Changing strategies for the management of invasive fungal infections

Abstract

The frequency of invasive fungal infections (IFIs) has increased with the increase in number of high-risk patients. United States trends in mortality due to invasive mycoses showed a striking increase in the past 2 decades. Human immunodeficiency virus-associated opportunistic mycoses accounted for part of the increase, as did mycoses in other immunocompromised populations. Those at-risk populations include recipients of solid organ transplants or hematopoietic stem cell transplants, those with hematologic malignancies, and others receiving immunosuppressive treatment. Infections due to Candida sp are the most common fungal infections. The mortality rate due to invasive aspergillosis has risen steadily, with a 357% increase from 1980-1997. Depending on whether an IFI is possible, probable, or proved, three treatment strategies are available: prophylactic, empiric, and specific. Options for preventing and treating IFIs have increased, with four classes of antifungal agents available: polyenes, azoles, nucleoside analogs, and echinocandins. The effectiveness of the polyene amphotericin B deoxycholate (the standard for > 40 yrs) is limited by toxic effects, notably renal and infusion-related toxicity. Three lipid formulations are approved for the treatment of IFIs in patients refractory to or intolerant of amphotericin B: amphotericin lipid complex, amphotericin B colloidal dispersion, and liposomal amphotericin B. The nucleoside analog class contains only flucytosine--an antimetabolite targeting the nucleus of the fungal cell and generally not given as monotherapy because of frequent development of resistance. The azoles debuted with ketoconazole, followed by fluconazole, itraconazole, and voriconazole. Fluconazole is largely active against Candida sp and Cryptococcus neoformans; itraconazole's activity is largely against moulds, such as Aspergillus, and dimorphic fungi, such as Histoplasma and Blastomyces; and voriconazole is active against both yeasts and moulds. The echinocandin class has one drug approved for clinical use--caspofungin, which targets the fungal cell wall. Deciding which antifungal agent to use involves weighing such clinical factors as mycoses susceptibility and drug toxicity, as well as pharmacoeconomic considerations. Besides the price of the drug, the cost of antifungal therapy includes costs of mortality associated with failed treatment, prolonged hospitalization and treatment related to complications, and additional antifungal treatment to compensate for primary treatment failure.