New and Emerging Antifungal Agents
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LEADING ARTICLE
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New and Emerging Antifungal Agents Impact on Respiratory Infections Marta Feldmesser Departments of Medicine and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA
Abstract
Fungal pathogens are increasingly important causes of respiratory disease, yet the number of antifungal agents available for clinical use is limited. Use of amphotericin B deoxycholate is hampered by severe toxicity. Triazole agents currently available have significant drug interactions; fluconazole has a limited spectrum of activity and itraconazole was, until recently, available only in oral formulations with limited bioavailability. The development of resistance to all three agents is increasingly being recognized and some filamentous fungi are resistant to the action of all of these agents. In the past few years, new antifungal agents and new formulations of existing agents have become available. The use of liposomal amphotericin B preparations is associated with reduced, but still substantial, rates of nephrotoxicity and infusion-related reactions. An intravenous formulation of itraconazole has been introduced, and several new triazole agents have been developed, with the view of identifying agents that have enhanced potency, broader spectra of action and improved pharmacodynamic properties. One of these, voriconazole, has completed large-scale clinical trials. In addition, caspofungin, the first of a new class of agents, the echinocandins, which inhibit cell wall glucan synthesis, was approved for use in the US in 2001 as salvage therapy for invasive aspergillosis. It is hoped that the availability of these agents will have a significant impact on the morbidity and mortality of fungal respiratory infections. However, at the present time, our ability to assess their impact is limited by the problematic nature of conducting trials for antifungal therapy.
Fungal respiratory infections have posed a formidable challenge for clinicians, as disease due to many fungal pathogens is difficult both to diagnose and to treat with currently available antifungal agents. The organisms responsible for respiratory fungal infections may be divided into three groups: the endemic dimorphic fungi; the filamentous fungi; and yeast. Most of the dimorphic fungi, including Histoplasma capsulatum, Blastomyces dermatitidis, and Coccidioides immitis, are found in limited geographic distribution. Primary pulmonary infection is frequently asymptomatic in the immunocompetent host and may resolve without specific therapy. However, primary infection may result in severe clinical illness, which may disseminate, or be followed by either chronic or reactivation disease.[1,2] Therapy is particularly difficult in immunocompromised hosts. In contrast, disease due to filamentous fungi occurs almost exclusively in immunocompromised patients, and invasive disease of the lung or sinus associated with these organisms is notoriously refractory to therapy. The incidence of inf
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