New paradigms for the treatment of aspergillosis: azoles

Thomas E Patterson

Author address: 

The University of Texas Health Science Center at San Antonio, Texas USA

Abstract: 

Invasive aspergillosis remains a major cause of morbidity and mortality in immunosuppressed patients. Even with the use of amphotericin B, which has been the standard therapy for critically ill patients with this disease, outcomes of invasive aspergillosis in high-risk patients remain unacceptably high. New classes of antifungal agents including the azole antifungals have been developed with activity against this lethal pathogen. The need for new therapies against Aspergillus was demonstrated in a review of 595 cases of invasive aspergillosis. Antifungal failures were common: progression of disease despite therapy occurred in 36% while complete antifungal responses were noted in only 27%. Overall, mortality in invasive aspergillosis remains over 60% but in high-risk patients such as those undergoing allogeneic bone marrow transplantation mortality is even greater, approaching 90%. Similarly, in patients with disseminated or central nervous system infection, mortality rates are over 90%. Early imidazole and triazole antifungals including fluconazole lacked Aspergillus activity. Itraconazole does have activity against Aspergillus but it has not been extensively utilized in patients with proven infection due to the fact that it has only recently been introduced in an intravenousformulation-a feature essential to use in critically-ill patients-and due to its erratic absorption, particularly in high risk patients such as those undergoing bone marrow transplantation or those with severe mucositis. Nevertheless, its activity has been demonstrated in patients with less severe immunosuppression and for use in sequential therapy following initial courses of amphotericin B. Newer triazoles such as voriconazole, ravuconazole, and posaconazole have been introduced. These agents were developed specifically for activity against Aspergillus and demonstrate fungicidal activity against the organism. Both posaconazole and ravuconazole have activity in animal models of aspergillosis and posaconazole has been effective in clinical studies using an oral formulation of drug. Voriconazole, which has recently been approved for clinical use, is available in both intravenous as well as a well-absorbed oral formulation. Recent studies demonstrate the efficacy of voriconazole as primary therapy of invasive aspergillosis, including patients with disseminated infection and central nervous system disease. In a comparative study with amphotericin B followed by other licensed therapy, voriconazole produced complete or partial responses in 53% as compared to 32% receiving amphotericin B. Importantly, survival was significantly improved in patients receiving voriconazole, with 71% survival as compared to 58% survival of patients receiving amphotericin B followed by other therapies. The activity of these newer azoles has increased interest in combinations of antifungal therapies along with immune reconstitution to further improve responses. Recent studies have not shown the antagonism between these azoles and polyene antifungals that was demonstrated in animal models using early azoles such as ketoconazole. While clinical utility of combination therapy has not been proven to be of benefit, preclinical studies suggest improved activity of azoles with the echinocandins in producing sterile tissues and combinations with echinocandins, polyenes and azoles have been suggested to have a potential benefit. In summary, the new azoles offer activity specifically targeted for moulds like Aspergillus. Recent studies suggest that these agents may become the new standard for primary therapy of this disease and combinations of antifungal agents, including the azoles, may begin to improve the outcomes of this often lethal disease.
2002

abstract No: 

s6

Full conference title: 

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