Pharmacy & Therapeutics- July 2008 - (Page 391) DRUG FORECAST Posaconazole (Noxafil), an ExtendedSpectrum Oral Triazole Antifungal Agent Mei Chang, BA, PharmD, and Larisa Chagan, PharmD, BCPS INTRODUCTION 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 immunocompromised 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 un- Disclosure: The authors have no commercial or financial relationships to disclose with regard to this article. Dr. Chagan is employed at Ortho-McNeil Janssen Scientific Affairs, LLC. At the time of this writing, she was Assistant Professor of Pharmacy Practice at the Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, and a Clinical Pharmacist in Critical Care at Saint Vincent’s Medical Center–Manhattan in New York, New York. Dr. Chang is a Pharmacy Practice Resident at James J. Peters Veterans Affairs Medical Center in Bronx, New York. At the time of the manuscript compilation, she was an Internal Medicine Pharmacy Intern at Saint Vincent Medical Center–Manhattan. Drug Forecast is a regular column coordinated by Alan Caspi, PhD, PharmD, MBA, President of Caspi & Associates in New York, New York. availability 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. Posa conazole 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 extendedspectrum 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). PHARMACOLOGY Similar to the other triazole antifungal medications, posaconazole alters the fungal cell membrane by inhibiting ergosterol synthesis via an interaction with 14α-demethylase.4 Ergosterol is an important component of the fungal cell membrane; inhibition of its biosynthesis O F F CH3 O N N N N N O H3C OH NN N Figure 1 Chemical structure of posaconazole (Noxafil). Vol. 33 No. 7 • July 2008 • P&T® 391
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