as 24 hour infusions of amphotericin B deoxycholate are under investigation. The following recommendations are based on currently available information and an attempt has been made to provide concordance with the treatment guidelines of the Infectious Diseases Society of America (IDSA) [5, 6]. The strength of recommendation and quality of evidence are rated according to the methods used in the IDSA guidelines [7], (Table 1).

Lipid formulations of amphotericin B

The three lipid formulations are; liposomal amphotericin B, (AmBisome®), amphotericin B lipid complex (Abelcet®) and amphotericin B colloidal dispersion (Amphocil®). They are more expensive than conventional amphotericin B but generally have the advantage of less infusional and renal toxicity and provide the opportunity to administer higher doses of amphotericin B. Liposomal amphotericin B is less nephrotoxic than amphotericin B lipid complex [8] . Whilst amphotericin B colloidal dispersion has less nephrotoxicity than conventional amphotericin B it has more infusional toxicity [9, 10]. Animal studies [11] suggest similar efficacy between liposomal amphotericin B and amphotericin B lipid complex, as do retrospective comparisons of patient outcomes [12].