Drosophila melanogaster as a model to study virulence and azole treatment of the emerging pathogen Candida auris.

OBJECTIVES: Candida auris is an emerging, often MDR, yeast pathogen. Efficient animal models are needed to study its pathogenicity and treatment. Therefore, we developed a C. auris fruit fly infection model. METHODS: TollI-RXA/Tollr632 female flies were infected with 10 different C. auris strains from the CDC Antimicrobial Resistance bank panel. We used three clinical Candida albicans strains as controls. For drug protection assays, fly survival was assessed along with measurement of fungal burden (cfu/g tissue) and histopathology in C. auris-infected flies fed with fluconazole- or posaconazole-containing food. RESULTS: Despite slower in vitro growth, all 10 C. auris isolates caused significantly greater mortality than C. albicans in infected flies, with >80% of C. auris-infected flies dying by day 7 post-infection (versus 67% with C. albicans, P < 0.001-0.005). Comparison of C. auris isolates from different geographical clades revealed more rapid in vitro growth of South American isolates and greater virulence in infected flies, whereas the aggregative capacity of C. auris strains had minimal impact on their growth and pathogenicity. Survival protection and decreased fungal burden of fluconazole- or posaconazole-fed flies infected with two C. auris strains were in line with the isolates' disparate in vitro azole susceptibility. High reproducibility of survival curves for both non-treated and antifungal-treated infected flies was seen, with coefficients of variation of 0.00-0.31 for 7 day mortality. CONCLUSIONS: Toll-deficient flies could provide a fast, reliable and inexpensive model to study pathogenesis and drug activity in C. auris candidiasis.

Adjuvant ß-Lactam Therapy Combined with Vancomycin for Methicillin-Resistant Staphylococcus aureus Bacteremia: Does ß-Lactam Class Matter?

We analyzed the impact of vancomycin (VAN) combined with adjuvant ß-lactam therapy (Combo) on persistent (≥5 days) methicillin-resistant Staphylococcus aureus bacteremia versus VAN alone by using pooled data from two previously published observational studies (n = 156). Combo was inversely associated with persistent bacteremia (adjusted odds ratio, 0.460; 95% confidence interval, 0.229 to 0.923). Acute kidney injury was more common with Combo than with VAN (18.9% and 7.6%, respectively; P = 0.062).

Rezafungin (CD101), a next-generation echinocandin: A systematic literature review and assessment of possible place in therapy.

OBJECTIVES: Rezafungin (CD101) is a novel echinocandin currently under development. The purpose of this study was to perform a systematic literature review of published evidence on rezafungin and an antimicrobial stewardship audit of real-world use of echinocandins to determine areas of unmet medical needs and potential places in therapy for rezafungin. METHODS: The systematic literature review identified 8 peer-reviewed manuscripts and 19 separate abstracts. A stewardship audit was performed on hospitalised patients receiving echinocandins to better understand potential future areas of use for rezafungin. RESULTS: Rezafungin is a cyclic hexapeptide with a lipophilic tail derived from anidulafungin, with a choline moiety at the C5 ornithine position resulting in increased in vitro and in vivo stability compared with other echinocandins. Microbiological data showed similar susceptibility and resistance development between rezafungin and other echinocandins. Rezafungin has a long half-life (80h) and a favourable safety profile that allows for high doses (up to 400mg) given once weekly. A phase 2 study is ongoing. The antimicrobial stewardship audit of echinocandin identified several areas of possible use for rezafungin, including patients receiving daily echinocandins for >7 days, patients who remained in the hospital to complete a full course of daily echinocandin therapy, and patients who required an echinocandin scheduled via an infusion clinic after discharge. CONCLUSION: Rezafungin is a novel echinocandin currently in phase 2 studies, differentiated by a long half-life that allows once-weekly dosing and a safety profile that allows higher doses. Several potential areas of use for rezafungin were identified.

Treatment of Candida famata bloodstream infections: case series and review of the literature.

OBJECTIVES: Candida famata (also known as Debaryomyces hansenii and Torulopsis candida) is a commensal yeast found in cheese, dairy products and the environment. C. famata accounts for 0.2%-2% of invasive candidiasis. The purpose of this study was to provide an overview of the treatment of C. famata bloodstream infections. METHODS: The clinical course of two hospitalized patients who developed C. famata fungaemia within 2 weeks of each other was summarized along with available data regarding in vitro susceptibility patterns, genotyping and clinical outcomes of these cases compared with the published literature. RESULTS AND CONCLUSIONS: C. famata appears to exhibit reduced susceptibility to echinocandins and azoles, particularly in the setting of prior antifungal exposure. The removal of indwelling central venous catheters and prompt initiation of therapy with liposomal amphotericin B is recommended for successful treatment of C. famata fungaemia, particularly in immunocompromised patients. These cases also help provide justification for routine antifungal susceptibility testing in patients with candidaemia to guide optimal antifungal therapy.

Echinocandin resistance in Candida species: mechanisms of reduced susceptibility and therapeutic approaches.

OBJECTIVE: To summarize published data regarding mechanisms of reduced echinocandin susceptibility in Candida spp., the impact of echinocandin resistance on the fitness and virulence of Candida isolates, and current and future treatment approaches. DATA SOURCES: A search of MEDLINE databases (1966-September 2011) was conducted. STUDY SELECTION AND DATA EXTRACTION: Databases were searched using the terms echinocandin, resistance, and Candida. Citations from publications were reviewed for additional references. DATA SYNTHESIS: Echinocandins have in vitro activity against most Candida spp. and are first-line agents in the treatment of candidemia. However, case reports describing echinocandin treatment failure due to resistant isolates have been published. Reduced echinocandin susceptibility has been shown to occur via 3 main mechanisms: (1) adaptive stress responses, which result in elevated cell wall chitin content and paradoxical growth in vitro at supra minimum inhibitory concentrations (MICs); (2) acquired FKS mutations, which confer reduced glucan synthase sensitivity, elevated MICs, and are associated with clinical failure; and (3) intrinsic FKS mutations, which are naturally occurring mutations in C. parapsilosis and C. guilliermondii, which confer elevated MIC levels but a lower level of reduced glucan synthase sensitivity compared with acquired FKS mutations. Some FKS mutants have been shown to have significantly reduced fitness and virulence versus wild type isolates and may contribute to the low incidence of echinocandin resistance reported in large surveillance studies. Treatment strategies evaluated for FKS mutants include echinocandin dose escalation and combination with agents such as calcineurin inhibitors, HSP90 inhibitors, and chitin synthase inhibitors. CONCLUSIONS: While the incidence of echinocandin resistance in Candida spp. is low, it can present a significant therapeutic challenge, especially in multidrug-resistant Candida isolates. Dose escalation is unlikely to be effective in treating FKS mutant isolates, and significant adverse effects limit the clinical use of agents evaluated as combination therapy. Patients with infections failing to respond to echinocandin therapy should undergo susceptibility testing and be treated with an alternative antifungal agent if possible.