New paradigms for the treatment of aspergillosis: polyenes

Claudio Viscoli

Author address: 

University of Genova, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy

Abstract: 

The principal advantage of amphotericin B (AmB) over other antifungal compounds is the very broad spectrum of fungicidal activity. AmB is effective against a large range of organisms, including the majority of human pathogens and opportunistic pathogens - most Candida spp., Aspergillus ~fumigatus, Blastomyces dermatitidis, Coccidioides immitis, Cryptococcus neoformans, Histoplasma capsulatum, and F’aracoccidioides brasiliensis. However, it is poorly active against Fusarium, certain Aspergillus and Trichosporon spp. Although the incidence of treatment emergent resistance is low, resistant strains of Cundida lusitaniae and C. tropicalis have occasionally been isolated.According to the Infectious Diseases Society of America (IDSA) guidelines for the management of invasive fungal infections, amphotericin B deoxycholate (AmBd) remains the drug of choice for the treatment of aspergillosis, with an overall response rate ranging from 14% to 83% (mean 37%). It is commonly believed that AmBd should be given at peak recommended doses, 1 to 1.5 mglkgid. Unfortunately, at this dosage this polyene drug is associated with significant toxicity, including infusionrelated events, such as chills, fever, headache, nausea and vomiting, and dose-limiting nephrotoxicity. Although this is not an absolute indication to change treatment if kidney function is artificially supported, amphotericin Binduced renal impairment may necessitate premature or temporary withdrawal of treatment, or a reduction in the dose. Such measures may subsequently result in a worsening of the infection. AmBd-related side effects may also lead to increased costs due to prolonged hospitalization, use of dialysis and the need to administer premeditation. Ensuring adequate hydration (IV administration of 500 ml saline) prior to the initiation of treatment may reduce the severity of renal impairment. The optimal duration of therapy is unknown and depends on the severity of disease, the response to therapy, and the patient’s underlying disease(s) or immune status. Antifungal therapy should be continued through cancer chemotherapy, or restarted in patients who are expected to receive additional chemotherapy. The recently developed lipid formulations of AmB have provided new therapeutic opportunities for the treatment of aspergillosis, especially in patients with renal failure or those who have failed therapy with amphotericin B. It is worthy to note that most lipid-based formulations are between 10 and 50 times more expensive than conventional formulations, although this evaluation does not include the total direct and indirect costs associated with the consequences and management of side effects. Unfortunately, no randomized, prospective, clinical trial comparing AmBd and a specific lipid formulation has ever been performed and therefore we must base our evaluations on open-label studies, with or without historical conventional amphotericin B controls. Most animal model studies have suggested that larger doses of the lipid preparations are required to produce therapeutic effects equivalent to AmBd. The adverse events reported in patients administered lipid-based formulations of amphotericin B are similar to those associated with conventional formulations, however the prevalence is significantly reduced. Immediate toxic reactions are less common, although fever, chills and flank pain may still be seen within the first few days of treatment. These effects are generally transient and respond well to treatment with hydrocortisone. Nephrotoxicity has not disappeared but it is much less common in patients treated with lipid-based amphotericin B and furthermore, individuals who develop renal impairment during treatment with a conventional formulation may be improved or stabilized when a lipid-based formulation is substituted. This is an important consideration for the treatment of mycoses in critically ill patients who may be renally insufficient through trauma or underlying illness.
2002

abstract No: 

s5

Full conference title: 

12th International Symposium on Infections in the Immunocompromised Host
    • ISIIH 12th