Australasian Society for Infectious Diseases

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

TREATMENT OF SUSPECTED/PROBABLE AND PROVEN FUNGAL INFECTION

Lipid formulations

There are only two randomised comparisons of a lipid formulation to conventional amphotericin B. The first was between liposomal amphotericin B at 5 mg/kg/day and amphotericin B at 1 mg/kg/day [28]. This small study compared neutropenic patients with a variety of IFIs but mostly suspected pulmonary aspergillosis. A complete response was seen in more patients receiving liposomal amphotericin B but there was no difference in the percentage of patients who failed therapy. The overall mortality was lower, and patients with progressive malignancy did better, with liposomal amphotericin B. The second was a randomised comparison of amphotericin B colloidal dispersion and amphotericin B for primary treatment of invasive aspergillosis [10]. Although not powered to detect equivalence, similar outcomes were seen in the 94 patients. There was less nephrotoxicity but more infusional toxicity with amphotericin B colloidal dispersion.

Two doses of liposomal amphotericin B, 1 versus 4 mg/kg/day, were compared for the treatment of proven or probable invasive aspergillosis [29]. This study evaluated response in 87 neutropenic haematology or HSCT patients, the majority with probable rather than proven aspergillosis. The definition of probable aspergillosis was less stringent than that now used [19]. Overall there was no difference in clinical or radiological response rates or survival at 6 months between the 2 doses. However, subgroups of patients with both proven invasive aspergillosis and prolonged neutropenia had better responses at 4 mg/kg/day and the power of the study to detect clinically meaningful differences in efficacy was very low given the small sample size.

The experience of one centre with amphotericin B lipid complex or liposomal amphotericin B in adult haematology and oncology patients was reported [12]. Proven infection accounted for only 15 of 68 treatment courses. The occurrence of nephrotoxicity was similar but fever and chills were significantly higher with amphotericin B lipid complex. Overall response rates and survival were similar.

Data from several compassionate use programs have been reported. However, patients entering compassionate use programs are highly selected with inherent biases. They are rarely undergoing initial therapy. They have survived initial therapy and required treatment with another antifungal agent due to toxicity or clinical failure. Walsh et. al. reported on the safety and efficacy of amphotericin B lipid complex in 556 patients [30]. Just over half the patients entered due to failure of another antifungal, mostly amphotericin B. Although one third of patients entered due to nephrotoxicity, the mean serum creatinine fell on treatment. The overall response rate was 57% and this was identical for the 291 mycologically proven cases. Response rates for aspergillosis (42%), disseminated candidiasis (67%), zygomycosis (71%) and fusariosis (82%) were higher than would be expected from experience using amphotericin B. Perhaps these patients had a better than expected outcome because only 24% were neutropenic at baseline and almost half received amphotericin B lipid complex for intolerance of prior antifungals rather than clinical failure. Similar findings were reported in HSCT recipients with suspected or proven fungal infections who received compassionate use amphotericin B lipid complex or amphotericin B colloidal dispersion [31, 32]. Analysis of the compassionate access program of amphotericin B colloidal dispersion revealed similar response rates of 58% for candidiasis and 34% for aspergillosis in 97 evaluable patients [33].

In summary, studies of lipid formulations in treatment of IFI reveal a relative lack of comparative data. Perhaps in the subgroup of patients with prolonged neutropenia or undergoing allogeneic transplant, liposomal amphotericin B at 4 mg/kg/day is a more effective treatment dose than 1 mg/kg/day. Liposomal amphotericin B may lead to more complete resolution of IFI than amphotericin B in haematology patients. The higher doses of lipid associated amphotericin B may be better than that of standard amphotericin for difficult to treat infections such as fusariosis and zygomycosis as well as for the non-albicans Candida species such as C. krusei, C. glabrata or C. lusitaniae although no direct comparisons have been performed. There is a cost advantage for amphotericin B lipid complex and amphotericin B colloidal dispersion over liposomal amphotericin B. However, in patients undergoing solid organ or haematopoietic stem cell transplants and receiving potentially nephrotoxic drugs liposomal amphotericin B may be preferable as it has the lowest rates of nephrotoxicity and infusional reactions.