Treatment of invasive fungal infections with amphotericin B colloidal dispersion in bone marrow transplant recipients

Abstract

Summary:Amphotericin B colloidal dispersion (ABCD, AMPHO-TEC, AMPHOCIL), a lipid complex of amphotericin B, was developed to reduce the nephrotoxicity of amphotericin B while retaining its antifungal efficacy. In this retrospective review, the efficacy and safety of ABCD were evaluated in 220 BMT recipients (167 allogeneic; 53 autologous) with suspected or documented lifethreatening fungal infections (primarily Candida or Aspergillus species). Patients were treated in five openlabel clinical trials of ABCD therapy. ABCD was administered intravenously once daily, median dose of 4 mg/kg, for up to 409 days (mean 23 days, median 16 days). Successful therapeutic response to treatment (complete or partial) was reported in 52% of the 99 evaluable patients with proven infection, and in 40% of all 220 patients. In the evaluable population, the response and mortality rates were 51% and 73%, respectively, in the allogeneic BMT patients, compared to 52% and 48% in the autologous BMT patients. The response rate for evaluable patients with Candida spp was 65%, 38% for patients with Aspergillus spp, and 42% for patients with other or multiple fungal infections. In this patient population at high risk of nephrotoxicity due to concomitant cyclosporine and/or other nephrotoxic agents, ABCD did not cause renal dysfunction. Although the majority of patients had pre-existing renal impairment (median baseline serum creatinine 1.8 mg/dl), there was no trend towards increasing serum creatinine. No unexpected toxicities were observed. In conclusion, ABCD appears to be safe and effective for the treatment of severe fungal infections in BMT patients. Keywords: ABCD; amphotericin B cholesteryl sulfate for injection; amphotericin B colloidal dispersion; marrow transplant; fungal infection; nephrotoxicity Opportunistic fungal infections are an increasing cause of morbidity and mortality in bone marrow transplant (BMT) patients. evolved, the problem of invasive fungal infection has assumed increased significance. In reports from marrow transplant centers 1-3 the incidence of systemic fungal infections ranges from 4 to 30% with a mortality rate approaching 100%. 4 The administration of prophylactic fluconazole may decrease the incidence of documented systemic fungal infection following high-dose chemotherapy and BMT. 5,6 However, despite fluconazole prophylaxis, over half of patients still require empiric therapy with amphotericin B for prolonged unexplained febrile episodes. 5 Additionally, fluconazole is not effective against Aspergillus spp infections and certain species of Candida, such as C. krusei and most strains of C. glabrata.Amphotericin B, a polyene antibiotic that has been used to treat fungal infections for four decades, is still considered the most reliable agent for therapy of mycoses in immunosuppressed patients. However, its well known adverse effects, particularly dose-limiting nephrotoxicity, often complicate and limit its effective use. 7 Although the reported incidence is quite variable, two recent reviews estimate that 6...

Amphotericin B colloidal dispersion (Amphocil) vs fluconazole for the prevention of fungal infections in neutropenic patients: data of a prematurely stopped clinical trial

“…28,29 In earlier reports, the use of ABCD is invariably labelled as 'safe'. [15][16][17][18][19] Although this may hold true with regard to its renal sparing effects, our data indicate, in line with recent observations, 24 that infusion-related toxicity of ABCD must not be underestimated and poses a major drawback to its use. We conclude that ABCD, administered for prophylactic reasons to patients without life-threatening fungal infections, was associated with major and intolerable side-effects during infusion of the compound.…”

“…In various open-label clinical trials, the use of ABCD showed promising results with regard to its antifungal efficacy and its safety. [15][16][17][18][19] Its assumed reduced toxicity offers the opportunity of investigating the feasibility of AmB as antifungal prophylaxis. In a recent randomised trial we reported a 100% mortality in patients with proven fungal infections due to Aspergillus or Mucor spp., the overall incidence of such infections in our population being 5%.…”

EUCAST Technical note on Amphotericin B

“…Wild-type isolates of each of the five common species (C. albicans, C. glabrata, C. krusei, C. parapsilosis and C. tropicalis) exhibit MICs £ 1 mg/L. The EUCAST breakpoints (Table 1) are based on pharmacokinetic [1][2][3][4][5][6][7] and microbiological data and clinical experience [8][9][10][11][12][13][14][15]. For most studies clinical outcome data were not specified for the individual Candida species.…”

Lipid-based Antifungal Agents Current Status

“…ABCD was found to be efficacious also in treatment of invasive mycoses, primarily due to Candida and Aspergillus spp. in marrow transplant patients [60,61]. Complete or partial response was achieved in 52% of the treated subjects [60].…”