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Posaconazole (Noxafil), an Extended-Spectrum Oral Triazole Antifungal Agent

Year: 2008
Type: article
Abstract: The incidence of fungal infections has dramatically increased in the past few decades.1,2 These infections contribute significantly to morbidity and mortality in hospitalized patients.1,2 The high prevalence of infection is primarily attributable to an increase in the number of immuno-compromised patients, such as those with human immunodeficiency virus/ acquired immune deficiency syndrome (HIV/AIDS); to hematological malignancies; and to transplant recipients, who are susceptible to invasive fungal infections (IFIs). Severely ill critical-care patients are also at high risk.1,2 Even with the addition of newer antifungal agents to the current list of avalable medications, the rise in resistant mycoses has led to challenges in how to manage these infections. The most common clinical pathogens include resistant organisms from Candida and Aspergillus species.1,2,5 The current management of IFIs is challenging because of the relative unavailability of tools to test the resistance of fungal isolates in microbiological laboratories and because of the development of resistance among Candida species. Clinically available antifungal agents include amphotericin B, anidulafungin (Eraxis, Pfizer), caspofungin (Cancidas, Merck), micafungin (Mycamine, Astellas), fluconazole (Diflucan, Pfizer), itraconazole (Sporanox, Janssen), voriconazole (Vfend, Pfizer), and posaconazole (Noxafil, Schering-Plough). The triazoles include fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole (Basilea Pharmaceutica), and pramiconazole (Barrier Therapeutics). Although amphotericin B is considered the gold standard and is recommended as a first-line therapy for severe mycoses, its use is limited by its toxicities of the conventional formulation and by the high cost of the lipid emulsions.1,2 Echinocandins such as anidulafungin, caspofungin, and micafungin have comparable activity against many species of fungi. Echinocandins also have improved toxicity profiles, compared with amphotericin B; however, no oral formulations are available. Fluconazole, itraconazole, posaconazole, and voriconazole make up the currently available triazole antifungals. Both fluconazole and voriconazole offer favorable safety profiles and are available in oral and intravenous (IV) forms.1 Itraconazole has a broad spectrum of activity, but its use is limited by the poor oral absorption.1 The U.S. Food and Drug Administration (FDA) approved posaconazole in September 2006. It is the newest orally administered triazole antifungal with an extended spectrum of activity. Posaconazole is indicated for the prophylaxis of invasive Aspergillus and Candida infections in severely immunocompromised patients 13 years of age or older.3 Immunocompromised patients are identified as hematopoietic stem-cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematological malignancies with prolonged febrile neutropenia from chemotherapy.3 Posaconazole is also indicated for the treatment of oral candidiasis, including cases refractory to itraconazole and fluconazole.3 Among the extended-spectrum triazoles, posaconazole has proved to be a promising addition to the antifungal group of medications for the treatment and prophylaxis of IFIs. Although posaconazole is structurally related to itraconazole, it is a more potent inhibitor of ergosterol synthesis (Figure 1). Figure 1 Chemical structure of posaconazole (Noxafil). PHARMACOLOGY Similar to the other triazole antifungal medications, posaconazole alters the fungal cell membrane by inhibiting ergosterol synthesis via an interaction with 14αethylase.4 Ergosterol is an important component of the fungal cell membrane; inhibition of its biosynthesis leads to alterations in cellular permeability and a loss of membrane fluidity, symmetry, and integrity.2,4 This results in either fungal cell death or inhibition of cell growth.1 Compared with other triazoles, posaconazole is more potent as an inhibitor of 14α-demethylase.4,5 The site of action for the triazole anti-fungals is a gene that codes for 14α-demethylase.2 Mutations at this gene have been reported with fluconazole, and cross-resistance with posaconazole may be possible.2,4 Some studies have identified a reduced susceptibility of clinical isolates of Candida albicans and Candida glabrata to posaconazole and other triazole antifungal agents.4 For this reason, data on susceptibility at each institution should be reviewed before empirical anti-fungal therapy is begun.4
Language: English
Field: Medicine
Open Access status: green
OpenAlex ID: W133887730
FWCI:
Cites: 11
Cited by: 2
Related to: 10