ABSTRACT
Medical advances over the last 30 years have led to a signi–- cant increase in the incidence of serious life-threatening invasive fungal infections (IFIs) due to an ever-increasing array of pathogens.1 This paradox seems to be linked to numerous factors such as the immunosuppressive therapies for cancer patients, the rise in the number of individuals undergoing organ transplantation and major surgery, and the AIDS epidemic.2 Furthermore, patients admitted to the intensive care unit are particularly susceptible to IFI because of the severity of their underlying illness and the excess use of medical and surgical interventions.3 Candida species are the fourth most common pathogen isolated from blood cultures, accounting for 8%–10% of all bloodstream infections acquired in the hospital, with crude mortality rates of 40%.4 Although Candida albicans is the most frequent etiologic agent of invasive candidiasis, Candida glabrata has undoubtedly emerged as an important opportunistic fungal pathogen in the United States, followed by Candida tropicalis, Candida parapsilosis, Candida krusei, and other minor Candida species, such as Candida guilliermondii, Candida lusitaniae, Candida kefyr, Candida famata, and Candida rugosa.4,5
While C. glabrata and, to a lesser extent, C. albicans remain a focus for the concern regarding antifungal resistance, some of rare Candida species, in addition to be responsible for clusters of infection in the hospital setting, exhibit decreased susceptibility to one or more antifungal agents, thus posing a threat of emergence in certain settings.4 Furthermore, Aspergillus infections account for more than 90% of nosocomial mold infections,6 with Aspergillus fumigatus causing the majority of cases of invasive aspergillosis; although less susceptible to antifungal agents, non-fumigatus aspergilli are increasingly reported in granulocytopenic and other immunocompromised patients.7-12 Invasive aspergillosis is also associated with a high mortality rate that ranges from 30% to 90%.13,14 Cryptococcus neoformans, a fungal pathogen with a worldwide distribution, causes disease predominantly in immunocompromised individuals such as human immunode–ciency virus (HIV)-infected patients and those receiving immunosuppressive agents for malignancy, organ transplantation, and other serious medical conditions.15,16 Beyond Candida, Aspergillus, and Cryptococccus species, opportunistic fungi causing deep fungal infections, however, include less common fungi such as Zygomycetes, Fusarium species, Geotrichum capitatum, Scedosporium species, and dematiaceous fungi, many of which are intrinsically resistant to the available antifungal agents.17-20
100.1 Introduction ................................................................................................................................................................... 903 100.1.1 Emergence of Fungal Pathogens and Antifungal Resistance .......................................................................... 903 100.1.2 Antifungal Drugs and Their Targets ............................................................................................................... 904 100.1.3 Mechanisms of Resistance to Antifungal Agents ........................................................................................... 906
100.1.3.1 Resistance to Polyenes .................................................................................................................... 906 100.1.3.2 Resistance to Flucytosine ............................................................................................................... 906 100.1.3.3 Resistance to Azole Compounds .................................................................................................... 907 100.1.3.4 Resistance to Echinocandins ...........................................................................................................910
