Abstract
ABSTRACTCandida species are a part of the human microbiome and can cause systemic infection upon immune suppression. Candida glabrata infections are increasing and have greater rates of antifungal resistance than other species. Here, we present a C. glabrata gastrointestinal (GI) colonization model to explore whether colonized yeast exposed to caspofungin, an echinocandin antifungal, develop characteristic resistance mutations and, upon immunosuppression, breakthrough causing systemic infection. Daily therapeutic dosing (5 mg/kg of body weight) of caspofungin resulted in no reduction in fecal burdens, organ breakthrough rates similar to control groups, and resistance rates (0 to 10%) similar to those reported clinically. Treatment with 20 mg/kg caspofungin initially reduced burdens, but a rebound following 5 to 9 days of treatment was accompanied by high levels of resistance (FKS1/FKS2 mutants). Although breakthrough rates decreased in this group, the same FKS mutants were recovered from organs. In an attempt to negate drug tolerance that is critical for resistance development, we cotreated mice with daily caspofungin and the chitin synthase inhibitor nikkomycin Z. The largest reduction (3 log) in GI burdens was obtained within 3 to 5 days of 20 mg/kg caspofungin plus nikkomycin treatment. Yet, echinocandin resistance, characterized by a novel Fks1-L630R substitution, was identified following 5 to 7 days of treatment. Therapeutic caspofungin plus nikkomycin treatment left GI burdens unchanged but significantly reduced organ breakthrough rates (20%; P < 0.05). Single-dose pharmacokinetics demonstrated low levels of drug penetration into the GI lumen posttreatment with caspofungin. Overall, we show that C. glabrata echinocandin resistance can arise within the GI tract and that resistant mutants can readily disseminate upon immunosuppression.
Highlights
While many pathogenic fungi, such as Aspergillus and Cryptococcus spp., are acquired from the environment, Candida is a natural human commensal living in the gastrointestinal (GI) tract
Echinocandins target the synthesis of beta-1,3-glucan, a polymer required for cell wall synthesis, and resistance arises through mutations that occur within “hot spot” regions of the catalytic subunits (FKS1/FKS2) of glucan synthase [9]
To assess the effect of echinocandin treatment on GI burden, immunocompetent mice were effectively colonized (107 to 108 CFU/g of stool) with a laboratory-derived mutator strain (Δmsh2) on day 0 and treated intraperitoneally (i.p.) with daily doses of 0.5, 5, or 20 mg/kg of body weight caspofungin beginning on day 3
Summary
While many pathogenic fungi, such as Aspergillus and Cryptococcus spp., are acquired from the environment, Candida is a natural human commensal living in the gastrointestinal (GI) tract. Patients considered at high risk for the development of an invasive fungal infection are commonly placed on antifungal therapy with either triazoles (which target ergosterol biosynthesis) or echinocandins (which target cell wall biosynthesis). C. albicans is the most frequently isolated Candida species, but C. glabrata has emerged as the most common cause of invasive infections in specific subsets of patients, such as hemato-. The high rate of MSH2 mutations may be related to the unusually high percentages (20 to 30%) of acquired triazole resistance and emerging MDR associated with C. glabrata infections. We have developed a murine model of C. glabrata gastrointestinal colonization and systemic breakthrough in order to better understand how antifungal therapy influences (i) yeast burden levels in the GI tract, (ii) the emergence of drug resistance within the GI tract, and (iii) breakthrough causing systemic dissemination following immunosuppression. This study is a proof of principle that antifungal drug exposure in the GI tract can lead to resistance among colonizing organisms
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