Abstract
Within the limited antifungal armamentarium, the azole antifungals are the most frequent class used to treat Candida infections. Azole antifungals such as fluconazole are often preferred treatment for many Candida infections as they are inexpensive, exhibit limited toxicity, and are available for oral administration. There is, however, extensive documentation of intrinsic and developed resistance to azole antifungals among several Candida species. As the frequency of azole resistant Candida isolates in the clinical setting increases, it is essential to elucidate the mechanisms of such resistance in order to both preserve and improve upon the azole class of antifungals for the treatment of Candida infections. This review examines azole resistance in infections caused by C. albicans as well as the emerging non-albicans Candida species C. parapsilosis, C. tropicalis, C. krusei, and C. glabrata and in particular, describes the current understanding of molecular basis of azole resistance in these fungal species.
Highlights
Candida albicans and emerging non-albicans Candida (NAC) species such as C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei can cause superficial infections of the oral and vaginal mucosa as well as disseminated bloodstream and deep-tissue infections
When sequencing orthologues of UPC2, MRR1, and TAC1 in order to identify putative gain-of-function mutations that would lead to overexpression of ERG11, MDR1, and CDR1, only one heterozygous mutation in UPC2 was recovered from one isolate, suggesting that ERG11 overexpression in fluconazole-resistant C. parapsilosis is not mediated by UPC2
While azole antifungals have long provided effective treatment for such infections, recent epidemiological studies indicate that intrinsic azole resistance in some Candida species as well as development of high-level azole resistance is a problem of critical importance in the clinical setting
Summary
Candida albicans and emerging non-albicans Candida (NAC) species such as C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei can cause superficial infections of the oral and vaginal mucosa as well as disseminated bloodstream and deep-tissue infections. C. tropicalis infections are commonly associated with malignancy, with some studies reporting higher prevalence among patients with hematologic diseases such as acute myeloid leukemia (Weinberger et al, 2005; Nucci and Colombo, 2007; Tang et al, 2014, 2015; Cornely et al, 2015). Mortality associated with C. tropicalis candidemia in these populations remains high, ranging from 30 to 70%, with the highest rates most commonly observed among the elderly (Weinberger et al, 2005; Nucci and Colombo, 2007; Morii et al, 2014; Cornely et al, 2015; Wang et al, 2015). Patients with hematologic malignancies and bone marrow transplants have been shown to be at increased risk of C. krusei infection (Merz et al, 1986; Wingard et al, 1991; Pfaller et al, 2008)
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