Impact of Antifungal Prophylaxis on Colonization and Azole Susceptibility of Candida Species

Abstract

Two large studies compared posaconazole and fluconazole or itraconazole for prophylaxis in subjects undergoing allogeneic hematopoietic stem cell transplantation or subjects with acute myelogenous leukemia. To assess the impact of prophylaxis on colonization and the development of resistance in Saccharomyces yeasts, identification and susceptibility testing were performed with yeasts cultured at regular intervals from mouth, throat, and stool samples. Prior to therapy, 34 to 50% of the subjects were colonized with yeasts. For all three drugs, the number of positive Candida albicans cultures decreased during drug therapy. In contrast, the proportion of subjects with positive C. glabrata cultures increased by two-and fourfold in the posaconazole and itraconazole arms, respectively. Likewise, in the fluconazole arm the proportion of subjects with positive C. krusei cultures increased twofold. C. glabrata was the species that most frequently exhibited decreases in susceptibility, and this trend did not differ significantly between the prophylactic regimens. For the subset of subjects from whom colonizing C. glabrata isolates were recovered at the baseline and the end of treatment, approximately 40% of the isolates exhibited more than fourfold increases in MICs during therapy. Molecular typing of the C. albicans and C. glabrata isolates confirmed that the majority of the baseline and end-of-treatment isolates were closely related, suggesting that they were persistent colonizers and not newly acquired. Overall breakthrough infections by Candida species were very rare (ϳ1%), and C. glabrata was the colonizing species that was the most frequently associated with breakthrough infections.Invasive fungal infections (IFIs) are a leading cause of morbidity and mortality in neutropenic patients with hematological malignancies and recipients of hematopoietic stem cell transplants (HSCT). Treatment of an established IFI is frequently very difficult, and the most effective agents have treatmentlimiting toxicities (19). Consequently, antifungal prophylaxis is increasingly being used for patients at high risk of acquiring a fungal infection; the benefits of antifungal prophylaxis include reduced mortality as well as reduced health care costs (5,6,10,12,17,18,20). However, there are concerns that the prophylactic agent may select for less susceptible isolates. Changes in susceptibility can be caused by mutations in existing colonizing isolates, through overgrowth (by a previously minor species), or by de novo colonization by inherently less susceptible species. This concern is particularly relevant for Candida, since colonization of the oral mucosa, gastrointestinal tract, and skin are risk factors associated with the acquisition of invasive Candida infections (11, 13).Two large randomized clinical trials compared orally administered posaconazole with either fluconazole or itraconazole for antifungal prophylaxis in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) or HSCT recipients receiving high-dose im...

Comparison of In Vitro Susceptibility Characteristics of Candida Species from Cases of Invasive Candidiasis in Solid Organ and Stem Cell Transplant Recipients: Transplant-Associated Infections Surveillance Network (TRANSNET), 2001 to 2006

“…These differences in species distribution may be due to dissimilar antifungal use and prophylaxis practices, with a higher proportion of HSCT patients than of SOT patients in our study receiving antifungal prophylaxis (63% versus 15%). Multiple studies have suggested that the use of azoles can drive the species distribution within a population toward species with intrinsic resistance (1,8,10,16,26,33,34). Still, other factors may be contributing to this change in species distribution (27,32), and a few studies have shown no increase in the incidence of azole-resistant Candida species following azole prophylaxis (14,29).…”

Fluconazole impacts the extracellular matrix of fluconazole-susceptible and -resistant Candida albicans and Candida glabrata biofilms

“…Candida albicans is the main species associated with candidiasis, while Candida glabrata is one of the most predominant non- albicans species that has been linked to the development of oral infections [1–6]. It is an opportunistic pathogen in immunocompromised individuals [7,8], and it has an innate resistance to azoles [9,10]. C. glabrata differs from other pathogenic yeasts because of its phylogenetic position and haploid state with unconfirmed sexual cycle and diploid phase, contrary to C. albicans [11].…”

Invasive fungal disease in patients treated for newly diagnosed acute leukemia

“…The use of itraconazole and fluconazole prophylaxis in patients with AL have both been assessed in a number of placebo-controlled studies, the results of which have been mixed [2,3,7]. While prophylactic itraconazole and fluconazole may decrease Candida colonization overall, their prophylactic use has been associated with reports of resistant Candida colonization and breakthrough infections as well as significant drug interactions and toxicities [8][9][10][11][12].…”