Effectiveness of an antifungal stewardship programme at a London teaching hospital 2010–16

Whitney, Laura; Al-Ghusein, Hasan; Koh, Mickey; Klammer, Matthias; Ball, Jonathan; Youngs, Jonathan; Wake, Rachel; Houston, Angela; Bicanic, Tihana

doi:10.1093/jac/dky389

Cited by 33 publications

(42 citation statements)

References 23 publications

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“…Post-prescription audits, often associated with pre-prescription restrictions, have demonstrated a significant reduction in antifungal consumption [ 8 , 25 , 26 , 27 , 28 ]. In a Spanish study of 100 patients admitted to different hospital wards, a non-mandatory bedside intervention significantly reduced consumption and cost of antifungal treatments [ 29 ]. Whitney et al published the results on a 6-year AFS program on more than 400 patients with a comprehensive approach that included stewardship rounds.…”

Section: Discussionmentioning

confidence: 99%

“…Whitney et al published the results on a 6-year AFS program on more than 400 patients with a comprehensive approach that included stewardship rounds. The authors found a significant decrease in overall antifungal consumption and financial costs [ 29 ]. A few other studies have shown significant decrease in costs [ 26 , 30 ] and adverse events [ 31 ], without a different impact on survival.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, it is reasonable that our intervention will be effective, even in patients receiving fluconazole as empiric antifungal therapy. Actually, in previous studies on AFS programs including fluconazole-treated patients, the majority of those who received empiric antifungal therapy had no diagnostic criteria for invasive fungal infection, and stopping antifungal therapy was one of the most commonly applied interventions [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

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Post-Prescription Audit Plus Beta-D-Glucan Assessment Decrease Echinocandin Use in People with Suspected Invasive Candidiasis

et al. 2021

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Background and Objectives: Overtreatment with antifungal drugs is often observed. Antifungal stewardship (AFS) focuses on optimizing the treatment for invasive fungal diseases. The objective of the present study was to evaluate the utility of a post-prescription audit plus beta-D-glucan (BDG) assessment on reducing echinocandin use in persons with suspected invasive candidiasis. Materials and Methods: This is a prospective, pre-post quasi-experimental study of people starting echinocandins for suspected invasive candidiasis. The intervention of the study included review of each echinocandin prescription and discontinuation of treatment if a very low probability of fungal disease or a negative BDG value were found. Pre-intervention data were compared with the intervention phase. The primary outcome of the study was the duration of echinocandin therapy. Secondary outcomes were length of hospital stay and mortality. Results: Ninety-two echinocandin prescriptions were reviewed, 49 (53.3%) in the pre-intervention phase and 43 (46.7%) in the intervention phase. Discontinuation of antifungal therapy was possible in 21 of the 43 patients in the intervention phase (48.8%). The duration of echinocandin therapy was 7.4 (SD 4.7) in the pre-intervention phase, 4.1 days (SD 2.9) in persons undergoing the intervention, and 8.6 (SD 7.3) in persons in whom the intervention was not feasible (p at ANOVA = 0.016). Length of stay and mortality did not differ between pre-intervention and intervention phases. Conclusions: An intervention based on pre-prescription restriction and post-prescription audit when combined with BDG measurement is effective in optimizing antifungal therapy by significantly reducing excessive treatment duration.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Post-Prescription Audit Plus Beta-D-Glucan Assessment Decrease Echinocandin Use in People with Suspected Invasive Candidiasis

et al. 2021

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“…In addition to high burdens on human life, fungal infections put a significant strain on health care costs. The United States alone spent $4.5 billion on 75,055 hospitalizations necessitated by fungal disease over ten years (Benedict et al, 2018) while English NHS trusts spend annually approximately £90 million on antifungal drugs (Whitney et al, 2018). This already dire situation is further exacerbated by the ever-growing number of patients at risk of contracting invasive fungal infections.…”

Section: Introductionmentioning

confidence: 99%

Identification and Phenotypic Characterization of Hsp90 Phosphorylation Sites That Modulate Virulence Traits in the Major Human Fungal Pathogen Candida albicans

Alaalm

Crunden

Butcher

et al. 2021

Front. Cell. Infect. Microbiol.

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The highly conserved, ubiquitous molecular chaperone Hsp90 is a key regulator of cellular proteostasis and environmental stress responses. In human pathogenic fungi, which kill more than 1.6 million patients each year worldwide, Hsp90 governs cellular morphogenesis, drug resistance, and virulence. Yet, our understanding of the regulatory mechanisms governing fungal Hsp90 function remains sparse. Post-translational modifications are powerful components of nature’s toolbox to regulate protein abundance and function. Phosphorylation in particular is critical in many cellular signaling pathways and errant phosphorylation can have dire consequences for the cell. In the case of Hsp90, phosphorylation affects its stability and governs its interactions with co-chaperones and clients. Thereby modulating the cell’s ability to cope with environmental stress. Candida albicans, one of the leading human fungal pathogens, causes ~750,000 life-threatening invasive infections worldwide with unacceptably high mortality rates. Yet, it remains unknown if and how Hsp90 phosphorylation affects C. albicans virulence traits. Here, we show that phosphorylation of Hsp90 is critical for expression of virulence traits. We combined proteomics, molecular evolution analyses and structural modeling with molecular biology to characterize the role of Hsp90 phosphorylation in this non-model pathogen. We demonstrated that phosphorylation negatively affects key virulence traits, such as the thermal stress response, morphogenesis, and drug susceptibility. Our results provide the first record of a specific Hsp90 phosphorylation site acting as modulator of fungal virulence. Post-translational modifications of Hsp90 could prove valuable in future exploitations as antifungal drug targets.

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“…In addition to high burdens on human life, fungal infections put a significant strain on health care costs. The United States alone spent $4.5 billion on 75,055 hospitalizations necessitated by fungal disease over ten years 3 while English NHS trusts spend annually approximately £90 million on antifungal drugs 4 . This already dire situation is further exacerbated by the ever-growing number of patients at risk of contracting invasive fungal infections.…”

mentioning

confidence: 99%

A novel Hsp90 phospho-switch modulates virulence in the major human fungal pathogenCandida albicans

Alaalm

Crunden

Butcher

et al. 2020

Preprint

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The ubiquitous molecular chaperone Hsp90 is a key regulator of cellular proteostasis and environmental stress responses. Hsp90 also regulates cellular morphogenesis, drug resistance, and virulence in human pathogenic fungi, which kill more than 1.6 million patients each year worldwide. Invasive fungal infections are difficult to treat due to the lack of effective antifungal therapies, resulting in mortality rates of up to 95%. As a key regulator of fungal virulence, Hsp90 is an attractive therapeutic target. However, fungal and animal homologs are highly conserved, impeding fungal-specific targeting. Thus, understanding the factors that regulate Hsp90 could provide an alternative strategy aimed at exclusively targeting this regulator of fungal virulence. Here, we demonstrate how CK2-mediated phosphorylation of two Hsp90 residues modulates virulence in a major fungal pathogen of humans, Candida albicans. We combined proteomics, molecular evolution and structural modelling with molecular biology to identify and characterize two Hsp90 phosphorylation sites. Phosphorylation negatively affects thermal stress response, morphogenesis, drug susceptibility and fungal virulence. Our results provide the first record of specific Hsp90 phosphorylation sites acting as modulators of fungal virulence. Post-translational modifications of Hsp90 could prove valuable in future exploitation as antifungal drug targets.

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Effectiveness of an antifungal stewardship programme at a London teaching hospital 2010–16

Cited by 33 publications

References 23 publications

Post-Prescription Audit Plus Beta-D-Glucan Assessment Decrease Echinocandin Use in People with Suspected Invasive Candidiasis

Post-Prescription Audit Plus Beta-D-Glucan Assessment Decrease Echinocandin Use in People with Suspected Invasive Candidiasis

Identification and Phenotypic Characterization of Hsp90 Phosphorylation Sites That Modulate Virulence Traits in the Major Human Fungal Pathogen Candida albicans

A novel Hsp90 phospho-switch modulates virulence in the major human fungal pathogenCandida albicans

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